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Background: Nuciferine (NUC), a natural compound extracted from lotus leaves, has been proven to have anti‐obesity effects. However, the development and application of NUC as an anti‐obesity drug in dogs are hindered due to its poor water solubility and low bioavailability. Objective: To promote the development of NUC‐related products for anti‐obesity in dogs, this study prepared NUC into a liposome formulation and evaluated its characteristics, pharmacokinetics in dogs, and anti‐obesity effects on high‐fat diet dogs. Methods: NUC liposomes were prepared by the ethanol injection method, using NUC, egg lecithin, and β‐sitosterol as raw materials. The characteristics and release rate in vitro of liposomes were evaluated by particle size analyser and dialysis method, respectively. The pharmacokinetics in dogs after oral administration of NUC‐liposomes was carried out by the high‐performance liquid chromatography (HPLC) method. Moreover, we investigated the anti‐obesity effect of NUC‐liposomes on obese dogs fed with a high‐fat diet. Results: NUC‐liposome was successfully prepared, with an EE of (79.31 ± 1.06)%, a particle size of (81.25 ± 3.14) nm, a zeta potential of (–18.75 ± 0.23) mV, and a PDI of 0.175 ± 0.031. The cumulative release rate in vitro of NUC from NUC‐liposomes was slower than that of NUC. The T1/2 and relative bioavailability of NUC‐liposomes in dogs increased, and CL reduced compared with NUC. In addition, the preventive effect of NUC‐liposomes on obesity in high‐fat diet dogs is stronger than that of NUC. Conclusions: The liposome formulation of NUC was conducive to improve its relative bioavailability and anti‐obesity effect in dogs. [ABSTRACT FROM AUTHOR]

BACKGROUND: Precision therapy based on multifunctional nanomaterials is a novel therapeutic model for malignancies that can integrate multiple imaging and therapeutic models into one nanoscale platform to achieve visual combination treatment. OBJECTIVE: To prepare novel nanoparticles loaded with Cu2(OH)PO4 nanoparticles (CuNPs) and nuciferine (NF) (h-PCuNF), and to explore their ability to mediate combined photothermal therapy/photodynamic therapy/chemodynamic therapy/chemotherapy for malignancy. METHODS: The h-PCuNF nanoparticles were synthesized through a double-emulsion procedure, through which the CuNPs and NF were loaded into the shell of hollow poly(lactic-co-glycolic) acid nanocarriers. The morphology, structure, particle size, and zeta potential of the h-PCuNF nanoparticles were characterized. In deionized water, the magnetic resonance imaging and photothermal conversion performances of the h-PCuNF nanoparticles, as well as their capability to implement reactive oxygen species production by mediating photocatalysis and Fenton-like reactions, were evaluated. In liver malignant tumor cell line HepG2 cells, the effectiveness of the photothermal therapy/photodynamic therapy/chemodynamic therapy/chemotherapy combination therapy mediated by the nanoparticles was detected by employing fluorescence imaging and MTT assay. RESULTS AND CONCLUSION: (1) The h-PCuNF nanoparticles possessed a hollow spherical structure in which the CuNPs (drug loading rate and encapsulation rate were 26.3% and 63.2%, respectively) and NF (drug loading rate and encapsulation rate were 11.0% and 52.6%, respectively) were loaded into the shell. The average particle size of the h-PCuNF nanoparticles was (309.2±10.0) nm, while the zeta potential was determined to be (-12.5±0.9) mV. In physiological environments, the nanoparticles possess favorable suspension stability. (2) In deionized water, the h-PCuNF nanoparticles could markedly enhance T1-weighted magnetic resonance imaging images. The h-PCuNF nanoparticles showed remarkable photothermal conversion and photocatalytic reactive oxygen species generation capabilities under near infrared laser irradiation. In addition, the h-PCuNF nanoparticles could consume glutathione and mediate Fenton-like reactions to produce OH. (3) The h-PCuNF nanoparticles could be taken up by HepG2 tumor cells and were mainly distributed in the cytoplasm. The synergistic therapeutic effect was demonstrated after the nanoparticles were activated by near infrared laser irradiation, because CuNPs mediated photothermal therapy/ photodynamic therapy/chemodynamic therapy and NF mediated chemotherapy could synergistically eliminate the tumor cells. [ABSTRACT FROM AUTHOR]

AbstractOn-line preconcentration incorporating cation-selective exhaustive injection (CSEI) and sweeping followed by micellar electrokinetic chromatography (MEKC) was developed for the simultaneous determination of the bioactive alkaloids nuciferine and O-nornuciferine. The parameters affecting the analytical performance were systematically investigated. Under the optimal conditions, the enrichment factor was significantly improved by 7000 to 13000-fold compared with traditional MEKC. The analytes were well separated within 15 min. The limits of detection for nuciferine and O-nornuciferine were 4.00 and 2.00 ng∙mL−1, and the limits of quantification were 8.00 and 10.00 ng∙mL−1, respectively. The relative standard deviations for intra-day and inter-day precision were less than 3.0%. The recoveries of the analytes were from 98.9% to 102%. Furthermore, the developed method was demonstrated to be suitable for the analysis of nuciferine and O-nornuciferine in lotus leaves, offering high performance without the loss of resolution. CSEI-sweeping-MEKC provides a simple, environmental-friendly option for preconcentration and quantification of nuciferine and O-nornuciferine. [ABSTRACT FROM AUTHOR]

Cisplatin is a widely used antineoplastic drug for treating various types of cancers. However, it can cause severe side effects, such as bilateral and irreversible hearing loss, which significantly impacts quality of life. Ferroptosis, an iron-dependent form of programmed cell death, has been implicated in the pathogenesis of cisplatin-induced ototoxicity. Here, we investigated the effects of nuciferine, a natural active ingredient isolated from lotus species, on the ferroptosis of cochlear hair cells. Firstly, our results demonstrated that nuciferine can protect hair cells against RSL3-induced and cisplatin-induced damage. Secondly, nuciferine treatment reduced ferrous iron (Fe2+) overload in cochlear hair cells via inhibiting NCOA4-mediated ferritinophagy. Inhibition of ferritinophagy by knocking down Ncoa4 alleviated cisplatin-induced ototoxicity. Importantly, nuciferine treatment mitigated cochlear hair cell loss and damage to ribbon synapse, and improved mouse hearing function in an acute cisplatin-induced hearing loss model. Our findings highlight the role of NCOA4-mediated ferritinophagy in the pathogenesis of cisplatin-induced ototoxicity and provide evidence for nuciferine as a promising protective agent for treating cisplatin-induced hearing loss. [ABSTRACT FROM AUTHOR]

Abstract Background Nuciferine (NUC), a natural compound extracted from lotus leaves, has been proven to have anti‐obesity effects. However, the development and application of NUC as an anti‐obesity drug in dogs are hindered due to its poor water solubility and low bioavailability. Objective To promote the development of NUC‐related products for anti‐obesity in dogs, this study prepared NUC into a liposome formulation and evaluated its characteristics, pharmacokinetics in dogs, and anti‐obesity effects on high‐fat diet dogs. Methods NUC liposomes were prepared by the ethanol injection method, using NUC, egg lecithin, and β‐sitosterol as raw materials. The characteristics and release rate in vitro of liposomes were evaluated by particle size analyser and dialysis method, respectively. The pharmacokinetics in dogs after oral administration of NUC‐liposomes was carried out by the high‐performance liquid chromatography (HPLC) method. Moreover, we investigated the anti‐obesity effect of NUC‐liposomes on obese dogs fed with a high‐fat diet. Results NUC‐liposome was successfully prepared, with an EE of (79.31 ± 1.06)%, a particle size of (81.25 ± 3.14) nm, a zeta potential of (–18.75 ± 0.23) mV, and a PDI of 0.175 ± 0.031. The cumulative release rate in vitro of NUC from NUC‐liposomes was slower than that of NUC. The T1/2 and relative bioavailability of NUC‐liposomes in dogs increased, and CL reduced compared with NUC. In addition, the preventive effect of NUC‐liposomes on obesity in high‐fat diet dogs is stronger than that of NUC. Conclusions The liposome formulation of NUC was conducive to improve its relative bioavailability and anti‐obesity effect in dogs.

Abstract The destruction of the microvascular structure and function can seriously affect the survival and prognosis of patients with acute myocardial infarction (AMI). Nuciferine has a potentially beneficial effect in the treatment of cardiovascular disease, albeit its role in microvascular structure and function during AMI remains unclear. This study aimed to investigate the protective effect and the related mechanisms of nuciferine in microvascular injury during AMI. Cardiac functions and pathological examination were conducted in vivo to investigate the effect of nuciferine on AMI. The effect of nuciferine on permeability and adherens junctions in endothelial cells was evaluated in vitro, and the phosphorylation level of the PI3K/AKT pathway (in the presence or absence of PI3K inhibitors) was also analyzed. In vivo results indicated that nuciferine inhibited ischemia-induced cardiomyocyte damage and vascular leakage and improved cardiac function. In addition, the in vitro results revealed that nuciferine could effectively inhibit oxygen–glucose deprivation (OGD) stimulated breakdown of the structure and function of human coronary microvascular endothelial cells (HCMECs). Moreover, nuciferine could significantly increase the phosphorylation level of the PI3K/AKT pathway. Finally, the inhibitor wortmannin could reverse the protective effect of nuciferine on HCMECs. Nuciferine inhibited AMI-induced microvascular injury by regulating the PI3K/AKT pathway and protecting the endothelial barrier function in mice.

Abstract High‐fat diets (HFDs) trigger oxidative stress, insulin resistance (IR), and inflammatory responses in the body, leading to cognitive dysfunction. This study aimed to elucidate the effects of nuciferine on HFD‐induced IR and cognitive impairment in the central nervous system of obese mice and further identify the possible underlying mechanisms. In behavioral experiments, nuciferine administration increased the total distance moved, the number of times mice entered the open arm, the duration of open dwell time, and the number of alternations while shortening the latency to escape. Nuciferine suppressed HFD‐induced synaptic structure damage, as evidenced by the increased expressions of neurotrophic factor BDNF and synaptic function proteins SYN, SNAP‐25, and PSD‐95. In addition, nuciferine effectively ameliorated HFD‐induced IR by IRS/PI3K/AKT pathway, alleviated HFD‐induced neurological damage through AMPK/SIRT1 pathway, and improved cognitive impairment via the Aβ‐tau‐neuroinflammation axis. Therefore, nuciferine could be a new food‐derived neuroprotective agent to counteract HFD‐induced damage.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by persistent synovial inflammation and joint degradation, posing challenges in the development of effective treatments. Nuciferine, an alkaloid found in lotus leaf, has shown promising anti-inflammatory and anti-tumor effects, yet its efficacy in RA treatment remains unexplored. This study investigated the antiproliferative effects of nuciferine on the MH7A cell line, a human RA-derived fibroblast-like synoviocyte, revealing its ability to inhibit cell proliferation, promote apoptosis, induce apoptosis, and cause G 1 /S phase arrest. Additionally, nuciferine significantly reduced the migration and invasion capabilities of MH7A cells. The therapeutic potential of nuciferine was further evaluated in a collagen-induced arthritis (CIA) rat model, where it markedly alleviated joint swelling, synovial hyperplasia, cartilage injury, and inflammatory infiltration. Nuciferine also improved collagen-induced bone erosion, decreased pro-inflammatory cytokines and serum immunoglobulins (IgG, IgG1, IgG2a), and restored the balance between T helper (Th) 17 and regulatory T cells in the spleen of CIA rats. These results indicate that nuciferine may offer therapeutic advantages for RA by decreasing the proliferation and invasiveness of FLS cells and correcting the Th17/Treg cell imbalance in CIA rats. [ABSTRACT FROM AUTHOR]

Abstract High‐fat diets (HFDs) can trigger lipid accumulation, insulin resistance, and inflammatory responses in the body, causing glucose and lipid metabolism dysfunction. This study aimed to explore the role of nuciferine on HFD‐induced disorders of glucose and lipid metabolism in obesity mice models, and further to identify the possible underlying mechanisms. In our experiments, nuciferine effectively ameliorated HFD‐induced insulin resistance by IRS/PI3K/AKT pathway, and alleviated HFD‐induced lipid accumulation via AMPK‐mediated regulation of FAS and ATGL expression. Nuciferine also suppressed HFD‐induced intestinal pathological damage, as evidenced by the improvement of intestinal barrier integrity and the increasing in expressions of tight junction proteins of claudin, ZO‐1, and occludin. In addition, 16S rRNA gene sequencing of the fecal microbiota suggested that nuciferine changed the diversity and the composition of gut microbiota in HFD‐fed mice. Nuciferine decreased the ratio of Firmicutes/Bacteroidetes, the relative abundance of LPS‐producing genus Desulfovibrio and the bacteria which involved in lipid metabolism. In summary, nuciferine ameliorated the disorders of glucose and lipid metabolism in obese mice via balancing the gut–liver axis.

Background: Lotus leaves are obtained from plants belonging to the genus Nelumbo in the Nymphaeaceae family. They serve both as agricultural produce and traditional Chinese medicinal herbs. Nuciferine, an amorphine alkaloid found in lotus leaves, holds significance due to its anti-inflammatory, lipid-lowering, and hypoglycemic properties. Objective: The factors influencing nuciferine extraction from lotus leaves using the dipping-acid-assisted ultrasonic extraction method (DAUEM) have received limited attention. This study aims to optimize DAUEM conditions (ethanol concentration, solvent-to-material ratio, and ultrasonic extraction time) through a Box-Behnken response surface design. Methods: Nuciferine purification from lotus leaves is achieved using D101 macroporous adsorptive resin. A single-factor test, with ethanol concentration (V/V), solvent-to-material ratio (V/M), and ultrasonic extraction time as variables, serves as a basis for optimizing the nuciferine extraction process via the response surface methodology. Results: The highest nuciferine yield (0.1035±0.005)% was obtained using 74% ethanol (V/V), a 26:1 solvent-to-material ratio, and an 82min extraction time. Nuciferine purity reached 67.14% using 70% ethanol as the eluent and high-performance liquid chromatography for determination. DAUEM effectively extracts nuciferine from lotus leaves, with optimization achieved using Box-Behnken response surface methodology. D101 macroporous adsorption resin efficiently separates and purifies nuciferine in lotus leaves. Conclusion: This experiment demonstrates good precision and accuracy, making it suitable for the extraction, separation, and purification of nuciferine in lotus leaves. The method lays the foundation for the development and utilization of nuciferine. [ABSTRACT FROM AUTHOR]

Nuciferine contained in lotus leaves have been confirmed to have the effect of ameliorating hyperlipemia and hyperglycemia. A laser scanning confocal microscope was used to track the translocation of glucose transporter 4 (GLUT4) in L6 cells and the changes in intracellular Ca2+ levels in real time, and related protease inhibitors combined with western blotting were used to explore the mechanism of nuciferine. Meanwhile, KK-Ay mice, the spontaneous type 2 diabetic mice, were used to evaluate the in vivo activity of nuciferine. In this study, the in vitro studies indicated that nuciferine-induced GLUT4 translocation was regulated by G protein-PLC-PKC and AMPK pathways and nuciferine-enhanced intracellular Ca2+ was mediated by G protein-PLC-IP3-IP3R pathway, the increase in intracellular Ca2+ caused by nuciferine was not directly related to GLUT4 translocation, but both promote glucose uptake. The in vivo results suggested that nuciferine ameliorated weight gain induced by high-fat diet, abnormal lipid metabolism and the symptoms of insulin resistance in KK-Ay diabetic mice. Western blot results suggested that nuciferine increased AMPK and PKC phosphorylation levels in skeletal muscle and liver, and enhanced GLUT4 expression in skeletal muscle. Taken together, this research showed that nuciferine has the non-negligible potential in the treatment of type 2 diabetes mellitus.

Cisplatin is a widely used antineoplastic drug for treating various types of cancers. However, it can cause severe side effects, such as bilateral and irreversible hearing loss, which significantly impacts quality of life. Ferroptosis, an iron-dependent form of programmed cell death, has been implicated in the pathogenesis of cisplatin-induced ototoxicity. Here, we investigated the effects of nuciferine, a natural active ingredient isolated from lotus species, on the ferroptosis of cochlear hair cells. Firstly, our results demonstrated that nuciferine can protect hair cells against RSL3-induced and cisplatin-induced damage. Secondly, nuciferine treatment reduced ferrous iron (Fe2+) overload in cochlear hair cells via inhibiting NCOA4-mediated ferritinophagy. Inhibition of ferritinophagy by knocking down Ncoa4 alleviated cisplatin-induced ototoxicity. Importantly, nuciferine treatment mitigated cochlear hair cell loss and damage to ribbon synapse, and improved mouse hearing function in an acute cisplatin-induced hearing loss model. Our findings highlight the role of NCOA4-mediated ferritinophagy in the pathogenesis of cisplatin-induced ototoxicity and provide evidence for nuciferine as a promising protective agent for treating cisplatin-induced hearing loss.

Background: Nuciferine's extensive therapeutic potential, including its robust antioxidant properties, is explored in response to the growing consumer preference for value-added organic foods. Objective: This study focuses on the formulation of gummy bear supplements fortified with nuciferine from Nelumbo nucifera. The research highlights nuciferine's ability to combat oxidative stress induced by reactive oxygen species (ROS) and examines its application in maintaining basal ROS levels during oxidative stress conditions in skin melanoma cells. Methods: Characterization of extracted nuciferine through FTIR and UV–vis spectroscopy ensures product quality, while sensory evaluation compares honey and sugar as natural sweeteners for optimal flavor and consumer preference. SK-Mel-28 cellular ROS levels were measured using 2′,7’ –dichlorofluorescin diacetate dye before and after nuciferine treatment. SK-Mel-28 cell viability and dose response of nuciferine treatment was assessed using MTT assay. Results: Nuciferine shows potent inhibition of SK-Mel-28 cell proliferation with an IC50 of 39.31 ± 5.280 μg/ml and showed no cytotoxicity in normal L6 skeletal muscle cells. This study compares the sensory properties of honey and sugar based gummy bear formulations. Conclusion: This project aims to create a high-quality, health-promoting dietary supplement that aligns with the evolving trends in organic nutrition and antioxidant supplementation.

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Pro-inflammatory factor-associated vascular cell adhesion molecule 1 (VCAM1) activation initiates cardiovascular events. This study aimed to explore the protective role of nuciferine on TNFa-induced VCAM1 activation. Nuciferine was administrated to both high-fat diet (HFD)-fed mice and the TNFa-exposed human vascular endothelial cell line. VCAM1 expression and further potential mechanism(s) were explored. Our data revealed that nuciferine intervention alleviated VCAM1 activation in response to both high-fat diet and TNFa exposure, and this protective effect was closely associated with autophagy activation since inhibiting autophagy by either genetic or pharmaceutical approaches blocked the beneficial role of nuciferine. Mechanistical studies revealed that Akt/mTOR inhibition, rather than AMPK, SIRT1, and p38 signal pathways, contributed to nuciferine-activated autophagy, which further ameliorated TNFa-induced VCAM1 via repressing AP1 activation, independent of transcriptional regulation by IRF1, p65, SP1, and GATA6. Collectively, our data uncovered a novel biological function for nuciferine in protecting VCAM1 activation, implying its potential application in improving cardiovascular events. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) poses a significant obstacle to the worldwide healthcare system. Discovering efficient and non-toxic medications is crucial for managing OSCC. Nuciferine, an alkaloid with an aromatic ring, is present in the leaves of Nelumbo nucifera. It has been proven to play a role in multiple biological processes, including the inhibition of inflammation, regulation of the immune system, formation of osteoclasts, and suppression of tumors. Despite the demonstrated inhibitory effects of nuciferine on different types of cancer, there is still a need for further investigation into the therapeutic effects and potential mechanisms of nuciferine in OSCC. Through a series of in vitro experiments, it was confirmed that nuciferine hindered the growth, movement, and infiltration, while enhancing the programmed cell death of OSCC cells. Furthermore, the administration of nuciferine significantly suppressed the signal transducer and activator of transcription 3 (STAT3) signaling pathway in comparison to other signaling pathways. Moreover, the activation of the STAT3 signaling pathway by colivelin resulted in the reversal of nuciferine-suppressed OSCC behaviors. In vivo, we also showed the anti-OSCC impact of nuciferine using the cell-based xenograft (CDX) model in nude mice. Nonetheless, colivelin diminished the tumor-inhibiting impact of nuciferine, suggesting that nuciferine might partially impede the advancement of OSCC by suppressing the STAT3 signaling pathway. Overall, this research could offer a fresh alternative for the pharmaceutical management of OSCC. [ABSTRACT FROM AUTHOR]

Objective: Chitosan-coated nuciferine liposomes (CS-LP) were prepared and their hypolipidemic effects in vivo were investigated. Methods: The CS-LP were prepared by thin film dispersion and pH gradient methods, and their particle size and potential distribution, encapsulation rate, microscopic morphology and in vitro release curves were determined, and their hypolipidemic effects on obese mice were investigated. Results: The CS-LP was produced in a homogeneous spherical structure with a particle size of 253.54±4.25 nm, a zeta potential of 32.50±3.44 mV. The encapsulation rate of CS-LP was 83.46%. Compared with nuciferine liposomes (LP), the stability of CS-LP in the simulated digestive solution was improved after adding the chitosan. Compared with the high-fat group, mice gavaged with CS-LP for 11 weeks showed a 12.91% and 41.03% significant reduction in body weight and adipose tissue weight, respectively (P

In order to optimize the process conditions of extracting the nuciferine in lotus leaves by cellulase enzymatic hydrolysis, the effects of the adding amount of cellulase, enzymatic temperature, enzymatic time and the ratio of liquor to material on the extraction rate of nuciferine in lotus leaves were investigated by using the method of combining the single factor test and orthogonal test. The best technological conditions for the extraction of nuciferine in lotus leaves by cellulase were as follows: the adding amount of cellulase was 2. 3 mg • g-1, the enzymatic temperature was 50°C, the enzymatic time was 55 min, and the ratio of liquor to material (mL/g) was 30:1. Under these conditions, the extraction rate of nuciferine in lotus leaves could be as high as 0. 67%. The research results could provide positive reference value for the subsequent development and utilization of nuciferine in lotus leaves. [ABSTRACT FROM AUTHOR]

Erhuangquzhi granules (EQG) have been clinically proven to be effective in nonalcoholic steatohepatitis (NASH) treatment. However, the active components and molecular mechanisms remain unknown. This study aimed to screen active components targeting tumor necrosis factor α (TNF-α) in EQG for the treatment of NASH by a surface plasmon resonance (SPR) biosensor–based active ingredient recognition system (SPR–AIRS). The amine-coupling method was used to immobilize recombinant TNF-α protein on an SPR chip, the specificity of the TNF-α-immobilized chip was validated, and nine medicinal herbs in EQG were prescreened. Nuciferine (NF), lirinidine (ID), and O-nornuciferine (NNF) from lotus leaves were found and identified as TNF-α ligands by UPLC‒MS/MS, and the affinity constants of NF, ID, and NNF to TNF-α were determined by SPR experiments (Kd = 61.19, 31.02, and 20.71 µM, respectively). NF, ID, and NNF inhibited TNF-α-induced apoptosis in L929 cells, the levels of secreted IL-6 and IL-1β were reduced, and the phosphorylation of IKKβ and IκB was inhibited in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. In conclusion, a class of new active small-molecule TNF-α inhibitors was discovered, which also provides a valuable reference for the material basis and mechanism of EQG action in NASH treatment. [ABSTRACT FROM AUTHOR]

An efficient and sustainable expanded‐bed adsorption (EBA) method was developed for the valorization of lotus leaf which is an agricultural by‐product. The in‐situ procedure was used to reduce the energy consumption of EBA. Comparing this in‐situ process to the conventional one, some additional advantages were observed, namely, significant enhancement of nuciferine recovery, considerable reduction of processing time, etc. Furthermore, a multistage procedure was investigated to reduce running cost and minimize environmental pollution by reusing solvents and adsorbents. Reusing of D101 macroporous resin, HCl and NaOH solution had almost no influence on the yield of nuciferine. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose still poses a major clinical challenge and is a leading cause of acute liver injury (ALI). N-acetylcysteine (NAC) is the only approved antidote to treat APAP toxicity while NAC therapy can trigger side effects including severe vomiting and even shock. Thus, new insights in developing novel therapeutic drugs may pave the way for better treatment of APAP poisoning. Previous research has reported that nuciferine (Nuci) possesses anti-inflammatory and antioxidant properties. Therefore, the objective of this study was proposed to investigate the hepatoprotective effects of Nuci and explore its underlying mechanisms. Mice were intraperitoneally (i.p.) administered with APAP (300 mg/kg) and subsequently injected with Nuci (25, 50, and 100 mg/kg, i.p.) at 30 min after APAP overdose. Then, all mice were sacrificed at 12 h after APAP challenge for further analysis. Nuci-treated mice did not show any side effects and our results revealed that treating Nuci significantly attenuated APAP-induced ALI, as confirmed by histopathological examinations, biochemical analysis, and diminished hepatic oxidative stress and inflammation. The in silico prediction and mRNA-sequencing analysis were performed to explore the underlying mechanisms of Nuci. GO and KEGG enrichment of the predicted target proteins of Nuci includes reactive oxygen species, drug metabolism of cytochrome P450 (CYP450) enzymes, and autophagy. Furthermore, the mRNA-sequencing analyses indicated that Nuci can regulate glutathione metabolic processes and anti-inflammatory responses. Consistently, we found that Nuci increased the hepatic glutathione restoration but decreased APAP protein adducts in damaged livers. Western blot analysis further confirmed that Nuci effectively promoted hepatic autophagy in APAP-treated mice. However, Nuci could not affect the expression levels of the main CYP450 enzymes (CYP1A2, CYP2E1, and CYP3A11). These results demonstrated that Nuci may be a potential therapeutic drug for APAP-induced ALI via amelioration of the inflammatory response and oxidative stress, regulation of APAP metabolism, and activation of autophagy. [ABSTRACT FROM AUTHOR]

Nuciferine aporphine alkaloid mainly exists in Nelumbo nucifera Gaertn and is a beneficial to human health, such as anti-obesity, lowering blood lipid, prevention of diabetes and cancer, closely associated with inflammation. Importantly, nuciferine may contribute to its bioactivities by exerting intense anti-inflammatory activities in multiple models. However, no review has summarized the anti-inflammatory effect of nuciferine. This review critically summarized the information regarding the structure-activity relationships of dietary nuciferine. Moreover, biological activities and clinical application on inflammation-related diseases, such as obesity, diabetes, liver, cardiovascular diseases, and cancer, as well as their potential mechanisms, involving oxidative stress, metabolic signaling, and gut microbiota has been reviewed. The current work provides a better understanding of the anti-inflammation properties of nuciferine against multiple diseases, thereby improving the utilization and application of nuciferine-containing plants across functional food and medicine.

Objectives: Nocturia was commonly treated with drugs burdened with high costs and numerous side effects; in fact, more than 70% of patients drop out of long-term treatment. Protopine and nuciferine are two alkaloids that have different effects on the neurotransmitter receptors involved in the regulation mechanism of the onset of urinary stimuli. The aim of the study was to evaluate the efficacy in controlling primarily nocturia and secondarily urgency and dysuria after 3 months of treatment with combination therapy of protopine and nuciferine syrup. Design: This is a prospective cohort study in which all patients were diagnosed with overactive bladder syndrome (OAB) and the presence of the following symptoms: nocturia, urgency, and dysuria. Thirty patients were administered 10 mL/die (16.6 mg of nuciferine, 0.09 mg of protopine) of syrup for 3 months. Patients were evaluated at baseline (T0) with the International Consultation on Incontinence Questionnaire (ICIQ), Visual Analogue Scale (VAS) for the evaluation of dysuria, Patient Perception of Intensity of Urgency Scale (PPIUS) and at 3 months (T1) with the Patients' Global Impression of Change (PGI-C) scale, PPIUS, VAS, and ICIQ. Participants: Women with diagnosis of OAB; the presence of nocturia, urgency, and dysuria symptoms agreeing to undergo treatment and compiling informed consent; and the absence of contraindications to the use of active ingredients were included in the study. Setting: Patients were recruited at T0 during the visit to the Uro-Gynecology clinic of the University of "Campus Bio-Medico" and visited again 3 months (T1) after the initiation of therapy. Methods: We explored survey data by descriptive statistics: in particular, continuous values (i.e., ICIQ) have been summarized by mean and standard deviation of discrete ordinal values (i.e., VAS, PPIUS, and bladder diary parameters at T0 and T1) by median, minimum, and maximum reported scores. Where we could assume normality in distribution, assessed by the Shapiro-Wilk test and the evaluation of the QQ plot, we compared the observation of T0 and T1 with the paired Student's t test; otherwise, we tested differences in distribution with the paired Mann-Whitney U test. Results: Thirty patients completed a 3-month therapy. The ICIQ and VAS questionnaires for the assessment of dysuria, both, reported an improvement in dysuria at T1 (p < 0.001). The PPIUS questionnaire reported an improvement in urinary urgency at T1 (p < 0.001). The PGI-C scale in T1 indicated an improvement in symptoms: 93% for nocturia, 70% for urinary urgency, and 63% for dysuria. Limitations: The weaknesses of this study are the small number of patients; as a pilot study, the study design was not randomized with a placebo and without blinding; and the short follow-up. Conclusions: Protopine and nuciferine can be an interesting alternative to primarily treat and reduce nocturia episodes, in addition to improving OAB-related urgency and dysuria. [ABSTRACT FROM AUTHOR]

Human dermal fibroblasts play an important role in skin homeostasis by producing and degrading extracellular matrix components. They have more replicative senescence when exposed to environmental and oxidative insults, resulting in human skin aging. However, this phenomenon can be mitigated by antioxidant phytochemicals. The aim of the present study was to investigate the potential of nuciferine (an alkaloid from Nelumbo nucifera leaf) in preventing stress-induced fibroblast senescence by using a hydrogen-peroxide (H2O2)-induced senescence model. We found that H2O2 treatment resulted in a significant increase in senescence-associated β-galactosidase (SA-β-gal)-positive cells. Nuciferine-treated cells, however, showed a reduction in senescent phenotype. Furthermore, we observed the key molecular markers including the senescence-associated secretory phenotype (SASP) and cell cycle regulators. The mRNA levels of CXCL1, CXCL2, IL-6, and IL-8 (pro-inflammatory cytokines) reduced significantly in nuciferine-treated cells. The extracellular IL-6 and IL-8 levels were also decreased in treated cells, whereas the key cell cycle regulators (p16 and p21) were markedly affected by nuciferine at the highest concentration. The results of the present study clearly show that the preventive activity of nuciferine against H2O2-induced senescence in dermal fibroblasts is fundamental and promising for further applications in anti-aging product research and development. [ABSTRACT FROM AUTHOR]

Nuciferine, isolated from Nelumbo nucifera (commonly known as lotus) leaves, has been shown to have beneficial effects, including antioxidant, anti-obesity, anti-diabetic, and anti-inflammatory properties. However, little is known about the mechanism of nuciferine action on the inflammatory response. This study aimed to investigate the anti-inflammatory effects of nuciferine and its underlying molecular mechanisms in lipopolysaccharide (LPS)-stimulated murine macrophages. In this study, nuciferine reduced LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production and mRNA expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2. Nuciferine also decreased the production of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Furthermore, nuciferine inhibited the LPS-mediated transcriptional activity of nuclear factor (NF)-κB and activator protein (AP)-1, and the nuclear translocation of NF-κB p65 and activating transcription factor 2 (ATF2), an AP-1 subunit. Nuciferine also decreased the phosphorylation of IκB kinase (IKK), inhibitor of NF-κB (IκB), NF-κB, mitogen-activated protein kinase 3 (MKK3), MKK6, p38 mitogen-activated protein kinase (MAPK), and ATF2. Overall, our findings suggest that nuciferine may exert anti-inflammatory effects in LPS-induced macrophages by inhibiting the NF-κB and p38 MAPK/ATF2 signaling pathways. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is an inflammatory condition primarily affecting the joints. Nuciferine (NCF), a key bioactive aporphine alkaloid biosynthesized in lotus leaves, exhibits promising anti-inflammatory and antioxidant properties. In this study, we investigated whether NCF could alleviate inflammatory arthritis conditions in a complete Freund's adjuvant (CFA)-mediated arthritis model in rats. The arthritis model was established through intradermal injection of CFA (100 μL) in the sub-plantar region of the right hind paw. The arthritic animals were treated orally with NCF at 5 and 10 mg/kg and indomethacin (Indo) at 5 mg/kg body weight as reference control. NCF treatment remarkably alleviated inflammatory joint swelling and arthritic index. The radiological and histological analysis revealed evidence of the beneficial effects of NCF. NCF treatment decreased the content of pro-inflammatory cytokines (TNF-α and IL-1β) and myeloperoxidase (MPO) activity and restored the anti-inflammatory cytokine (IL-10) in the paw joints. The serum levels of pro-inflammatory cytokines were also markedly reduced in the NCF (10 mg/kg) treatment group. Moreover, the arthritis-induced inflammatory mediators, including cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) and the toll-like receptor (TLR)-4, mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signaling proteins were substantially decreased in the NCF treatment groups. NCF treatment also restored the antioxidant defense enzymes and abrogated lipid peroxidation in the paw tissue. Our findings strongly suggest that NCF is a promising therapeutic molecule for rheumatoid arthritis, inspiring further research, and development in this area. [Display omitted] • Nuciferine alleviated adjuvant-induced arthritis in rats. • Nuciferine substantially decreased inflammation in the paw joints. • Nuciferine interferes with TLR-4/MAPK/NF-κB signaling proteins in the paw tissues. • Nuciferine treatment restored the antioxidant defense in the paw tissue. • Nuciferine could be a promising therapeutic molecule for rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

The leaves of Nelumbo nucifera Gaertn. Are recorded in the earliest written documentation of traditional Chinese medicinal as "Ben Cao Gang Mu", a medicinal herb for blood clotting, dysentery and dizziness. Nuciferine, one of N. nucifera Gaertn. leaf extracts, has been shown to possess several pharmacological properties, including but not limited to ameliorating hyperlipidemia, stimulating insulin secretion, inducing vasodilation, reducing blood pressure, and demonstrating anti-arrhythmic properties. In light of the latest research findings on nuciferine, this article provides a comprehensive overview of its chemical properties, pharmacological activities, and the underlying regulatory mechanisms. It aims to serve as a dependable reference for further investigations into the pharmacological effects and mechanisms of nuciferine. Use Google Scholar, Scifinder, PubMed, Springer, Elsevier, Wiley, Web of Science and other online database search to collect the literature on extraction, separation, structural analysis and pharmacological activity of nuciferine published before November 2023. The key words are "extraction", "isolation", "purification" and "pharmacological action" and "nuciferine". Nuciferine has been widely used in the treatment of ameliorating hyperlipidemia and lose weight, Nuciferine is a monomeric aporphine alkaloid extracted from the leaves of the plant Nymphaea caerulea and Nelumbo nucifera Gaertn. Nuciferine has pharmacological activities such as relaxing smooth muscles, improving hyperlipidemia, stimulating insulin secretion, vasodilation, inducing hypotension, antiarrhythmic effects, and antimicrobial and anti-HIV activities. These pharmacological properties lay a foundation for the treatment of tumors, inflammation, hyperglycemia, lipid-lowering and weight-loss, oxidative stress and other diseases with nuciferine. Nuciferine has been clinically used to treat hyperlipidemia and aid in weight loss due to its effects on lipid levels, insulin secretion, vasodilation, blood pressure reduction, anti-tumor properties, and immune enhancement. However, other potential benefits of nuciferine have not yet been fully explored in clinical practice. Future research should delve deeper into its molecular structure, toxicity, side effects, and clinical pharmacology to uncover its full range of effects and pave the way for its safe and expanded clinical use. • In This review covers pharmacology, and regulatory mechanisms comprehensively. • This review will facilitate further research and development of the nuciferine. • This review will and provide theoretical references for subsequent researchers. • This review boosts nuciferine's impact in pharmaceuticals and health products. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) poses a significant obstacle to the worldwide healthcare system. Discovering efficient and non-toxic medications is crucial for managing OSCC. Nuciferine, an alkaloid with an aromatic ring, is present in the leaves of Nelumbo nucifera. It has been proven to play a role in multiple biological processes, including the inhibition of inflammation, regulation of the immune system, formation of osteoclasts, and suppression of tumors. Despite the demonstrated inhibitory effects of nuciferine on different types of cancer, there is still a need for further investigation into the therapeutic effects and potential mechanisms of nuciferine in OSCC. Through a series of in vitro experiments, it was confirmed that nuciferine hindered the growth, movement, and infiltration, while enhancing the programmed cell death of OSCC cells. Furthermore, the administration of nuciferine significantly suppressed the signal transducer and activator of transcription 3 (STAT3) signaling pathway in comparison to other signaling pathways. Moreover, the activation of the STAT3 signaling pathway by colivelin resulted in the reversal of nuciferine-suppressed OSCC behaviors. In vivo, we also showed the anti-OSCC impact of nuciferine using the cell-based xenograft (CDX) model in nude mice. Nonetheless, colivelin diminished the tumor-inhibiting impact of nuciferine, suggesting that nuciferine might partially impede the advancement of OSCC by suppressing the STAT3 signaling pathway. Overall, this research could offer a fresh alternative for the pharmaceutical management of OSCC.

Ischemic heart disease and myocardial infarction contribute to the leading cause of death in worldwide. The prevention and management of myocardial ischemia/reperfusion (I/R) injury is an essential part of coronary heart disease surgery and is becoming a major clinical problem in the treatment of ischemic heart disease. Nuciferine has potent anti-inflammatory and antioxidative stress effects, but its role in myocardial ischemia-reperfusion (I/R) is unclear. In this study, we found that nuciferine could reduce the myocardial infarct size in a mouse myocardial ischemia-reperfusion model and improve cardiac function. Furthermore, nuciferine could effectively inhibit hypoxia and reoxygenation (H/R) stimulated apoptosis of primary mouse cardiomyocytes. In addition, nuciferine significantly reduced the level of oxidative stress. The peroxisome proliferator-activated receptor gamma (PPAR-γ) inhibitor GW9662 could reverse the protective effect of nuciferine on cardiomyocytes. These results indicate that nuciferine can inhibit the apoptosis of cardiomyocytes by upregulating PPAR-γ and reducing the I/R-induced myocardial injury in mice.

This study aims to enhance the stability and bioavailability of nuciferine (NF) and epigallocatechin-3-gallate (EGCG) by loading NF into liposomes and then incorporating the liposomes and EGCG into porous microgels (NFEG-microgel) prepared with chitosan and proanthocyanidin. Analysis of particle size (0.5–3.0 μm), electron microscopy, rheology, stability, and simulated gastrointestinal release confirmed that the prepared microgels had high encapsulation rate and good stability and release characteristics. Intervention experiments were performed by orally administering NFEG-microgel to high-fat diet rats to evaluate its efficacy and regulatory mechanism for blood lipid metabolism. NFEG-microgel intervention significantly reduced the body weight and serum lipid level, and the mechanism was related to the expression regulation of key genes involved in lipid metabolism and miRNAs (miR-126a-5p and miR-30b-5p) in serum extracellular vesicles. In addition, NFEG-microgel improved the diversity of gut microbiota by enriching short-chain fatty acids (SCFA)-producing bacteria and reducing harmful bacteria, suggesting that it can ameliorate lipid metabolism by regulating the intestinal flora community in rats.

Lotus (Nelumbo nucifera) leaves are widely used for both edible and medicinal applications. For its further utilization, we studied the vasodilatory activity of lotus leaf extract for the first time. In this study, we obtained the extracts using different ratios of water and ethanol, which was followed by polarity-dependent extraction. We found that the CH2Cl2 layer exhibited better vasodilatory activity (EC50 = 1.21 ± 0.10 µg/ml). HPLC and ESI-HRMS analysis of the CH2Cl2 layer using the standard product as a control revealed that nuciferine (Emax = 97.95 ± 0.76%, EC50 = 0.36 ± 0.02 µM) was the main component in this layer. Further research revealed that nuciferine exerts a multi-target synergistic effect to promote vasodilation, via the NO signaling pathway, K+ channel, Ca2+ channel, intracellular Ca2+ release, α and β receptors, etc. Nuciferine exhibits good vasodilatory activity, and it exhibits the potential to be utilized as a lead compound. [ABSTRACT FROM AUTHOR]

The present study is aimed to determine the efficacy and dose response of the nuciferine (1), norcoclaurine (2) and crude extract of Nelumbo nucifera in managements of diabetes, Alzheimer disease and related allergies. Experimentally, alloxan (100 mg/kg body weight (b.w.))-induced diabetic rats (200–250 g) were divided into seven groups (n = 6). Group I: normal control, Group II: diabetic control, Group III: standard treated with glibenclamide and Group lV-VII: treated with methanolic crude extracts (100, 200 mg/kg), nuciferine and norcoclaurine (10 mg/kg b.w.) for 15 days. Different tests were performed, including blood glucose, body weights and antioxidant enzyme assays, i.e., superoxide dismutase (SOD), catalase test (CAT), lipid peroxidation assay (TBARS), glutathione assay (GSH) and acetylcholinesterase (AChE) assay. Nuciferine and norcoclaurine significantly reduced blood glucose (p < 0.05) and restored body weight in diabetic rats. Moreover, nuciferine and norcoclaurine (10 mg/kg) significantly recovered the antioxidant enzymes (SOD, CAT, GPx and GSH) which decreased during induced diabetes. Significant increase in TBARS was also observed in the diabetic group and nuciferine as well as norcoclaurine (10 mg/kg) inhibited the increase in TBARS in diabetic animals (p < 0.05), as compared to glibenclamide. AChE activity was significantly recovered by nuciferine and norcoclaurine (10 mg/kg) both in the blood and brain of the diabetic group (p < 0.05). Nuciferine and norcoclaurine showed potent inhibitory effects against α-glucosidase and α-amylase with IC50, 19.06 ± 0.03, 15.03 ± 0.09 μM and 24.07 ± 0.05, 18.04 ± 0.021 μM, as confirmed by molecular docking studies. This study concludes that nuciferine and norcoclaurine significantly improve memory and could be considered as an effective phytomedicine for diabetes, Alzheimer's disease (AD) and oxidative stress. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) causes significant global mortality and healthcare costs with no recommended pharmacological intervention for clinical management. Nuciferine (Nuc) is an alkaloid with aromatic rings, abundantly found in Nelumbo nucifera Gaertn . In this study, we explored the protective mechanisms of Nuc against hepatic steatosis and ferroptosis in NAFLD. High-fat diet (HFD) and healthy male ApoE -/- mice were used to induce NAFLD and a hypercholesterolemia model. Nuc was administered to the mice for four consecutive weeks from the ninth week. Various assessments, including histopathology, RNA sequencing, lipid metabolism, and ferroptosis-related protein expression, showed that Nuc alleviated hepatic steatosis and ferroptosis. We further showed that Nuc improves fatty acid accumulation and ferroptosis through the PPARα signaling pathway in mice and RSL3-treated AML-12 cells. The PPARα inhibitor GW6471 blocked Nuc's protective effects, leading to excess accumulation of iron ions. Thus, Nuc may be a potential therapeutic agent for NAFLD.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that can cause menstrual irregularities, infertility, polycystic ovaries, and metabolic abnormalities. Female reproductive health and quality of life are significantly affected by PCOS, which has recently been associated with ferroptosis in granulosa cells (GCs). Nuciferine (NF) is a naturally extracted substance with multiple pharmacological activities, which is reported with anti-ferroptosis function. Herein, the influence of NF for androgen-induced ferroptosis in GCs was investigated to explore the potential value of NF on treating PCOS. 10 μM NF and 20 μM NF were employed for treating KGN cells according to cell viability results. KGN cells were treated with 10 μM dehydroepiandrosterone (DHEA) for 1 day, followed by introducing 10 μM NF and 20 μM NF for 24 h. Strikingly reduced cell viability, increased lactate dehydrogenase release and reactive oxygen species (ROS) production, enhanced apoptosis, upregulated Bax, downregulated Bcl-2, restrained malondialdehyde contents, and declined superoxide dismutase activity were observed in DHEA-treated KGN cells, which were significantly reversed by NF. Significantly repressed GPX4, SLC7A11, and SOX2 levels, as well as increased ACSL4 levels and Fe 2+ levels in DHEA-treated KGN cells, were notably rescued by NF. Furthermore, the inhibitory effect of NF on ROS production and ferroptosis in DHEA-treated KGN cells was partially abrogated by silencing SOX2. Collectively, NF protected DHEA-injured ovarian GCs by inhibiting ferroptosis via upregulating SOX2., (© 2024 John Wiley & Sons, Ltd.)

The study explored the cardioprotective role of the methanolic leaf extract of Nelumbo nucifera and nuciferine against isoproterenol‐induced myocardial infarction (MI) in Wistar rats. Pretreatment with leaf extract and nuciferine (200 and 20 mg/kg body weight, respectively) against MI induced by isoproterenol (85 mg/kg body weight) significantly decreased heart weight; levels of cardiac markers such as lactate dehydrogenase and creatine kinase‐MB were similar to those in controls. The treatment significantly increased the content of endogenous antioxidants and decreased lipid peroxidation in all treated groups. Treated groups showed a significant reduction in heartbeats per minute as compared with the MI‐induced positive control. The MI‐induced group showed pathological implications such as tachycardia, left atrial enlargement, and anterolateral ST‐elevated MI, which were absent in treated groups. Histology confirmed that the leaf extract and nuciferine prevented structural abnormality and inflammation in heart and liver tissues of treated groups. On in silico analysis, nuciferine showed stronger binding interaction with both β1 and β2 adrenergic receptors than isoproterenol. Hence, the leaf extract of N. nucifera and nuciferine could be used as plant‐based cardioprotective agents. [ABSTRACT FROM AUTHOR]

Introduction: Folium nelumbinis is used as vegetable, functional food and herbal medicine in Asia. p‐Sulfonatocalix[6]arene (SC6A) is a water‐soluble supramolecular macrocycle and has never been applied to the extraction of herbal products. Objective: In this study, SC6A‐assisted extraction of nuciferine from Folium nelumbinis has been carried out to develop an eco‐friendly extraction process with high extraction efficacy and easy operation. Methods: Single‐factor experiments were adopted to obtain the optimal conditions for the SC6A‐assisted extraction of nuciferine from Folium nelumbinis, and then nuciferine and SC6A were separated easily by one‐step alkalization. The host–guest complexes between nuciferine and SC6A were analyzed by competitive fluorescence titration, DSC, FT‐IR and 1H‐NMR. Results: The optimal SC6A/Folium nelumbinis/solution ratio for extraction was 0.4:1:20 (g/g/mL), with a granulometric fraction below 180 μm and an extraction time of 1 h with soaking. The purity and recovery of nuciferine extracted with SC6A were increased 29.24 and 35.73 times compared with extraction with aqueous solution, respectively. Moreover, a good reusability of SC6A in the extraction of nuciferine was demonstrated. Competitive fluorescence titration, DSC, FT‐IR and 1H‐NMR characterization indicated that SC6A could form host–guest complexes with nuciferine at a ratio of 1:1. Conclusion: The study provided an eco‐friendly, safe and effective nuciferine extraction method, which can be used for the development of nutrition supplements containing nuciferine. SC6A‐assisted extraction of nuciferine from Folium nelumbinis has been carried out to develop an eco‐friendly, safe and effective nuciferine extraction method. The host‐guest complexes between nuciferine and SC6A were analyzed by competitive fluorescence titration, DSC, FT‐IR and 1H‐NMR. A good reusability of SC6A in the extraction of nuciferine was demonstrated. [ABSTRACT FROM AUTHOR]

• Nuciferine(Nuc) exerts anti-inflammatory and ameliorate the degradation of extracellular matrix in IL-1β-induced chondrocytes. • Nuciferine(Nuc) mitigates the progression of osteoarthritis in a mouse model. • Nuciferine(Nuc) exerts a protective effect on chondrocytes by activating the PTEN/AKT/NF-κB signaling pathway. Osteoarthritis (OA) is the most common musculoskeletal disease and a leading cause of pain and disability. A key hallmark of OA is cartilage degradation, which occurs due to an imbalance between the synthesis and degradation of the extracellular matrix (ECM). Interleukin-1β(IL-1β) has been reported to regulate ECM metabolism. Nuciferine (Nuc), a natural peptide extracted from the lotus leaf, possesses several significant pharmacological properties. However, the anti-inflammation of Nuc in OA has not been reported. In this study, ELISA and Western blot analyses were used to measure the production of inflammatory mediators in IL-1β-Induced mouse chondrocytes. Additionally, mice with or without surgical destabilization of the medial meniscus (DMM) were treated with intra-articular injection of Nuc. We found that Nuc significantly reduces the level of iNOS, PEG2, and IL-6 in IL-1β-induced chondrocytes. Furthermore, Nuc can ameliorate the development of OA in mice. Mechanistically, we found that the chondrocyte-protective effects of Nuc occur via the PTEN/NF-κB pathway. These findings suggest that Nuc could be a potential therapeutic agent for improving OA development. [ABSTRACT FROM AUTHOR]

We investigated the effects of nuciferine rich in Lotus leaf on the amelioration of hepatic steatosis and dyslipidemia of hyperlipidemic rats, and explored the underlying mechanism on miRNAs and genes expression. Serum extracellular vesicles (EVs) from rats were prepared and characterized, and interactions between miRNAs and target mRNAs were validated in 293T cell line with the double luciferase reporter gene assay. Results showed that nuciferine significantly induced the expression of PPARα, ABCA1, CYP7A1, LXRα in liver and ABCG5 in intestine, while NPC1L1 expression was markedly reduced. In vitro, double luciferase reporter assays showed that miRNA-764-5p, miRNA-758-3p, and miRNA-126-5p interacted with the target mRNAs of PPARα, ABCA1, and CYP7A1, respectively. And the effect of nuciferine on lipid metabolism in rats was related to regulate intestinal absorption and serum EVs miRNAs. These miRNAs were able to reduce lipid levels by targeting lipid metabolism genes and up-regulating PPARα-LXRα-ABCA1 pathway and CYP7A1 expression.

Nuciferine, a major aporphine alkaloid obtained from the leaves of Nelumbo nucifera, exhibits anti-cancer and anti-inflammatory properties; however, its protective effects against inflammatory bowel diseases (IBD) has never been explored. In this study, an ulcerative colitis (UC) model was established in BALb/c mice by the continuous administration of 5% dextran sulfate sodium (DSS) in drinking water for 1 week. From day 8 to day 14, the DSS-treated mice were divided into a high-dose and a low-dose nuciferine treatment group and were intraperitoneally injected with the corresponding dose of the drug. Body weight loss, disease activity index (DAI), and colon length were measured. Histological changes were observed using hematoxylin and eosin staining. T lymphocyte proliferation was assessed by MTT assay. The ratio of CD3+, CD4+, CD8+, Th1, Th2, Th17, and Treg cells were estimated by flow cytometry. Finally, 16S rRNA sequencing was performed to compare the composition and relative abundance of the gut microbiota among the different treatment groups. The results showed that nuciferine treatment led to a significant improvement in symptoms, such as histological injury and colon shortening in mice with DSS-induced UC. Nuciferine treatment improved the Th1/Th2 and Treg/Th17 balance in the DSS-induced IBD model, as well as the composition of the intestinal microflora. At the phylum level, compared with the control group, the abundance of Firmicutes and Actinobacteriota was decreased in the model group, whereas that of Bacteroidetes increased. Meanwhile, at the genus level, compared with the control group, the numbers of the genera Lachnospiraceae_Clostridium, Bilophila and Halomonas reduced in the model group, while those of Bacteroides, Parabacteroides, and Paraprevotella increased. Notably, nuciferine administration reversed this DSS-induced gut dysbiosis. These results indicated that nuciferine modulates gut microbiota homeostasis and immune function in mice with DSS-induced UC.

Acetaminophen (APAP) overdose still poses a major clinical challenge and is a leading cause of acute liver injury (ALI). N-acetylcysteine (NAC) is the only approved antidote to treat APAP toxicity while NAC therapy can trigger side effects including severe vomiting and even shock. Thus, new insights in developing novel therapeutic drugs may pave the way for better treatment of APAP poisoning. Previous research has reported that nuciferine (Nuci) possesses anti-inflammatory and antioxidant properties. Therefore, the objective of this study was proposed to investigate the hepatoprotective effects of Nuci and explore its underlying mechanisms. Mice were intraperitoneally (i.p.) administered with APAP (300 mg/kg) and subsequently injected with Nuci (25, 50, and 100 mg/kg, i.p.) at 30 min after APAP overdose. Then, all mice were sacrificed at 12 h after APAP challenge for further analysis. Nuci-treated mice did not show any side effects and our results revealed that treating Nuci significantly attenuated APAP-induced ALI, as confirmed by histopathological examinations, biochemical analysis, and diminished hepatic oxidative stress and inflammation. The in silico prediction and mRNA-sequencing analysis were performed to explore the underlying mechanisms of Nuci. GO and KEGG enrichment of the predicted target proteins of Nuci includes reactive oxygen species, drug metabolism of cytochrome P450 (CYP450) enzymes, and autophagy. Furthermore, the mRNA-sequencing analyses indicated that Nuci can regulate glutathione metabolic processes and anti-inflammatory responses. Consistently, we found that Nuci increased the hepatic glutathione restoration but decreased APAP protein adducts in damaged livers. Western blot analysis further confirmed that Nuci effectively promoted hepatic autophagy in APAP-treated mice. However, Nuci could not affect the expression levels of the main CYP450 enzymes (CYP1A2, CYP2E1, and CYP3A11). These results demonstrated that Nuci may be a potential therapeutic drug for APAP-induced ALI via amelioration of the inflammatory response and oxidative stress, regulation of APAP metabolism, and activation of autophagy.

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The purpose of this study was to investigate whether dietary nuciferine affects lipid metabolism in broiler chickens. Four treatment groups were made from 120 1-day-old broiler chickens including the base diet group (normal control [NC], supplemented with 0 mg/kg of nuciferine) and groups treated with 25 mg/kg, 100 mg/kg, and 400 mg/kg of dietary nuciferine, which was supplemented for 42 d. The results showed that body weight, average daily weight gain, and absolute and relative fat and liver weight were significantly decreased with nuciferine supplementation. The plasma concentration of triiodothyronine, free triiodothyronine, thyroxine, and free thyroxine was significantly decreased in the nuciferine-supplemented group, but the plasma glucagon concentration was significantly increased. The plasma and hepatic triglyceride (TG) and total cholesterol (TC) concentrations were significantly decreased in the nuciferine group, but plasma and hepatic nonesterified fatty acid concentration, hepatic lipase activity, and hepatic glycogen content were significantly increased. Hepatic histological examination showed that fat cell volume and size in the 100 and 400 mg/kg group were smaller than those in the NC group. The fatty degeneration in the liver was decreased with nuciferine supplementation. The fat cell volume and size were shrunk in the nuciferine group. Dietary nuciferine supplementation significantly decreased the gene expression level of HMGCR, SREBP2, ACC, and SPEBP-1C, but significantly increased the gene expression level of LXR-α, CYP7A1, and CPT-I. The results indicated that nuciferine exhibited strong reduced fat deposition activities and reflected not only by decrease of the concentration of TG and TC but also by reduction in the key gene expression level of HMGCR, SREBP2, ACC, and SPEBP-1c and elevation of the key gene expression level of LXR-α, CYP7A1, and CPT-I. Taken together, our results suggested that the ability of nuciferine on reducing fat deposition in broiler chickens by regulating lipid metabolism was associated with the balance of TG and TC concentration.

Nuciferine is an important drug candidate for the treatment of many diseases. However, there is no general method for its low - cost production. In this work, a feasible method for the production of nuciferine from lotus leaf, using ultrasonic-assisted extraction-solid phase extraction (UAE-SPE) as extraction and cleanup procedure, was developed. Petroleum ether and silica gel have been successfully used as extraction solvent and adsorbent to integrate UAE with SPE, respectively. Except for filtration, no treatment (e.g. concentration and redissolution, etc) was needed on UAE extract before SPE and the effluents obtained in the loading process of SPE could be used as UAE extraction solvent without purification. No obvious decline in the extraction efficiency of UAE and adsorption capacity of SPE was observed at least for 5 runs, which provides a feasible way for the continuous production of nuciferine in industry, i.e. Cyclic UAE-SPE. Moreover, SPE column could be conveniently regenerated and reused without significant decline in its adsorption capacity at least for 5 cycles, which can be used to reduce the cost of the whole system further. In comparison with other cleanup procedures, Cyclic UAE-SPE showed apparent advantages in energy conservation and emission reduction. LLE and crystallization were applied to separate nuciferine from other impurities further. Under optimum conditions, the total recovery rate of nuciferine with a purity over 90.0% from lotus leaf reached 50.1%. All in all, the developed method has advantages in convenient operation, low cost, and high efficiency, thus, is fitting for the production of high purity nuciferine.

Nonalcoholic fatty liver disease (NAFLD) has been demonstrated to be closely associated with intestinal barrier functions. The aim of this study is to investigate the effects of nuciferine on preventing hepatic steatosis with relation to intestinal barrier functions in HFD-fed rats. The results showed nuciferine mitigated body weight gain, hyperlipemia and hepatic steatosis with regulating lipid metabolic gene expressions. Meanwhile, nuciferine decreased LPS-induced inflammation through inhibiting TLR4/MyD88/NF-κB pathway and reinforced intestinal barriers through increasing occludin and zonula occluden-1 expression, goblet cells, mucin2 (MUC2) expression. Furthermore, we found that nuciferine changed the relative abundance of mucus-related microbiota (Akkmensia muciniphila, Ruminococcaceae) and LPS-producing microbiota (Desulfovibrionaceae), increased the concentration of fecal acetic acid and propionic acid accompanied by decreased fecal pH. Together, anti-NAFLD effects of nuciferine are related to improving multiple intestinal barrier functions. These findings imply that nuciferine could be a promising agent for NAFLD with a target towards gut-liver axis.

This study investigatesthe nuciferine capacity to regulate the liver’s lipid metabolism regarding steatosis and injury in STZ-induced diabetic rats.

Chemotherapeutic drugs are a known factor that impairs the system of life due to their severe side effects. A more worrying fact is that the patients administered with doxorubicin fall under the risk of cardiotoxicity. The evolution of exploring plant-derived compounds is a possible way to combat health issues in therapeutic applications. Hence, this study focuses on the protective effect of plant-based compound nuciferine (NFN) against doxorubicin-induced cardiotoxicity in both in vitro and in vivo models. In this investigation, nuciferine significantly reduces DOX-mediated cardiotoxicity by mitigating reactive oxygen species, thereby preventing DNA fragmentation, regulating apoptosis genes and reducing the caspase 3/7 levels in vitro. Besides, nuciferine has shown significant protection against DOX-induced cardiac impairment and the upregulation of cardiogenic markers in vivo. The DOX-induced oxidative stress can be mitigated via enhancing the endogenous antioxidants, thereby controlling ROS-mediated apoptosis. In virtue of these potential features, nuciferine can be a budding candidate to address therapeutic needs. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA), a chronic disease featured by severe pain and persistent inflammation, significantly affects human health and lowers the quality of life. Nuciferine (Nuf) is major alkaloids abundant in lotus leaf and has various biological activities. In current study, we aimed to explored the protective effect of Nuf against OA and its underlying mechanism in vitro and in vivo. It was found that Nuf alleviated the degradation of extracellular matrix (ECM) under the stimulation of IL-1β and inhibited the production of inflammation cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in vitro. Meanwhile, it was demonstrated that Nuf suppressed the activation of PI3K/Akt/NF-κB signaling pathway induced by IL-1β. Besides, there was favorable binding ability between Nuf and PI3K. Nuf significantly alleviated the development of OA in vivo in the rat OA model established by anterior cruciate ligament transaction (ACLT). Together, our results indicated that Nuf attenuates the progression of OA by targeting PI3K/Akt/NF-κB signaling pathway, which makes Nuf as a promising candidate for the treatment of OA.

Human dermal fibroblasts play an important role in skin homeostasis by producing and degrading extracellular matrix components. They have more replicative senescence when exposed to environmental and oxidative insults, resulting in human skin aging. However, this phenomenon can be mitigated by antioxidant phytochemicals. The aim of the present study was to investigate the potential of nuciferine (an alkaloid from Nelumbo nucifera leaf) in preventing stress-induced fibroblast senescence by using a hydrogen-peroxide (H2O2)-induced senescence model. We found that H2O2 treatment resulted in a significant increase in senescence-associated β-galactosidase (SA-β-gal)-positive cells. Nuciferine-treated cells, however, showed a reduction in senescent phenotype. Furthermore, we observed the key molecular markers including the senescence-associated secretory phenotype (SASP) and cell cycle regulators. The mRNA levels of CXCL1, CXCL2, IL-6, and IL-8 (pro-inflammatory cytokines) reduced significantly in nuciferine-treated cells. The extracellular IL-6 and IL-8 levels were also decreased in treated cells, whereas the key cell cycle regulators (p16 and p21) were markedly affected by nuciferine at the highest concentration. The results of the present study clearly show that the preventive activity of nuciferine against H2O2-induced senescence in dermal fibroblasts is fundamental and promising for further applications in anti-aging product research and development.

The present study is aimed to determine the efficacy and dose response of the nuciferine (1), norcoclaurine (2) and crude extract of Nelumbo nucifera in managements of diabetes, Alzheimer disease and related allergies. Experimentally, alloxan (100 mg/kg body weight (b.w.))-induced diabetic rats (200–250 g) were divided into seven groups (n = 6). Group I: normal control, Group II: diabetic control, Group III: standard treated with glibenclamide and Group lV-VII: treated with methanolic crude extracts (100, 200 mg/kg), nuciferine and norcoclaurine (10 mg/kg b.w.) for 15 days. Different tests were performed, including blood glucose, body weights and antioxidant enzyme assays, i.e., superoxide dismutase (SOD), catalase test (CAT), lipid peroxidation assay (TBARS), glutathione assay (GSH) and acetylcholinesterase (AChE) assay. Nuciferine and norcoclaurine significantly reduced blood glucose (p < 0.05) and restored body weight in diabetic rats. Moreover, nuciferine and norcoclaurine (10 mg/kg) significantly recovered the antioxidant enzymes (SOD, CAT, GPx and GSH) which decreased during induced diabetes. Significant increase in TBARS was also observed in the diabetic group and nuciferine as well as norcoclaurine (10 mg/kg) inhibited the increase in TBARS in diabetic animals (p < 0.05), as compared to glibenclamide. AChE activity was significantly recovered by nuciferine and norcoclaurine (10 mg/kg) both in the blood and brain of the diabetic group (p < 0.05). Nuciferine and norcoclaurine showed potent inhibitory effects against α-glucosidase and α-amylase with IC50, 19.06 ± 0.03, 15.03 ± 0.09 μM and 24.07 ± 0.05, 18.04 ± 0.021 μM, as confirmed by molecular docking studies. This study concludes that nuciferine and norcoclaurine significantly improve memory and could be considered as an effective phytomedicine for diabetes, Alzheimer’s disease (AD) and oxidative stress.