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Globally, based on traditional knowledge, different parts of Cissampelos pareira plant are being used individually or in combination in various forms to manage malaria. However, the scientific investigation for validating the most effective part of this plant against malaria parasite has not been done. Thus, the study aims to explore the antiplasmodial potential of different parts of the plant against malaria parasite by bio-assay guided isolation of compounds from different extracts and fractions. Antiplasmodial activities of the whole plant parent extract and its fractions along with decoctions (roots, stem, leaves and whole plant) and isolated molecules were evaluated against chloroquine-sensitive Pf 3D7 and chloroquine-resistant Pf INDO strains of Plasmodium falciparum. A UPLC-DAD based method was developed to quantify the marker compounds in all samples by utilizing isolated molecules as analytical standards. The chloroform fraction of the whole plant was found to be the most potent with IC 50 (µg/mL) of 0.79 (Pf 3D7) and 2.26 (Pf INDO) followed by root decoction with IC 50 (µg/mL) 10.22 (Pf 3D7) and 7.7 (Pf INDO). Further, phytochemical analysis of active chloroform fraction led to the isolation of two potent bisbenzylisoquinoline compounds, namely O,O -dimethylcurine (1) [IC 50 (µM) 1.46 (Pf 3D7) and 0.51 (Pf INDO)], and curine (2) [IC 50 (µM) 1.46 (Pf 3D7) and 0.51 (Pf INDO)]. Analysis of developed UPLC-DAD method showed the highest quantities of curine (2) (∼107 mg/g) and O,O -dimethylcurine (1) (∼15 mg/g) in chloroform fraction which might be responsible for its potent activity. This study showed that the root decoction was more effective than decoctions of each of the other parts of the plant and the whole plant hydroalcoholic extract. [Display omitted] • Antiplasmodial activity evaluation of different parts of Cissampelos pareira. • Isolation of secondary metabolites from active extracts/fractions and decoctions. • New UPLC-DAD-based analytical method for quantification of marker compounds. • Quantification of marker compounds in all prepared samples. • Identification of active extract/ fractions/ compounds. [ABSTRACT FROM AUTHOR]

Humantenmine, koumine, and gelsemine are three indole alkaloids found in the highly toxic plant Gelsemium. Humantenmine was the most toxic, followed by gelsemine and koumine. The aim of this study was to investigate and analyze the effects of these three substances on tissue distribution and toxicity in mice pretreated with the Cytochrome P450 3A4 (CYP3A4) inducer ketoconazole and the inhibitor rifampicin. The in vivo test results showed that the three alkaloids were absorbed rapidly and had the ability to penetrate the blood-brain barrier. At 5 min after intraperitoneal injection, the three alkaloids were widely distributed in various tissues and organs, the spleen and pancreas were the most distributed, and the content of all tissues decreased significantly at 20 min. Induction or inhibition of CYP3A4 in vivo can regulate the distribution and elimination effects of the three alkaloids in various tissues and organs. Additionally, induction of CYP3A4 can reduce the toxicity of humantenmine, and vice versa. Changes in CYP3A4 levels may account for the difference in toxicity of humantenmine. These findings provide a reliable and detailed dataset for drug interactions, tissue distribution, and toxicity studies of Gelsemium alkaloids. • Cytochrome P450 3A4 crucially impacts the tissue distribution and elimination of the three Gelsemium alkaloids. • The three Gelsemium alkaloids were mainly distributed in the spleen and pancreas after administration. • The difference in cytochrome P450 3A4 content may account for the difference in humantenmine toxicity. [ABSTRACT FROM AUTHOR]

• Phaleria macrocarpa is widely used as a remedy to reduce blood glucose levels. • GC–MS is a distinctive method dominating the metabolomics research area. • Chemometric analysis can be applied to resolve large data sets. Phaleria macrocarpa is a medicinal plant widely available in Malaysia. The plant parts have been traditionally used as an antidiabetic remedy. This study aimed to identify the putative inhibitors of the α-glucosidase enzyme from P. macrocarpa using a gas chromatography-mass spectrometry (GC–MS)-based metabolomics approach and further subjected them to in silico molecular docking analysis to elucidate the possible mechanism of action. This study assessed the inhibitory potential of P. macrocarpa fruit extracts (aqueous, 20 %, 40 %, 60 %, 80 %, and 100 % ethanol) against the α-glucosidase enzyme using GC–MS and chemometric analysis. Orthogonal partial least squares (OPLS) combined with GC–MS analysis were applied to correlate the inhibition of enzyme activity to the metabolites profile of P. macrocarpa. All the potential inhibitors identified were further docked to the yeast (Saccharomyces cerevisiae) protein crystal structure (PDB3A4A). The generated score scatter plot of OPLS showed a recognizable separation of all the extracts into six different clusters. GC–MS, incorporated with multivariate data analysis techniques, was used to identify significant chemical markers. Methyl α- d -glucopyranoside, squalene, palmitic acid, myo-inositol and isoquinoline metabolites were identified as putative inhibitors against α-glucosidase activity from P. macrocarpa. In conclusion, the GC–MS-based metabolomics approach identified potential chemical markers of P. macrocarpa that could be utilized in the development of herbal based medicine. [ABSTRACT FROM AUTHOR]

The diverse chemical scaffolds of the Cissampelos pareira make it pharmacologically distinct because of its pleiotropic therapeutical applications. Phytochemically, C. pareira is primarily known for its isoquinoline alkaloids, but flavonoids and their glycosides have also been reported from the aerial part. Among the several traditional uses of C. pareira, the juice of leaves that are enriched with flavonoids has been used to cure malarial fever. In silico molecular docking of phytomolecules from C. pareira revealed that flavonoids exhibited good binding affinity with the selected antimalarial targets. Among the screened molecules, quercetin, quercetin-3- O -sophoroside, and kaempferol-3- O - β -D-glucuronopyranoside showed the most prominent binding with the selected Plasmodium proteins. However, quercetin-3- O -sophoroside (Q3S) showed a broad-spectrum binding affinity with falcipain-2 (-9.53 Kcal/mol), plasmepsin-2 (-12.08 Kcal/mol), Pf 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Pf DXR) (-14.35 Kcal/mol), Pf lactose dehydrogenase (Pf LDH) (-9.57 Kcal/mol), and Pf dihydrofolate reductase (Pf DHFR) (-11.62 Kcal/mol). The pharmacokinetics evaluation showed that identified hits follow several ADME-Tox properties. MD Simulation suggests that Q3S forms a highly stable complex with Pf LDH. The RMSF value range of docked complexes of Q3S with Plasmepsin-2, Pf DHFR, Pf DXR, and Falcipain-2 is 0.1 to 0.5, 0.8, 0.7, and 0.6 nm, respectively. These findings suggest that C. pareira and its flavonoids hold potential as broad-spectrum antimalarial agents, which could pave the way for further investigation and development of novel therapeutics to combat this deadly disease. [Display omitted] • In silico screening of flavonoids from aerial parts of Cissampelos pareira against antimalarial targets. • Quercetin-3- O -sophoroside showed a broad-spectrum binding affinity with falcipain-2, plasmepsin-2, Pf DXR , Pf LDH , and Pf DHFR. • Pharmacokinetics evaluation and molecular dynamics study of the potential leads i.e., quercetin-3- O -sophoroside. [ABSTRACT FROM AUTHOR]

New drug delivery systems have rarely been used in the formulation of traditional Chinese medicine, especially those that are crude active Chinese medicinal ingredients. In the present study, hyaluronic acid decorated lipid-polymer hybrid nanoparticles were used to prepare a targeted drug delivery system (TDDS) for total alkaloid extract from Picrasma quassioides (TAPQ) to improve its targeting property and anti-inflammatory activity. Picrasma quassioides , a common-used traditional Chinese medicine (TCM), containing a series of hydrophobic total alkaloids including β -carboline and canthin-6-one alkaloids show great anti-inflammatory activity. However, its high toxicity (IC 50 = 8.088±0.903 μg/ml), poor water solubility (need to dissolve with 0.8% Tween-80) and poor targeting property severely limits its clinical application. Herein, hyaluronic acid (HA) decorated lipid-polymer hybrid nanoparticles loaded with TAPQ (TAPQ-NPs) were designed to overcome above mentioned deficiencies. TAPQ-NPs have good water solubility, strong anti-inflammatory activity and great joint targeting property. The in vitro anti-inflammatory activity assay showed that the efficacy of TAPQ-NPs was significantly higher than TAPQ(P <0.001). Animal experiments showed that the nanoparticles had good joint targeting property and had strong inhibitory activity against collagen-induced arthritis (CIA). These results indicate that the application of this novel targeted drug delivery system in the formulation of traditional Chinese medicine is feasible. The total alkaloids extract of Picrasma quassioides was encapsulated in the interior of poly γ-glutamic acid benzyl ester (BzPGA) by nanoprecipitation, the outer layer was coated with amphiphilic phospholipids (PC) and 1,2-dipalmitoyl-sn‑glycero-3-phosphoethanolamine (DPPE), and hyaluronic acid was added by chemical grafting. The nanoparticles can reach the inflamed joint site through the targeting of hyaluronic acid to CD44 receptors in the blood circulation, thereby enhancing the anti-rheumatoid effect of the total alkaloid extract of Picrasma quassioides and reducing its side effects. [Display omitted] [ABSTRACT FROM AUTHOR]

Aminoglycoside, a medicinal category of antibiotics, are used in treatment of Gram-negative bacterial infections. Although they are the most widely-used antibiotics due to their high efficacy and low cost, several main adverse effects have been reported including nephrotoxicity and ototoxicity. Since drug-induced ototoxicity is one of the major etiological causes of acquired hearing loss, we examined cochlear hair cell damages caused by three aminoglycosides (amikacin, kanamycin, and gentamicin), and investigated protective property of an isoquinoline-type alkaloid, Berberine chloride (BC). Berberine, a well-known bioactive compound found from medicinal plants, has been known to have anti-inflammatory, antimicrobial effects. To determine protective effect of BC in aminoglycoside-induced ototoxicity, hair cell damages in aminoglycoside- and/or BC-treated hair cells using ex vivo organotypic culture system of mouse cochlea. Mitochondrial ROS levels and depolarization of mitochondrial membrane potential were analyzed, and TUNEL assay and immunostaining of cleaved caspase-3 were performed to detect apoptosis signals. As the results, it was found that BC significantly prevented aminoglycoside-induced hair cell loss and stereocilia degeneration by inhibiting excessive accumulation of mitochondrial ROS and subsequent loss of mitochondrial membrane potential. It eventually inhibited DNA fragmentation and caspase-3 activation, which were significant for all three aminoglycosides. This study is the first report suggested the preventative effect of BC against aminoglycoside-induced ototoxicity. Our data also suggests a possibility that BC has the potential to exert a protective effect against ototoxicity caused by various ototoxic drugs leading to cellular oxidative stress, not limited to aminoglycoside antibiotics. [Display omitted] • Aminoglycoside results in ototoxicity due to the overproduction of reactive oxygen species. • Berberine chloride prevents aminoglycoside-provoked increase in ROS production in cochlear explants. • Berberine chloride reduced apoptotic cell death of hair cells in cisplatin-treated cochlear explants. [ABSTRACT FROM AUTHOR]

Malaria is a life-threatening infectious disease, which affected more than 247 million people worldwide in 2021, causing close to 619,000 deaths. WHO recommends region-specific combination therapies based on the susceptibility of the parasite as the standard treatment for P. falciparum malaria. In recent years, the primary cause of concern is the upsurge of resistance against almost all clinically used antimalarial drugs. Herbal medicines have been reported to be therapeutically effective and have played an important role in the treatment of malaria since time immemorial. The discovery of quinine from the cinchona tree's bark and artemisinin from Artemisia annua L. are the leading examples of bioactive compounds used in modern medicine identified from plant-based traditional medicines. Several plants from the Annonaceae family are used traditionally as antimalarials in different parts of the world endemic to malaria. This article reviews and analyses in vitro and in vivo antimalarial studies of plants from the Annonaceae family published from 1991 to 2021 to reveal the SAR of potential phytochemical antimalarial hits. A web-based systematic literature search for papers reporting antimalarial plants from the Annonaceae family was performed to classify plants and their bioactive compounds based on their potency and elucidation of structure-activity relationship (SAR) studies. The analysis is discussed based on the plant part used, country of origin, ethnomedical use, antimalarial methods, the strain used for screening, and activity. The phytoconstituents were classified based on the activity and the chemical scaffolds. The SAR for bioactive scaffolds from the family was elucidated and leads were identified for follow-up studies as potential antimalarials. The phytochemical analysis of active antimalarial plants indicates that isoquinoline, protoberberine, and aporphine scaffolds are most prominently associated with antiplasmodial activity. The SAR is discussed to suggest follow-up studies. There is scope to develop semi-synthetic derivatives to reveal the detailed SAR of hits for optimization of activity and drug-like properties. [Display omitted] • Several plants from the annonaceae family are traditionally used as antimalarials in geographies endemic to malaria. This article reviews and analyses in vitro and in vivo antimalarial studies of plants from the annonaceae family to reveal the SAR of potential phytochemical antimalarial hits. • A web-based systematic literature search for papers reporting antimalarial plants from the annonaceae family was performed to classify plants and their bioactive compounds based on their potency and elucidation of structure-activity relationship (SAR) studies. • Thirty-four plants used traditionally, eighty-six plants showing in vitro antimalarial activity, thirteen plants evaluated for in vivo activity, and ninety-seven compounds evaluated for antimalarial activity are discussed. • Alkaloids with isoquinolines, protoberberine, and aporphine scaffolds are most prominently associated with antiplasmodial activity. • The SAR analysis indicates that isoquinoline-based alkaloidal scaffolds ia (compound 1) and IIIa (compound 26) are potential leads for follow-up studies. [ABSTRACT FROM AUTHOR]

• Sambucus wightiana Wall. ex Wight & Arn. is a perennial shrub, rich in alkaloids. • Alkaloids have well established antidiabetic activities. • S. wightiana showed antidiabetic potential in Streptozotocin-Nicotinamide induced diabetic rats. Diabetes mellitus is the most prevalent metabolic disease, and almost 1200 plants are reported with hypoglycaemic potential. Some of these plants are scientifically proven for the hypoglycaemic and antidiabetic effects. This study was designed to assess the hypoglycaemic effect of Sambucus wightiana Wall. ex Wight & Arn. extract in streptozotocin-nicotinamide induced diabetic Wistar Albino rats. An acute toxicity study was performed to establish the safe dose of total alkaloids extracted from S. wightiana (TASW). TASW was administered orally (50 mg, 100 mg, and 200 mg/kg body weight per day) to diabetic rats for 21 days. Fasting blood glucose level was determined, along with other associated parameters that may fluctuate in diabetes, consisting of the lipid profile, body weight, serum liver marker enzymes and Hb level. The test groups that were administered TASW at three different doses showed a marked reduction in hyperglycaemia when compared to the control group. Moreover, body weight and food intake improved among test group animals. Administration of TASW also reduced the levels of triglycerides, cholesterol and LDL while increasing HDL and Hb levels. Serum liver enzyme activity is generally increased in diabetes, and this was reduced after dosing with TASW. The findings of this study elucidate that the total alkaloids extracted from S. wightiana are not toxic at the tested doses, and present potential hypoglycaemic activity. [ABSTRACT FROM AUTHOR]

The present review seeks to associate the bioactive profile, forms of extraction, and possible applications of the compounds present in non-endemic species of Crinum L. (Amaryllidaceae) found in Brazil. This genus is well-known for its isoquinoline alkaloids with variable biological activities and chemical structures. In this work, a bibliometric analysis was carried out with a literature review in the SCOPUS database to highlight and correlate research on the selected Crinum species: C. ornatum (Aiton) Herb., C. americanum L., C. x powellii hort. ex Baker, C. jagus (J.Thomps) Dandy., C. erubescens L.f. ex Aiton. To date, only 43 studies have been published on these species. These works reveal that these plants are rich mainly in alkaloids and other bioactive compounds, such as phenolic compounds, alcohols, fatty acids, etc. The alkaloids present in these plants are mainly responsible for their biological properties with cytotoxic, antibacterial, antifungal, and anti-diabetic potential, and as an acetylcholinesterase inhibitor. In addition, different solvents, extraction, and separation methods have been reported to obtain these biomolecules. The bioactives found in these plants can supply the search for compounds for applications in the medical and pharmaceutical industries, being, therefore, potential sources to be used in the promotion of human health. Thus, this review contributes to the valorization of these species and instigates new research in multidisciplinary areas. [Display omitted] • This review examined the research progress, trends, and updates about 5 Crinum species. • Last 52 years, 43 articles were published on the properties of these species. • Literature focused mainly on the pharmacological activity of alkaloids. • Data on other compounds need to be further developed. • These species have an excellent technological potential to be used. [ABSTRACT FROM AUTHOR]

Aptamers have aroused tremendous applications in sensors, drug deliveries, diagnosis, and therapies. In particular, target-induced global structure switching of aptamers has been widely used to develop selective sensors. However, fluorophore and/or quencher modification, sequence elongation, and nano-interface adsorption are required to design such global structure-switching aptamer sensors (SSAS) in order to signal target binding events. Accordingly, these requirements make SSAS at a high cost and expense of sensors' sensitivity. In this aspect, efforts should be made to overcome these drawbacks of SSAS. Herein, we tried to develop label-free folding-unswitching aptamer sensors (FUAS) by searching fluorogenic target competitors. Using adenine nucleoside/nucleotide as the proof-of-concept model targets, we screened out berberine (BER) from natural isoquinoline alkaloids (having rings comparable to targets) as the best fluorogenic target competitor. Binding of BER at the conserved nucleotides of intact aptamer foldings turned on this fluorogenic target competitor' fluorescence. Targets then competed with this fluorogenic target competitor over the same conserved nucleotides to cause its release in favor of a resultant fluorescence change. We found that the developed FUAS are much more sensitive than the previously reported SSAS. The FUAS were successfully applied to assays of ATP and adenosine deaminase in serums, and to screening of the adenosine deaminase's inhibitor, verifying the reliability and applicability of this FUAS platform in variant fields. We demonstrate that by designing fluorogenic target competitors, FUAS can be alternatively developed in a label-free manner and with a higher sensitivity than the previously developed SSAS. This work opens a new way to develop high-performance aptamer-based sensors. Furthermore, our developed FUAS should inspire more interest for wide applications incluidng target-triggered drug deliveries when therapeutic fluorogenic target competitors are used. Label-free folding-unswitching aptamer sensors (FUAS) are developed using fluorogenic target competitors with a much higher sensitivity than structure-switching aptamer sensors (SSAS). [Display omitted] • Fluorogenic target competitors can be used to develop folding-unswitching aptamer sensors (FUAS). • Developed label-free FUAS are much more senstitive than the previously developed structure-switching aptamer sensors (SSAS). • Developed FUAS can be applied to serum analysis of ATP and adenosine deaminase, and to evaluation of inhibitors. [ABSTRACT FROM AUTHOR]

Aptamers are good affinity receptors for bio-assays, while colorimetric method is suitable for point-of-care sensing via direct visualization. But previously aptamers often need complex re-engineering for colorimetric measurement at the cost of affinity and performance. Here isoquinoline alkaloids are found to own unique light-activated oxidative capacity, which can be specifically triggered by unmodified aptamers. This feature is universal for two alkaloids to efficiently oxidize four chromogenic substrates with obvious color changes. Based on a dye-displacement process, we have developed a novel light-activated aptamer system for the colorimetric assay of estradiol. It shows a good sensitivity with a detection limit of 326 nM, and this homogeneous assay is reliable to avoid artifacts in previous heterogeneous scheme. Besides, it is proven to be a universal design to assay other two targets. Significantly, they do not employ any aptamers re-engineering but only simply use their parental aptamers. Therefore, this light-activated oxidative capacity of isoquinoline alkaloid can serve as an ideal tool for colorimetric assay of various targets based on aptamer's specific recognition. [Display omitted] • Isoquinoline alkaloids were found to own light-activated oxidative capacity. • A light-activated aptamer system was developed for universal colorimetric assay. • It did not employ any aptamers re-engineering. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide, and endoplasmic reticulum stress (ERS) and mitochondrial Ca2+ overload have been involved in apoptotic cardiomyocyte death during MI. 13-Methylpalmatine (13-Me-PLT) is a natural isoquinoline alkaloid isolated from Coptis chinensis and has not been systematically studied for their potential pharmacological effects in cardiovascular diseases. We conducted the present study to elucidate whether 13-Me-PLT modulates MI pathology in animal MI and cellular hypoxic models, employing state-of-the-art molecular techniques. The results demonstrated that 13-Me-PLT preserved post-ischemic cardiac function and alleviated cardiomyocyte apoptosis. 13-Me-PLT decreased ERS and the communication between ER and mitochondria, which serves as a protective mechanism against mitochondrial Ca2+ overload and structural and functional injuries to mitochondria. Our data revealed mitigating mitochondrial Ca2+ overload and apoptosis by inhibiting CHOP-mediated Ca2+ transfer between inositol 1,4,5-trisphosphate receptor (IP 3 R) in ER and VDAC1 in mitochondria as an underlying mechanism for 13-Me-PLT action. Furthermore, 13-Me-PLT produced superior effects in alleviating cardiac dysfunction and apoptosis post-MI to diltiazem and palmatine. Collectively, our research suggests that the CHOP/IP 3 R/VDAC1 signaling pathway mediates ER-mitochondrial Ca2+ transfer and 13-Me-PLT activates this axis to maintain cellular and organellar Ca2+ homeostasis, protecting against ischemic myocardial injury. These findings may offer an opportunity to develop new agents for the therapy of ischemic heart disease. [Display omitted] • 13-Me-PLT ameliorates ER stress and apoptosis in cardiomyocytes of mice with MI. • 13-Me-PLT inhibits the crosstalk between the ER and mitochondria in cardiomyocytes of mice with MI. • The CHOP/IP3R/VDAC1 signalling pathway mediates the axis of ER-mitochondrial Ca2+ transfer. [ABSTRACT FROM AUTHOR]

[Display omitted] Berberine hydrochloride (BBR), used in various traditional medicinal practices, has a variety of pharmacological effects. It is a plant-derived quaternary isoquinoline alkaloid with a low water solubility and can be used in the treatment of various conditions. However, the therapeutic use of BBR has been compromised because of its hydrophobic characteristics, in addition to its low stability and poor bioavailability. To overcome these drawbacks of BBR's oral bioavailability, technologies like liposomal delivery systems have been developed to ensure enhanced absorption. But conventional liposomes have low physical and chemical stability due to delicate liposomal membranes, peroxidation and rapid clearance from the bloodstream. Surface modification of liposomes could be a solution and creating a liposome with plant-based fibers as surface material will provide enhanced stability, aqueous solubility and protection against degradation. Consequently, the aim of this study is to create and describe a Fiber Interlaced Liposome™ (FIL) as a vehicle for an enhanced bioavailability platform for BBR and other biomolecules. This optimised FIL-BBR formulation was analysed for its structural and surface morphological characteristics by using FTIR, SEM, TEM, XRD, zeta potential and DSC. Encapsulation efficiency, stability, and sustained release studies using an in vitro digestion model with simulated gastric and intestinal fluids were also examined. FIL formulation showed a sustained release of BBR at 59.03 % as compared to the unformulated control (46.73 %) after 8 h of dialysis. Furthermore, the FIL-BBR demonstrated enhanced stability in the simulated gastric fluid (SGF) in addition to a more sustained release in the simulated intestinal fluid (SIF). The efficacy of FIL-BBR were further anlaysed by an in vivo bioavailability study using male Wistar rats and it demonstrated a 3.37−fold higher relative oral bioavailability compared to the unformulated BBR. The AUC 0-t for BBR in FIL-BBR was 1.38 ng.h/mL, significantly greater than the unformulated BBR (0.41 ng.h/mL). Similarly, the C max for BBR in FIL-BBR (50.98 ng/mL) was discovered to be far greater than unformulated BBR (15.54 ng/mL) after the oral administration. These findings imply that fruit fiber based liposomal encapsulation improves the stability and slows down BBR release, which could be advantageous for applications requiring a higher bioavailability and a more sustained release. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by neuronal loss due to hyperphosphorylated proteins induced by oxidative stress. AD remains a formidable challenge in the medical field, as current treatments focusing on single biomarkers have yielded limited success. Hence, there's a burgeoning interest in investigating novel compounds that can target mechanisms, offering alternative therapeutic approaches. The aim of this study is to investigate the effects of allocryptopine, an isoquinoline alkaloid, on mechanisms related to AD in order to develop alternative treatment strategies. In this study, the in vitro AD cell model was obtained by inducing nerve growth factor (NGF)-differentiated PC12 (dPC12) cells to oxidative stress with H 2 O 2 , and also the effect mechanism of different allocryptopine concentrations on the in vitro AD cell model was studied. The treatments' antioxidative effects at the ROS level and their regulation of the cell cycle were assessed through flow cytometry, while their anti-apoptotic effects were evaluated using both flow cytometry and qRT-PCR. Additionally, the phosphorylation levels of Akt, GSK-3β, and tau proteins were analyzed via western blot, and the interactions between Akt, GSK-3β, CDK5 proteins, and allocryptopine were demonstrated through molecular docking. Our study's conclusive results revealed that allocryptopine effectively suppressed intracellular ROS levels, while simultaneously enhancing the Akt/GSK-3β signaling pathway by increasing p -Akt and p -GSK-3β proteins. This mechanism played a critical role in inhibiting neural cell apoptosis and preventing tau hyperphosphorylation. Moreover, allocryptopine demonstrated its ability to regulate the G1/S cell cycle progression, leading to cell cycle arrest in the G1 phase, and facilitating cellular repair mechanisms, potentially contributing to the suppression of neural apoptosis. The in silico results of allocryptopine were shown to docking with the cyclin-dependent kinase 5 (CDK 5) playing a role in tau phosphorylation Akt and GSK-3β from target proteins. Therefore, the in silico study results supported the in vitro results. The results showed that allocryptopine can protect dPC12 cells from oxidative stress-induced apoptosis and hyperphosphorylation of the tau protein by regulating the Akt/GSK-3β signaling pathway. Based on these findings, it can be suggested that allocryptopine, with its ability to target biomarkers and its significant effects on AD-associated mechanisms, holds promise as a potential candidate for drug development in the treatment of AD. Further research and clinical trials are recommended in the future. [Display omitted] • Allocryptopine suppressed ROS levels, increased p -Akt and p -GSK-3β, enhancing the Akt/GSK-3β signaling pathway. • Allocryptopine regulated G1/S cell cycle, causing G1 arrest, aiding repair, potentially suppressing neural apoptosis. • In silico , allocryptopine docked with CDK 5, impacting tau phosphorylation, targeting Akt and GSK-3β proteins. • Allocryptopine protected dPC12 cells from oxidative stress-induced apoptosis, regulated Akt/GSK-3β, preventing tau hyperphosphorylation. • Findings suggest allocryptopine, targeting biomarkers and AD mechanisms, is a promising candidate for AD drug development. [ABSTRACT FROM AUTHOR]

[Display omitted] Berberine is a quaternary ammonium isoquinoline alkaloid derived from traditional Chinese medicines Coptis chinensis and Phellodendron chinense. It has many pharmacological activities such as hypoglycemic, hypolipidemic, anti-tumor, antimicrobial and anti-inflammatory. Through structural modifications at various sites of berberine, the introduction of different groups can change berberine's physical and chemical properties, thereby improving the biological activity and clinical efficacy, and expanding the scope of application. This paper reviews the research progress and structure–activity relationships of berberine in recent years, aiming to provide valuable insights for the exploration of novel berberine derivatives. [ABSTRACT FROM AUTHOR]

Aberrant accumulation of dysfunctional mitochondria in renal cells during hyperglycemia signifies perturbed autophagy and mitochondrial turnover. This study aims to focus on the underlying mechanism involved in autophagy and mitophagy inducing efficacy of Berberine (isoquinoline alkaloid) in hyperglycemic NRK-52E cells. Berberine mediated protection to hyperglycemic cells prevented alteration in mitochondrial structure and function. Treatment with SRT-1720 (Sirt1 activator) enhanced autophagy, decreased apoptosis, upregulated expression of downstream moieties (FoxO3a and Bnip3) and ameliorated mitochondria related anomalies while nicotinamide (Sirt1 inhibitor) treatment exhibited reversal of the same. GFP reporter assay ascertained enhanced transcriptional activity of FoxO in Berberine-treated hyperglycemic cells, which was found to be correlated to increased expression of downstream protein Bnip3. Knocking down FoxO3a disrupted autophagy and stimulated apoptosis. N -acetyl-L-cysteine pre-treatment confirmed that generation of ROS intervened high glucose induced toxicity in NRK-52E cells. Berberine co-treatment resulted in differential expressions of key proteins involved in autophagy and mitophagy like LC3B, ATGs, Beclin1, Sirt1, Bnip3, FoxO3a and Parkin. Further, enhanced mitophagy in Berberine-treated cells was confirmed by transmission electron microscopy. Thus, our findings give evidence that the protection accorded by Berberine against hyperglycemia in renal proximal tubular cells (NRK-52E) involves instigation of Sirt1-FoxO3a-Bnip3 axis and autophagy mediated mitophagy induction. [Display omitted] • Berberine enhances autophagy via Sirt-1-FoxO3a-Bnip3 axis. • ROS mediates hyperglycemia induced renal toxicity by disrupting autophagy. • Berberine attenuates hyperglycemia induced mitochondrial dysfunction in NRK-52E cells. • Mitophagy is induced by berberine for the removal of dysfunctional mitochondria. [ABSTRACT FROM AUTHOR]

Phosphorescent metal complexes find widespread application in organic light-emitting diodes (OLEDs), with iridium(III) complexes being particularly favored for their superior performance. Owing to the flexible modifications of both main and auxiliary ligands, the photophysical properties of iridium(III) complexes can be finely tuned. In this study, two red neutral iridium(III) complexes, designated as Ir1 and Ir2 , are successfully synthesized and characterized. Various auxiliary ligands including acetylacetone and 2-picolinic acid are employed in combination with 1-(6-methoxynaphthalene-2-yl)isoquinoline as the cyclometalating ligand. Both complexes exhibit red emission, with Ir1 emitting at 631 nm and Ir2 at 615 nm. Furthermore, they demonstrated good solubility in common organic solvents, facilitating device fabrication via solution methods. Electroluminescent (EL) devices based on complexes Ir1 and Ir2 are further prepared using spin-coating method, achieving maximum external quantum efficiencies (EQEs) of 3.30 % and 4.52 %, respectively, and both devices exhibited bright red EL with CIE coordinates of (0.68, 0.32) and (0.66, 0.34), which were very close to the standard red coordinates of (0.67, 0.33). [Display omitted] • Two neutral red iridium(III) complexes were designed using naphthalenyl isoquinoline as the main ligand. • Solution-processed OLEDs were prepared to investigate the electroluminescence of these complexes. • The Ir2-based device demonstrated the best electroluminescent performance with an external quantum efficiency of 4.52 %. [ABSTRACT FROM AUTHOR]

The effect of heat treatment on the abundant bioactive compounds in moringa seed kernels (MSKs) during different degrees of roasting remains sparingly explored despite the flour of roasted MSKs has been incorporated into the human diet (e.g., cakes, cookies, and burgers) as a substitute to enrich the nutritional content. Therefore, we investigated the impacts of different roasting conditions (e.g., temperature and duration) on bioactive compounds (e.g., glucosinolates (GSLs), phenolic acids and alkaloids) and antioxidant capacity of MSKs. Our results showed that light and medium roasting increased the glucomoringin (GMG, the main GSL in MSKs) content from 43.7 (unroasted MSKs) to 69.7–127.3 μmol/g MSKs (dry weight), while excessive/dark roasting caused thermally-induced degradation of GMG (trace/undetectable level) in MSKs, resulting in the formation of various breakdown products (e.g., thiourea, nitrile, and amide). In addition, although roasting caused a significant reduction of some phenolic compounds (e.g., gallic, chlorogenic, p -coumaric acids, and trigonelline), other phenolic acids (e.g., caffeic and ferulic acids) and alkaloids (e.g., caffeine, theobromine, and theophylline) remarkably increased after roasting, which may contribute to the enhanced total phenolic content (up to 2.9-fold) and antioxidant capacity (up to 5.8-fold) of the roasted MSKs. • Light roasting increased glucomoringin content of moringa seed kernels. • Medium and dark roasting led to degradation of glucomoringin in moringa seed kernels. • Thermal degradation mechanism of glucomoringin was proposed. • Roasting increased the total phenolic content and antioxidant capacity of moringa seed kernels. [ABSTRACT FROM AUTHOR]

Eleven alkaloids including four previously undescribed oxoisoaporphine alkaloids, menisoxoisoaporphines A-D (1 – 4), four known analogues (5 – 8), and three aporphine alkaloids (9 – 11), were isolated and identified from the rhizomes of Menispermum dauricum. Their structures were elucidated by extensive spectroscopic data and single-crystal X-ray diffraction analyses. Among them, compounds 1 and 4 were the first samples of oxoisoaporphine with C-6 isopentylamino moiety, and 2 was a rare C-4 methylation product of oxoisoaporphine alkaloid. The in vitro anti-inflammatory activity of compounds 1 – 11 was performed by evaluating the inhibition of NO level in LPS-induced RAW264.7 macrophages. Among them, compound 4 exhibited the most potent NO inhibition activity with an IC 50 value of 1.95 ± 0.33 μ M. The key structure-activity relationships of those oxoisoaporphine alkaloids for anti-inflammatory effects have been summarized. Four undescribed oxoisoaporphine alkaloids, together with seven known analogues were isolated from the rhizomes of Menispermum dauricum DC., which were evaluated for their their inhibitory activity towards the LPS-induced NO production in RAW 264.7 cells. Menisoxoisoaporphine D exhibited the most potent NO inhibition activity with an IC 50 value of 1.95 ± 0.33 μM. [Display omitted] • Four undescribed alkaloids were isolated from the rhizomes of Menispermum dauricum. • Menisoxoisoaporphine A was the first sample of oxoisoaporphine with C-6 isopentylamino moiety. • Menisoxoisoaporphine B was a rare C-4 methylation product of oxoisoaporphine alkaloid. • Menisoxoisoaporphine D showed the most potent NO inhibition activity (IC 50 1.95 ± 0.33 μM). [ABSTRACT FROM AUTHOR]

Aphis craccivora and Planococcus lilacinus are significant plant virus carriers and severe pests of legumes, fruits, and commercial crops. Inappropriate use of inorganic pesticides for the management of pests leads to resistance, detrimental to natural enemies of pests and the environment. In this study, methanolic root extract, different fractions, and isolated compounds from Thalictrum foliolosum DC were investigated for their pesticidal and enzyme inhibition potential against target pests. The findings revealed that thalidasine and berberine were most effective against A. craccivora (LD 50 = 0.43–0.47 μl/insect), followed by n -butanol fraction (LD 50 = 1.37 μl/insect). Similarly, the aqueous fraction was more promising against P. lilacinus (LD 50 = 0.24 μl/insect) as compared to jatrorrhizine and thalidasine (LD 50 = 0.60–0.64 μl/insect). Further UHPLC-PDA-based analysis revealed that chloroform fraction showed higher thalidasine (37.86 ± 0.923 mg/g) and berberine (37.76 ± 0.398 mg/g) content, whereas berberine (36.06 ± 0.045 mg/g) also quantified in dominating amount in n -butanol fraction, together with jatrorrhizine (23.74 ± 0.177 mg/g). In reproduction inhibition assay, the chloroform and methanol extract showed a higher inhibition rate at 10 000 mg/L (98.69–99.46%). Additionally, methanolic extract significantly inhibited the detoxifying enzymes (glutathione S -transferase and acetylcholinesterase) in target pests. Therefore, based on field bio efficacy data of extract/fractions and compounds, the lead (s) can be employed further for the preparation of botanical insecticide. The present finding provides the first report on simultaneous quantification of three isoquinoline alkaloids by UHPLC-PDA and the bio-insecticidal potential of T. foliolosum. [Display omitted] • Quantitative analysis of methanolic extract and fractions of T. foliolosum. • Chemical characterization of n -hexane fraction of T. foliolosum by GC-MS. • n - butanol/fractions and compounds are effective against target pests. • Methanolic extract and chloroform fraction inhibited aphid reproduction. • Methanolic extract inhibited the detoxifying enzymes (AChE and GST). [ABSTRACT FROM AUTHOR]

Berberine (BBR), an isoquinoline alkaloid, has been found in many plants, such as Coptis chinensis Franch and Phellodendron chinense Schneid. Although BBR has a wide spectrum of pharmacological effects, its oral bioavailability is extremely low. In recent years, gut microbiota has emerged as a cynosure to understand the mechanisms of action of herbal compounds. Numerous studies have demonstrated that due to its low bioavailability, BBR can interact with the gut microbiota, thereby exhibiting altered pharmacological effects. However, no systematic and comprehensive review has summarized these interactions and their corresponding influences on pharmacological effects. Here, we describe the direct interactive relationships between BBR and gut microbiota, including regulation of gut microbiota composition and metabolism by BBR and metabolization of BBR by gut microbiota. In addition, the complex interactions between gut microbiota and BBR as well as the side effects and personalized use of BBR are discussed. Furthermore, we provide our viewpoint on future research directions regarding BBR and gut microbiota. This review not only helps to explain the mechanisms underlying BBR activity but also provides support for the rational use of BBR in clinical practice. [Display omitted] • Low bioavailability enables interactions between berberine and the gut microbiota. • Berberine can shape the composition and metabolism of the gut microbiota. • Gut microbiota can metabolize and transform berberine. • Personalized use of berberine can reduce the occurrence of side effects. [ABSTRACT FROM AUTHOR]

Adhatoda vasica is used in the treatment of cold, cough, chronic bronchitis, asthma, diarrhea, and dysentery. The biological activities of this species are attributed with the presence of alkaloids, triterpenoids, and flavonoids. Agrobacterium rhizogenes -mediated transformation of A. vasica , produces pyrroloquinazoline alkaloids, was achieved by infecting leaf discs with strain ATCC15834. The bacterial strain infected 82.7% leaf discs and 5–7 hairy root initials were developed from the cut edges of leaf discs. In this study, seven strains of Azotobacter chroococcum and five strains of Pseudomonas putida were used for the biotization of hairy roots. Plant growth-promoting rhizobacteria (PGPR) develops symbiotic association with roots of plants and increases the growth parameters of plants. PGPR (A. chroococcum and P. putida) increased the profiles of nitrogenase and acid phosphatase enzymes, biomass, dry matter contents, anthranilate synthase activity and accumulation of pyrroloquizoline alkaloids in the biotized hairy roots. Both enzymes (nitrogenase and acid phosphatase) maintain sufficient supply of nitrogen and dissolved phosphorus to the cells of hairy roots therefore, the levels of anthranilate synthase activity and pyrroloquinazoline alkaloids are increased. Total seven pyrroloquinazoline alkaloids (vasicine, vasicinone, vasicine acetate, 2-acetyl benzyl amine, vasicinolone, deoxyvasicine and vasicol) were identified from the biotized hairy roots of A. vasica. In our study, biotization increased the profiles of pyrroloquinazoline alkaloids therefore, this strategy may be used in increasing the production of medicinally important secondary metabolites in other plant species also. Our hypothetical model demonstrates that P. putida cell surface receptors receive root exudates by attaching on hairy roots. After attachment, the bacterial strain penetrates in the biotized hairy roots. This endophytic interaction stimulates acid phosphatase activity in the cells of biotized hairy roots. The P. putida plasmid gene (ppp1) expression led to the synthesis of acid phosphatase in cytosol. The enzyme enhances phosphorus availability as well as induces the formation of phosphoribosyl diphosphate. Later, phosphoribosyl diphosphate metabolizes to tryptophan and finally tryptophan converts to anthranilic acid. The synthesized anthranilic acid used in the synthesis of alkaloids in A. vasica. • Adhatoda vasica is used for the treatment of cold, cough, asthma, diarrhea, and dysentery. • Agrobacterium rhizogenes -mediated transformation of A. vasica was achieved by infecting leaf discs with strain ATCC15834. • PGPR increased the profiles of nitrogenase and phosphatases, anthranilate synthase and pyrroloquizoline alkaloids in biotized hairy roots. • The study may be useful in increasing the profiles of medicinally important phytochemicals in other plant species. [ABSTRACT FROM AUTHOR]

• Magnoflorine, a natural isoquinoline alkaloid was experimentally analyzed by different spectroscopies techniques. • The optimized structural and electronic properties of the molecule were predicted by DFT calculations. • Vibrational frequencies assignments were performed based on PED calculations. • The reactivity sites were evaluated by theoretical calculation. • The preference of anxiolytic activity toward the extracellular in comparison with intracellular domains of GABAA receptor was predicted. Magnoflorine (MGF), an isoquinoline alkaloid, emerges as a quaternary aporphine alkaloid derived from L-tyrosine amino acid, found in families Magnoliaceae plants and it presents important biological activity being noted for its effect on the nervous system. In this work, a deep study of structural, vibrational and electronic properties has been carried out for the MGF. From Potential Energy Surface (PES) scan the most stable conformer of alkaloid was identified and geometrical parameters were determined by Density Functional Theory (DFT) using B3LYP/6–311++G** method. A complete vibrational assignment of the normal modes was theoretical and experimentally achieved from FT-IR and Raman spectroscopies and scaled SQM methodology. Electronic transitions observed in UV–visible spectrum in aqueous medium were identified using TD-DFT methodology, with the π→π* transition being the most probable UV signal. The MEPs, the electric charge distribution along with the HOMO and LUMO frontier orbitals were analyzed and the GAP energy values justified the stability of the molecule in aqueous medium. The molecular electrostatic potential map reveals the most favourable region for electrophilic attack on MGF. Molecular docking was used to analyze the anxiolytic biological activity of the title molecule on the GABA A receptor. The results suggest an intermolecular binding capability of MFG toward both intracellular and extracellular domains of GABA A receptor, and the extracellular domain presents a higher affinity by alkaloid. Finally, the biological study infers that MGF could be used as a potential anxiolytic compound. [Display omitted] [ABSTRACT FROM AUTHOR]

The presence of phytotoxins in plants constitutes a health risk for herbivores, particularly on ruminants who accidently consume them. Among the adverse effects produced by these are reproductive alterations, represented by abortion, infertility, and morphological alterations in neonates, which are frequently attributed to other causes. While in some cases the plants that contain such metabolites are known, other times they are not, leading to alterations that are difficult to treat considering that their toxicodynamics are unknown. The objective of this documentary research is to provide information on how metabolites such as phytoestrogens, L-mimosine, labdane diterpenoids - isocupressic acid, quinolizidine alkaloids and piperidine swainsonine, anabasine, coniine and associated alkaloids, among others, exert their action in the animal organism and the effects they produce. [Display omitted] • Corrected spelling and reviewed the proper classifications used for all compounds. • All metabolites and scientific names of the plants were reviewed. • Isocupressic acid. labdane resin acid, agathic acid, coniine were corrected. [ABSTRACT FROM AUTHOR]

[Display omitted] • Shell powder addition improves compost environment in response to pathogen removal. • The abundance of pathogens is closely associated with fungal diversity. • Shell powder addition reduces the pathogens abundance by altering fungal diversity. • Anti-pathogenic metabolites are induced after the shell powder supplementation. The effective elimination of pathogens during the composting process is essential for ensuring the safe utilization of organic fertilizers and maintaining food security. However, the development of innovative, cost-effective, and environmentally friendly techniques for pathogen eradication remains insufficient. Actually, the improper disposal of shell powder, a prominent by-product of the seafood industry, can result in environmental pollution and the wastage of resources. The present study examined the effectiveness of incorporating shell powder as a composting amendment for the efficient eradication of pathogens. Metagenomic and metabolomic analyses were utilized to elucidate the underlying biological mechanisms. Our findings revealed that the addition of shell powder enhanced compost temperature, pH, electrical conductivity, and extracellular enzyme activity, creating a conducive environment for pathogens elimination. Furthermore, fungal diversity was positively correlated with pathogens abundances. The addition of shell powder altered critical compounds levels such as 11(E)-Eicosenoic Acid, Arachidonic Acid, Daidzein, and Erucic Acid, resulting in reduced fungal diversity during the thermophilic phase and indirectly suppressing the pathogenic fungi abundance. Additionally, anti-pathogenic metabolites were induced after shell powder supplementation demonstrating greater diversity including alkaloids, terpenoids flavonoids and phenolic compounds exhibiting higher selectivity and specificity for different pathogens. In conclusion, incorporating shell powder during composting is recommended as a viable strategy for utilizing seafood waste resources, reducing pathogen risks, and thereby enhancing the quality of organic fertilizer. [ABSTRACT FROM AUTHOR]

In this study we have identified POLθ-S6K-p62 as a novel druggable regulator of radiation response in prostate cancer. Despite significant advances in delivery, radiotherapy continues to negatively affect treatment outcomes and quality of life due to resistance and late toxic effects to the surrounding normal tissues such as bladder and rectum. It is essential to develop new and effective strategies to achieve better control of tumor. We found that ribosomal protein S6K (RPS6KB1) is elevated in human prostate tumors, and contributes to resistance to radiation. As a downstream effector of mTOR signaling, S6K is known to be involved in growth regulation. However, the impact of S6K signaling on radiation response has not been fully explored. Here we show that loss of S6K led to formation of smaller tumors with less metastatic ability in mice. Mechanistically we found that S6K depletion reduced NFκB and SQSTM1 (p62) reporter activity and DNA polymerase θ (POLθ) that is involved in alternate end-joining repair. We further show that the natural compound berberine interacts with S6K in a in a hitherto unreported novel mode and that pharmacological inhibition of S6K with berberine reduces Polθ and downregulates p62 transcriptional activity via NFκB. Loss of S6K or pre-treatment with berberine improved response to radiation in prostate cancer cells and prevented radiation-mediated resurgence of PSA in animals implanted with prostate cancer cells. Notably, silencing POLQ in S6K overexpressing cells enhanced response to radiation suggesting S6K sensitizes prostate cancer cells to radiation via POLQ. Additionally, inhibition of autophagy with CQ potentiated growth inhibition induced by berberine plus radiation. These observations suggest that pharmacological inhibition of S6K with berberine not only downregulates NFκB/p62 signaling to disrupt autophagic flux but also decreases Polθ. Therefore, combination treatment with radiation and berberine inhibits autophagy and alternate end-joining DNA repair, two processes associated with radioresistance leading to increased radiation sensitivity. Combination of berberine plus radiation could be an attractive strategy to overcome biochemical recurrence post radiotherapy in subsets of prostate cancer patients. [Display omitted] • Berberine, a benzyl isoquinoline alkaloid interacts with RPS6KB1 (S6K) in a hitherto unreported novel mode. • S6K inhibition suppresses autophagic flux and alternate end-joining DNA repair, processes associated with radio resistance. • Berberine downregulates NFkB-mediated transcriptional activation of SQSTM1. • Berberine inhibits feedback loop between POLQ-S6K. • Berberine's radio-sensitization effects prevent biochemical recurrence (BCR) in vivo. • Berberine plus radiation, an attractive strategy to overcome BCR post-radiotherapy for prostate cancer patients. • Silencing POLQ sensitizes S6K overexpressing prostate cancer cells to radiation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Three new deep-red neutral Ir(III) complexes featuring anthraquinonyl isoquinoline as the main ligand were successfully synthesized. • Solution-processed OLEDs were prepared to investigate the electroluminescent properties of these complexes. • The Ir-acac-based device demonstrated the best electroluminescent performance with an external quantum efficiency of 5.94%. Three high-efficiency deep-red neutral iridium(III) complexes are rationally designed and prepared using a mild method by introducing condensed ring (anthraquinonyl isoquinoline) as the cyclometalated ligand. The frequently-used ancillary ligands (acetylacetone, hexafluoroacetylacetone, picolinic acid) help to regulate the photophysical properties of the three iridium(III) complexes. In both solution and aggregated states, these three iridium(III) phosphors presented the intense deep-red phosphorescence, with the peak wavelength at 676, 634, and 648 nm, respectively. Additionally, Ir-acac, Ir-CF 3 and Ir-pic exhibited high photoluminescence quantum yields (PLQYs) of 20 %, 18 %, and 17 % in dichloromethane, respectively. Furthermore, the efficient solution-processed electroluminescent devices were demonstrated with these emitters. The maximum external quantum efficiencies for the devices reached 5.94 % (Ir-acac), 0.55 % (Ir-CF 3), and 3.16 % (Ir-pic), featuring the electroluminescent spectral peaks at 654, 632, 644 nm, respectively. [ABSTRACT FROM AUTHOR]

Continued interest in the bioactive alkaloids led to the isolation of five undescribed alkaloids (1–5), ophiorglucidines A-E, and seven known analogues (6–12) from the water-soluble fraction of Ophiorrhiza japonica. The structures were elucidated based on spectroscopic data and quantum calculations as well as X-ray crystallographic analysis. The structure of 1 was characterized as a hexacyclic skeleton including a double bridge linking the indole and the monoterpene moieties, which is the first report of a single crystal with this type of structure. Moreover, the inhibitory effect of zwitterionic indole alkaloid glycosides on xanthine oxidase was found for the first time. The alkaloids 2 and 3 , both of which have a pentacyclic zwitterionic system, were more active than the reference inhibitor, allopurinol (IC 50 = 11.1 μ M) with IC 50 values of 1.0 μ M, and 2.5 μ M, respectively. Structure-activity relationships analyses confirmed that the carbonyl group at C-14 was a key functional group responsible for the inhibitory effects of these alkaloids. [Display omitted] • Five undescribed alkaloids are identified from Ophiorrhiza japonica. • For the first time, the inner salt indole alkaloid glycosides were found to have an inhibitory effect on xanthine oxidase. • The key pharmacophore with inhibitory activity was identified. [ABSTRACT FROM AUTHOR]

Extensive phytochemical study of the methanol extract of twigs and leaves of Buxus sinica resulted in the identification of forty-one Buxus alkaloids, including twenty undescribed ones, namely cyclobuxusinines A-I (1 – 7 , 16 and 20), as well as secobuxusinines A-K (8 – 15 and 17 – 19). Their structures were delineated by detailed analysis using various spectroscopic techniques. cyclobuxusinines B (2) was the first Buxus alkaloid, whose CH 3 -18 was oxidized, implying the presence of special oxidative enzymes in this plant. Secobuxusinines C (10), D (11), and E (12), whose C-12 or C-19 have an OH group substitution, enriched the substituent pattern in Buxus alkaloid and suggested more structurally diverse alkaloids in the Buxus spp. In the assessment of their bioactivities, some of them exhibited significant cytotoxic effects on two human tumor ovarian cancer cell lines. Notably, compound 36 displayed more potent cytotoxic effect against ES2 and A2780 cell lines with the IC 50 value of 1.33 μM and 0.48 μM, respectively. Forty-one metabolites, including twenty undescribed Buxus alkaloids, were isolated from the aerial part of Buxus sinica. Some of them showed good cytotoxic activity. [Display omitted] • 1, Twenty undescribed and twenty-one known Buxus alkaloids were isolated from Buxus sinica. • 2, Some Buxus alkaloids showed significant cytotoxicity against ES2 and A2780 cell lines. • 3, Compound 36 displayed more potent cytotoxic with the IC 50 value of 1.33 μM and 0.48 μM, respectively. [ABSTRACT FROM AUTHOR]

Tylophora indica (Burm f.) Merrill, belong to family Asclepiadaceae, is considered to be a natural remedy with high medicinal benefits. The objective of this work is to assess the metabolomic profile of T. indica leaves enriched in alkaloids, as well as to evaluate the in vitro cytotoxicity of these leaves using the MTT assay on human breast MCF-7 and liver HepG2 cancer cell lines. Dried leaves of T. indica were extracted by sonication, using methanol containing 2 % (v /v) of acetic acid and obtained fraction was characterized by HPTLC and UPLC-MS. The UPLC-MS study yielded a preliminary identification of 32 metabolites, with tylophorine, tylophorine B, tylophorinine, and tylophorinidine being the predominant metabolites. The cytotoxicity of the extract of T. indica was evaluated on HepG2 and MCF-7 cell lines, yielding inhibitory concentration (IC 50) values of 75.71 μg/mL and 69.60 μg/mL, respectively. Data suggested that the phytochemical screening clearly showed presence of numerous secondary metabolites with moderate cytotoxic efficacy. In conclusion, the future prospects of T. indica appear promising for the advancement of phytopharmaceutical-based anticancer medications, as well as for the design of contemporary pharmaceuticals in the field of cancer chemotherapy. [Display omitted] • The alkaloid-rich fraction of T. indica leaves comprises phenanthroindolizidine alkaloids and other secondary metabolites. • It has been observed that these alkaloids possess significant cytotoxic properties against MCF-7 and HepG2 cancer cell lines. • These compounds can be tested for their ability to selectively affect metabolic pathways in lab settings and living organisms. • The potential of T. indica for the development of phytopharmaceutical-based anticancer drugs is highly promising. • T. indica has great potential in the development of advanced pharmaceuticals for cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Mitragyna speciosa , more commonly known as kratom, has emerged as an alternative to treat chronic pain and addiction. However, the alkaloid components of kratom, which are the major contributors to kratom's pharmaceutical properties, have not yet been fully investigated. In this study, matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry was used to map the biodistribution of three alkaloids (corynantheidine, mitragynine, and speciogynine) in rat brain tissues. The alkaloids produced three main ion types during MALDI analysis: [M + H]+, [M − H]+, and [M − 3H]+. Contrary to previous reports suggesting that the [M − H]+ and [M − 3H]+ ion types form during laser ablation, these ion types can also be produced during the MALDI matrix application process. Several strategies are proposed to accurately map the biodistribution of the alkaloids. Due to differences in the relative abundances of the ions in different biological regions of the tissue, differences in ionization efficiencies of the ions, and potential overlap of the [M − H]+ and [M − 3H]+ ion types with endogenous metabolites of the same empirical formula, a matrix that mainly produces the [M + H]+ ion type is optimal for accurate mapping of the alkaloids. Alternatively, the most abundant ion type can be mapped or the intensities of all ion types can be summed together to generate a composite image. The accuracy of each of these approaches is explored and validated. [Display omitted] • Biodistribution of kratom alkaloids is mapped in rat brains using imaging mass spectrometry. • Alkaloids produced three main ion types during MALDI mass spectrometry analysis. • Dehydrogenated ion formation is an artifact of MALDI, and not due to endogenous metabolism. [ABSTRACT FROM AUTHOR]

Eleven undescribed isoquinoline alkaloids (1 − 8 , 14 , 15 , and 24), along with 19 analogues (9 − 13 , 16 − 23 , and 25 − 30) were isolated from the barks of Alangium salviifolium. The structures of the undescribed compounds were elucidated through the analysis of their HR-ESI-MS, 1D and 2D NMR, IR, UV, and X-ray diffraction. The absolute configuration of 8 was established via the ECD calculation. Notably, compounds 1 / 2 and 3 / 4 were two pairs of C-14 epimers. The isolated alkaloids were evaluated for their cytotoxicity against various cancer cell lines, including SGC-7901, HeLa, K562, A549, BEL-7402, HepG2, and B16, β -carboline-benzoquinolizidine (14 − 22) and cepheline-type (24 − 28) alkaloids exhibited remarkable cytotoxicity, with IC 50 values ranging from 0.01 to 48.12 μM. Remarkably, compounds 17 and 21 demonstrated greater cytotoxicity than the positive control doxorubicin hydrochloride. Furthermore, a significant proportion of these bioactive alkaloids possess a C-1′ epimer configuration. The exploration of their structure-activity relationship holds promise for directing future investigations into alkaloids derived from Alangium , potentially leading to novel insights and therapeutic advancements. [Display omitted] • Eleven undescribed alkaloids were identified from Alangium salviifolium. • All structures were elucidated by spectroscopic, X-ray crystallographic data, and ECD analyses. • β -carboline-benzoquinolizidine and cepheline-type alkaloids exhibited cytotoxicity. [ABSTRACT FROM AUTHOR]

[Display omitted] Berberine, a natural isoquinoline alkaloid, exhibits a variety of pharmacological effects, but the pharmacological targets and mechanisms remain elusive. Here, we report a novel finding that berberine inhibits acetylcholine (ACh)-induced intracellular Ca2+ oscillations, mediated through an inhibition of the muscarinic subtype 3 (M 3) receptor. Patch-clamp recordings and confocal Ca2+ imaging were applied to acute dissociated pancreatic acinar cells prepared from CD1 mice to examine the effects of berberine on ACh-induced Ca2+ oscillations. Whole-cell patch-clamp recordings showed that berberine (from 0.1 to 10 µM) reduced ACh-induced Ca2+ oscillations in a concentration-dependent manner, and this inhibition also depended on ACh concentrations. The inhibitory effect of berberine neither occurred in intracellular targets nor extracellular cholecystokinin (CCK) receptors, chloride (Cl-) channels, and store-operated Ca2+ channels. Together, the results demonstrate that berberine directly inhibits the muscarinic M 3 receptors, further confirmed by evidence of the interaction between berberine and M 3 receptors in pancreatic acinar cells. [ABSTRACT FROM AUTHOR]

• A practical method for the synthesis of 2-alkyl- and 2-arylthiazolo[5,4- c ]isoquinoline derivatives is reported. • The single-crystal X-ray diffraction structures of five new compounds are presented. • In silico prediction of biological activity and toxicological risk. • One of the thiazolo[5,4- c ]isoquinoline derivatives is a promising kinases inhibitor. A practical method for the synthesis of 2-alkyl- and 2-arylthiazolo[5,4- c ]isoquinoline derivatives starting from simple commercially available reagents is presented. The recently reported La(OTf) 3 catalysed reaction of dithiooxamide with 2-halobenzaldehydes to afford 2-arylthiazolo[5,4- c ]isoquinolines is now extended to the synthesis of 2-alkylthiazolo[5,4- c ]isoquinolines and "mixed" 2-arylthiazolo[5,4- c ]isoquinolines. The new compounds can be prepared under the previously reported experimental conditions but using a 1:1 mixture of a 2-halobenzaldehyde and an aliphatic or (hetero)aromatic aldehyde. The new approach also allows the access to 2-alkyl-5-arylthiazolo[5,4- d ]thiazoles that are hitherto unknown structures. The single-crystal X-ray diffraction structures of three thiazolo[5,4- c ]isoquinolines and of two non-symmetrical thiazolo[5,4- d ]thiazoles are presented. The photophysical properties of the new thiazolo[5,4- c ]isoquinoline derivatives, and their potential biological activities and toxicological risks, are discussed. Some of the new compounds show interesting bioactivity scores as kinase inhibitors. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • It was reported about the synthesis procedure of new isoquinoline derivatives. • The structure of the synthesized compounds was confirmed by NMR spectroscopy method and X-Ray analysis. • Inhibition activity of compounds 5(a-d) were tested against AChE, BChE and α-Gly as in vitro. • Molecular docking IFD XP Gscores, dynamics simulations and MM-GBSA ΔG binding free energies studied. In the presented work, it was reported about the synthesis procedure of new isoquinoline derivatives starting from chalcones and acetoacetanilide, a multi-step synthesis pathway yielded four isoquinoline derivatives (5a-d). At the first stage of our research, corresponding cyclohexanone derivatives are synthesized from the Michael addition reaction of chalcones with acetoacetanilide. After that, on the based cyclohexanone derivative was obtained novel isoquinoline derivatives. According to the structures, a plausible reaction mechanism was suggested. The structure of the synthesized compounds was confirmed by NMR spectroscopy method and X-Ray analysis. Additionally, to determine cholinesterase and α-glycosidase inhibition activity compounds 5(a-d) were tested against AChE, BChE and α-Gly as in vitro. In this work, the novel isoquinoline derivatives 5(a-d) demonstrated encouraging inhibitory action against α-glucosidase, as seen by their IC 50 values ranging from 9.95 to 19.25 nM. This indicates that they were approximately 1–3 times more active than acarbose (IC 50 = 23.07 nM). Also, the molecular docking IFD XP Gscores, dynamics simulations and MM-GBSA ΔG binding free energies of the isoquinoline derivatives on hAChE, hBChE and α-Gly are determined. The molecular dynamics (MD) simulations conducted in this study provided valuable insights into the dynamic behaviors, stabilities, and interaction profiles of ligand–protein complexes involving the R and S isomers of compounds 5c-hAChE , 5c-hBChE , and 5a-αGly. The MD simulations were crucial for understanding the complex stabilities and dynamic mechanisms of the ligand–protein interactions, shedding light on the potential inhibitory roles of these compounds.. [ABSTRACT FROM AUTHOR]

Fuke Qianjin capsules (FKQJ) exhibit obvious advantages and characteristics in the treatment of pelvic inflammatory disease. At present, information regarding the in vivo process of FKQJ is lacking, which has become a bottleneck in further determining the therapeutic effect of this traditional Chinese medicine. In the present study, a sensitive, simple and reliable method was developed and validated for the simultaneous quantification of 12 main components (4 flavonoids, 4 alkaloids, 2 phthalides and 2 diterpene lactones) in plasma and seven tissues of rats to study the pharmacokinetic and distribution characteristics of these components in vivo by using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the first time. Plasma and tissue were prepared by protein precipitation with acetonitrile and methanol, followed by its separation on a Waters Acquity UPLC BEH C 18 column. The quantification was performed via multiple reaction monitoring (MRM) by a triple quadrupole mass spectrometer under positive electrospray ionization (ESI) mode. The method was validated to demonstrate its selectivity, linearity, accuracy, precision, recovery, matrix effect and stability. For 12 analytes, the low limit of quantification (LLOQs) reached 0.005–2.44 ng/mL, and all calibration curves showed good linearity (r2 ≥ 0.990) in linear ranges. The intra-day and inter-day precision (relative standard deviation) for all analytes was less than 14.96%, and the accuracies were in the range of 85.29%−114.97%. Extraction recoveries and matrix effects of analytes were acceptable. The pharmacokinetic results showed that the main components could be absorbed quickly, had a short residence time, and were eliminated quickly in vivo. At different time points, the 12 components were widely distributed with uneven characteristics in the body, which tended to be distributed in the liver, kidney and lung and to a lesser extent in the uterus, brain and heart. The pharmacokinetic process and tissue distribution characteristics of FKQJ were expounded in this study, which can provide a scientific theory for in-depth development of FKQJ and guide FKQJ use in the clinic. [Display omitted] • A sensitive and reliable UPLC-MS/MS method was developed and validated. • 12 bioactive compounds from FKQJ were quantified in rat plasma and 7 tissues. • Pharmacokinetic parameters and oral bioavailability were listed. • The first study report on tissue distribution of FKQJ. [ABSTRACT FROM AUTHOR]

C2-formyl indoles are important building blocks for the organic synthesis of alkaloids and small molecules with broad biological activities. Generally, its preparation involves both direct formylation of indoles at the activated C2-position with as unstable carbonyl sources and oxidative cleavage of tedious prepared tetrahydro- β -carbolines (TH β Cs) in the harsh conditions. In continuation of our research on the oxidative functionalization of indoles, in this letter, we report that straightforward effectively oxidation of easily available 2-methylindoles bearing C3-heteroatom functional group proceeds regioselectively C2-formyl indoles in good and excellent yields employing an oxidative combination of NCS/DMSO. This methodology presents a reasonably broad substrate scope and excellent functional group tolerance, thus enabling the preparation of highly versatile building blocks susceptible to further functionalization. An additional feature of this approach includes high efficiency, ease of operation, facile purification, and short reaction time, making it a promising strategy for organic synthesis and drug discovery. To create your abstract, type over the instructions in the template box below.Fonts or abstract dimensions should not be changed or altered. [Display omitted] [ABSTRACT FROM AUTHOR]

Nine 3-arylisoquinoline alkaloids including five undescribed ones, hypectumines A-E (1 – 5), were isolated from the whole herb of Hypecoum erectum L. with the guidance of 1H-NMR. Their structures were established by a combination of 1D, 2D NMR, and HRESIMS spectrometry. Among them, hypectumines A and B possessed rare urea moieties while hypectumines C and D were characterized by 3-(methylamino)propanoic acid scaffolds. Biological assay demonstrated that alkaloids hypectumine B and 2,3-dimethoxy- N -formylcorydamine had anti-inflammatory effects by inhibiting NO production on LPS-induced RAW264.7 cells with IC 50 values of 24.4 and 44.2 μM, respectively. Furthermore, hypectumine B could reduce the expression of pro-inflammatory cytokines TNF- α and IL-6, suggesting it might be a potential candidate for treating inflammatory disease. [Display omitted] • Nine 3-arylisoquinoline alkaloids were isolated with the guidance of 1H NMR. • Hypectumines A and B (1 and 2) possessed rare urea moieties within isoquinoline categories. • Provided thoughts for biosynthetic pathway of 3-arylisoquinoline alkaloids. • Hypectumine B (2) could reduce NO level secreted by LSP-induced RAW264.7 cells. • Hypectumine B (2) could inhibit the expression of pro-inflammatory cytokines TNF- α and IL-6. [ABSTRACT FROM AUTHOR]

Seventeen piperidine alkaloids, including 15 previously undescribed 2-substituted-6-(9-phenylnonyl)-piperidine-3,4-diol alkaloids and a previously undescribed 2-substituted-6-(9-phenylnonyl)-piperidine-3-ol alkaloid, were isolated from the leaves of Alocasia macrorrhiza (L.) Schott. Their planar structures and configurations were elucidated based on HR-ESI-MS, 1D and 2D NMR, Snatzke's method, modified Mosher method, single-crystal X-ray crystallography, as well as quantum chemical calculation. It was found that Δ δ H5b - H5a can be used to elucidate the relative configuration of 2,3,4,6-tetrasubstituted piperidine, by analyzing the NMR data of 2-substituted-6-(9-phenylnonyl)-piperidine-3,4-diol. Antiproliferative activity was evaluated for all of the alkaloids, and compounds 6 – 8 showed considerable inhibitory activity against K562 cell line, with the IC 50 values of 17.24 ± 1.62, 19.31 ± 0.9 and 18.77 ± 1.09μM, respectively. Furthermore, compounds 6 and 7 exerted an antiproliferative effect by inducing apoptosis. • Bioactive phytochemicals of the leaves of Alocasia macrorrhiza were studied. • Sixteen new piperidine alkaloids were isolated and identified. • Piperidine alkaloids have exhibited potential antiproliferative activity. • The relative configuration of piperidine can be elucidated by calculating Δ δ H5b-H5a. • Alocasia macrorrhiza may be beneficial to cancer related diseases. [ABSTRACT FROM AUTHOR]

Endophytic fungi are capable of producing a great diversity of bioactive metabolites. However, the presence of silent and lowly expressed genes represents a main challenge for the discovery of novel secondary metabolites with different potential uses. Epigenetic modifiers have shown to perturb the production of fungal metabolites through the induction of silent biosynthetic pathways leading to an enhanced chemical diversity. Moreover, the addition of bioprecursors to the culture medium has been described as a useful strategy to induce specific biosynthetic pathways. The aim of this study was to assess the effects of different chemical modulators on the metabolic profiles of an endophytic fungal strain of Cophinforma mamane (Botryosphaeriaceae), known to produce 3 thiodiketopiperazine (TDKP) alkaloids (botryosulfuranols A-C), previously isolated and characterized by our team. Four epigenetic modifiers, 5-azacytidine (AZA), sodium butyrate (SB), nicotinamide (NIC), homoserine lactone (HSL) as well as 2 amino acids, l -phenylalanine and l -tryptophan, as bioprecursors of TDKPs, were used. The metabolic profiles were analysed by UHPLC-HRMS/MS under an untargeted metabolomics approach. Our results show that the addition of the two amino acids in C. mamane culture and the treatment with AZA significantly reduced the production of the TDKPs botryosulfuranols A, B and C. Interestingly, the treatment with HSL significantly induced the production of different classes of diketopiperazines (DKPs). The treatment with AZA resulted as the most effective epigenetic modifier for the alteration of the secondary metabolite profile of C. mamane by promoting the expression of cryptic genes. [ABSTRACT FROM AUTHOR]

[Display omitted] • Influence of pore structure of Pt/ m -SiO 2 on catalytic performance in enantioselective hydrogenation of ethyl pyruvate. • Effect of different cinchona alkaloid modifiers on catalytic performance of Pt/ m -SiO 2. • Effect of hydrogen pressure on enantioselectivity of cinchona alkaloid-modified Pt/ m -SiO 2. Catalytic properties of Pt catalysts supported on mesoporous silica (Pt/ m -SiO 2) have been studied in enantioselective hydrogenation of ethyl pyruvate. The influences of pore structure of mesoporous silica (m -SiO 2), type of chiral modifier, and H 2 pressure on the catalytic performance have been investigated by using various m -SiO 2 supports and cinchona alkaloids and by varying H 2 pressure. The use of MCM-41, SBA-15, KIT-6, and MCF reveals that characteristic pore structure and size of m -SiO 2 supports significantly affect both activity and enantioselectivity. A facile diffusion of chiral modifier through large mesopores of MCF support enables Pt/MCF to exhibit excellent performance. A comparison of the efficiency of cinchona alkaloids-modified Pt catalysts shows that QN and QD lead to higher performance than CD and CN at ambient H 2 pressure. The influence of cinchona alkaloids on enantioselectivity noticeably depends on H 2 pressure. Cinchona alkaloid-modified Pt/ m -SiO 2 exhibit superior enantioselectivity to the corresponding Pt/Al 2 O 3 under various H 2 pressures. These results imply that m -SiO 2 is a promising support and that fine control of pore structure can further improve catalytic performance of Pt/ m -SiO 2 in heterogeneous enantioselective hydrogenation. [ABSTRACT FROM AUTHOR]

[Display omitted] Natural products of pharmaceutical interest often do not reach the drug market due to the associated low yields and difficult extraction. Knowledge of biosynthetic pathways is a key element in the development of biotechnological strategies for plant specialized metabolite production. Erythrina species are mainly used as central nervous system depressants in folk medicine and are important sources of bioactive tetracyclic benzylisoquinoline alkaloids (BIAs), which can act on several pathology-related biological targets. In this sense, in an unprecedented approach used with a non-model Fabaceae species grown in its unique arid natural habitat, a combined transcriptome and metabolome analyses (seeds and leaves) is presented. The Next Generation Sequencing-based transcriptome (de novo RNA sequencing) was carried out in a NextSeq 500 platform. Regarding metabolite profiling, the High-resolution Liquid Chromatography was coupled to DAD and a micrOTOF-QII mass spectrometer by using electrospray ionization (ESI) and Time of Flight (TOF) analyzer. The tandem MS/MS data were processed and analyzed through Molecular Networking approach. This detailed macro and micromolecular approach applied to seeds and leaves of E. velutina revealed 42 alkaloids, several of them unique. Based on the combined evidence, 24 gene candidates were put together in a putative pathway leading to the singular alkaloid diversity of this species. Overall, these results could contribute by indicating potential biotechnological targets for modulation of erythrina alkaloids biosynthesis as well as improve molecular databases with omic data from a non-model medicinal plant, and reveal an interesting chemical diversity of Erythrina BIA harvested in Caatinga. [ABSTRACT FROM AUTHOR]

• Five genera of the South African Amaryllidaceae surveyed for the period 2013–2020. • These are inclusive of Crinum, Ammocharis, Amaryllis, Cyrtanthus and Brunsvigia. • Around 90 isoquinoline alkaloids and 25 non-alkaloidal entities described. • Chemosystematics of selected alkaloids considered. • Biological properties of isolated compounds also described. There is considerable interest in the plant family Amaryllidaceae for its biologically-active isoquinoline alkaloid principles. Some of these (such as galanthamine and narciclasine) have demonstrated their applicability in the clinical arena, particularly as cancer and motorneuron disease therapeutics. While synthetic organic chemistry affords ideal opportunities for drug development with such targets, the phytochemical approach is considered a somewhat more amenable option. In this regard, southern Africa has garnered widespread attention due to the abundance of Amaryllidaceae plants in its territory. Crinum, Ammocharis, Amaryllis, Cyrtanthus and Brunsvigia are genera of the family that are likewise well-represented in southern Africa. Up to 2012, thirty members from these genera were examined for their chemical and biological properties, culminating with the identification of nearly one-hundred alkaloid entities several of which exhibited notable biological activities. The present effort covers studies since 2013 that have been undertaken on the title genera in regards to their chemical and biological characteristics. Close to ninety alkaloids and twenty-five non-alkaloid entities were described during this time-frame from fifteen representative species. Biological studies included cholinesterase inhibiton, cytotoxicity, antidiabetes and antihypertensive effects, herbicidal, insecticidal and plant growth regulatory effects, as well as anti-inflammatory, antioxidant and antiplasmodial effects. The structural variety of the compounds isolated in cases allowed for structure-activity probes to be made in some of the assays. There were also studies carried out to establish the molecular basis to these activities, notably in the area of molecular cancer chemotherapeutics. [ABSTRACT FROM AUTHOR]

Benzylisoquinoline alkaloids (BIAs) are compounds naturally found in plants and can have significant value in clinical settings. Metabolic engineering and synthetic biology are both promising approaches for the heterologous acquisition of benzylisoquinoline alkaloids. (S)– N -methylcoclaurine 3′-hydroxylase (NMCH), a member of the CYP80 family of CYP450, is the penultimate catalytic enzyme that forms the central branch-point intermediate (S)-reticuline and plays a key role in the biosynthesis of BIAs. In this study, an NMCH gene was cloned from Corydalis yanhusuo, while in vitro reactions demonstrated that CyNMCH can catalyze (S)– N -methylcoclaurine to produce (S)-3′-hydroxy- N -methylcoclaurine. The Km and Kcat of CyNMCH were estimated and compared with those identified in Eschscholzia californica and Coptis japonica. This newly discovered CyNMCH will provide alternative genetic resources for the synthetic biological production of benzylisoquinoline alkaloids and provides a foundation to help analyze the biosynthetic pathway of BIAs biosynthesis in C. yanhusuo. • Benzylisoquinoline alkaloids have commercial potential in the field of pharmaceutical. • Synthetic biology provides an alternative for production of BIAs which relies on varied genetic elements. • A NMCH gene was identified from Corydalis yanhusuo. • Enzyme activity of CyNMCH was compared with those reported NMCHs. • The newly identified NMCH provides elements for production of BIAs by synthetic biology. [ABSTRACT FROM AUTHOR]

Berberine (BBR) is an isoquinoline alkaloid extracted from Coptis chinensis that improves diabetes, hyperlipidemia and inflammation. Due to the low oral bioavailability of BBR, its mechanism of action is closely related to the gut microbiota. This study focused on the CYP51 enzyme of intestinal bacteria to elucidate a new mechanism of BBR transformation by demethylation in the gut microbiota through multiple analytical techniques. First, the docking of BBR and CYP51 was performed; then, the pharmacokinetics of BBR was determined in ICR mice in vivo, and the metabolism of BBR in the liver, kidney, gut microbiota and single bacterial strains was examined in vitro. Moreover, 16S rRNA analysis of ICR mouse feces indicated the relationship between BBR and the gut microbiota. Finally, recombinant E. coli containing cyp51 gene was constructed and the CYP51 enzyme lysate was induced to express. The metabolic characteristics of BBR were analyzed in the CYP51 enzyme lysate system. The results showed that CYP51 in the gut microbiota could bind stably with BBR, and the addition of voriconazole (a specific inhibitor of CYP51) slowed down the metabolism of BBR, which prevented the production of the demethylated metabolites thalifendine and berberrubine. This study demonstrated that CYP51 promoted the demethylation of BBR and enhanced its intestinal absorption, providing a new method for studying the metabolic transformation mechanism of isoquinoline alkaloids in vivo. [Display omitted] • The demethylation metabolism of natural drugs difficult to absorb through the gut microbiota was first reported. • Six different methods were presented to explain the metabolic mechanism of natural isoquinoline alkaloids. • The findings provided a new idea for studying the mechanism of drug metabolism of gut microbiota. [ABSTRACT FROM AUTHOR]

• 110 and 92 differential metabolites were shared from various organs of PS and PC, respectively. • L -tyrosine and 4-hydroxycinnamic acid in PS were directly involved in five and three metabolic pathways. • L -glutamic acid and oxoglutaric acid in PC were involved in seven and two metabolic pathways, respectively. Piper sarmentosum Roxb. (PS) and Piper cathayanum M. G. Gilbert & N. H. Xia (PC) are both listed as Traditional Chinese Medicine herbs. In this study, ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS) was used to analyze secondary metabolites and metabolically profile the leaves, stems and roots in PS and PC. A total of 110 and 92 differential metabolites were shared from various organs of PS and PC, respectively. Compared to the stems and roots of PS or PC, alkaloids and phenols in leaves of PS or PC accounted for 70% and 57% of the total alkaloids and phenols, respectively. An analysis of enriched metabolic pathways demonstrated that L -tyrosine and 4-hydroxycinnamic acid in PS were directly involved in five and three metabolic pathways, which are related to the biosynthesis of isoquinoline alkaloids and phenol backbones, respectively. The L -glutamic acid and oxoglutaric acid in PC were involved in seven and two metabolic pathways, respectively. L -glutamic acid synthesizes heme, tropane, piperidine and pyridine alkaloids, and the type Ⅱ polyketide backbone. Moreover, oxoglutaric acid generated via L -glutamic acid was mainly involved in the citrate cycle and played a fundamental role in determining these important metabolic processes. [ABSTRACT FROM AUTHOR]

[Display omitted] A novel series of benzo[6,7]indolo[3,4-c]isoquinolines 3a - 3f was designed by scaffold hopping of topoisomerase I inhibitor benzo[ g ][1]benzopyrano[4,3- b ]indol-6(13 H)-ones (BBPIs), which were developed by structural modification of the natural marine product lamellarin. The unconventional pentacycle was constructed by Bischler-Napieralski-type condensation of amide 11 and subsequent intramolecular Heck reaction. In vitro anticancer activity of the synthesized benzo[6,7]indolo[3,4-c]isoquinolines was evaluated on a panel of 39 human cancer cell lines (JFCR39). Among the compounds tested, N -(3-morpholinopropyl) derivative 3e showed the most potent antiproliferative activity, with a mean GI 50 value of 39 nM. This compound inhibited topoisomerase I activity by stabilizing the enzyme–DNA complex. [ABSTRACT FROM AUTHOR]

Hypertension, a highly prevalent chronic disease, is known to inflict severe damage upon blood vessels. In our previous study, isoliensinine, a kind of bibenzyl isoquinoline alkaloid which isolated from a TCM named Lotus Plumule (Nelumbo nucifera Gaertn), exhibits antihypertensive and vascular smooth muscle proliferation-inhibiting effects, but its application is limited due to poor water solubility and low bioavailability. In this study, we proposed to prepare isoliensinine loaded by PEG-PLGA polymer nanoparticles to increase its efficacy We synthesized and thoroughly characterized PEG-PLGA nanoparticles loaded with isoliensinine using a nanoprecipitation method, denoted as, PEG-PLGA@Isoliensinine. Additionally, we conducted comprehensive investigations into the stability of PEG-PLGA@Isoliensinine, in vitro drug release profiles, and in vivo pharmacokinetics. Furthermore, we assessed the antihypertensive efficacy of this nano-system through in vitro experiments on A7R5 cells and in vivo studies using AngII-induced mice. The findings reveal that PEG-PLGA@Isoliensinine significantly improves isoliensinine absorption by A7R5 cells and enhances targeted in vivo distribution. This translates to a more effective reduction of AngII-induced hypertension and vascular smooth muscle proliferation. In this study, we successfully prepared PEG-PLGA@Isoliensinine by nano-precipitation, and we confirmed that PEG-PLGA@Isoliensinine surpasses free isoliensinine in its effectiveness for the treatment of hypertension, as demonstrated through both in vivo and in vitro experiments. This study lays the foundation for isoliensinine's clinical use in hypertension treatment and vascular lesion protection, offering new insights for enhancing the bioavailability of traditional Chinese medicine components. Importantly, no toxicity was observed, affirming the successful implementation of this innovative drug delivery system in vivo and offers a promising strategy for enhancing the effectiveness of Isoliensinine and propose an innovative avenue for developing novel formulations of traditional Chinese medicine monomers. [Display omitted] [ABSTRACT FROM AUTHOR]

• Sanguinarine-based isoquinoline alkaloids (IQ) modulates the cecal microbiota to improve relating functional amino acid pathways supporting growth performance outcome in broilers exposed to natural tropical heat stress • Sanguinarine-based isoquinoline alkaloids (IQ) modulates the cecal microbiota improving the biosynthesis of l -tryptophan and l -methionine of cecum microbiome in broilers during exposed to natural heat stress in tropical climates. • Sanguinarine-based isoquinoline alkaloids (IQ) has the potentially modulated stress via the microbiome-gut-brain axis by improving Turicibacter sanguini , a spore-forming bacterium, that promotes serotonin biosynthesis. Broilers reared under tropical conditions are exposed to Heat Stress (HS) yielding adverseness in production. The study aimed to evaluate the effect of plant-derived sanguinarine-based Isoquinoline alkaloids (IQ) on integrating performance of growth with the cecal microbiome and functional metabolism profiles of amino acid metabolism for either precision nutrition or productivity promotion using nutrition strategies with intestinal microecological balance in broilers of 14-and 35-day of age under HS conditions. IQ significantly improved performance, body weight, average daily weight gain, feed intake, and mortality. IQ significantly modulated the cecum microbiome (14- and 35-dayo of age) by enriching microbiome diversity with increase in Bacteriodetes and Cyanobacteria, but decrease in Firmicutes and Proteobacteria. It was found on 14-day of age that abundances of Turicibactor sanguinis, Lactobacillus salivarious, Lactobacillus sacidophilus, and Akkermansia municiphila in the cecum of boiler fed with IQ60 were higher than in that of the control group. While abundances of Enteroccucus cecorum, Enteroccuus villorum, Escherichia fergusonii , and Helicobacter pullorum were lower in broiler fed with IQs demonstrating the potential to suppress Antimicrobial-Resistant (AMR) reservoirs in the cecum. IQs significantly increased amino acid metabolism namely, l -arginine degradation VII and l -tryptophan degradation I, l -tryptophan degradation VI on day 14, and l -alanine degradation VII, l -tryptophan biosynthesis, l -methionine biosynthesis I, l -methionine salvage cycle, and l -threonine degradation II on day 35 (Kruskal-Wallis p-value < 0.05) in which positively correlated with BW and FI but negative correlation with FCR (Pearson correlation, P < 0.05). It is the first finding that IQs potentially modulated the crosstalk between host and microbiota via the microbiome-gut-brain axis for gut homeostasis by improving Turicibacter sanguini , that promoted serotonin biosynthesis from colonic Enterochromaffin Cells (EC) in modulating Gastro-Intestinal tract (GI) motility. It can be concluded that IQ exhibited the potential to modulate cecal microbiota to improve functional amino acid pathways supporting growth performance in stress broilers. The phenotypic activity related to genotype prediction under in silico model of functional microbiome systems with multi-Omics methods relating with microbiome community is worthwhile to be further investigated leading to discovering potential phytogenic compounds for precision feed additives in stress broilers. [ABSTRACT FROM AUTHOR]