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Traditional biotechnology has been utilized by human civilization for long in wide aspects of our daily life, such as wine and vinegar production, which can generate new phytochemicals from natural products using micro-organism. Today, with advanced biotechnology, diverse applications and advantages have been exhibited not only in bringing benefits to increase the diversity and composition of herbal phytochemicals, but also helping to elucidate the treatment mechanism and accelerate new drug discovery from Chinese herbal medicine (CHM). Applications on phytochemical biotechnologies and microbial biotechnologies have been promoted to enhance phytochemical diversity. Cell labeling and imaging technology and −omics technology have been utilized to elucidate CHM treatment mechanism. Application of computational methods, such as chemoinformatics and bioinformatics provide new insights on direct target of CHM. Overall, these technologies provide efficient ways to overcome the bottleneck of CHM, such as helping to increase the phytochemical diversity, match their molecular targets and elucidate the treatment mechanism. Potentially, new oriented herbal phytochemicals and their corresponding drug targets can be identified. In perspective, tighter integration of multi-disciplinary biotechnology and computational technology will be the cornerstone to accelerate new arena formation, advancement and revolution in the fields of CHM and world pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Pathogenesis of neurodegenerative diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD) are closely related to the formation of protein aggregates and inclusion body. For instance, active autophagic components from Chinese herbal medicines (CHMs) are highlighted to modulate neurodegeneration via degradation of disease proteins. In this study, the neuroprotective effect of the purified Hedera helix (HH) fraction containing both hederagenin and α-hederin, is confirmed by the improvement of motor deficits in PD mice model. Furthermore, hederagenin and α-hederin derived from HH are confirmed as novel autophagic enhancers. Both compounds reduce the protein level of mutant huntingtin with 74 CAG repeats and A53T α-synuclein, and inhibit the oligomerization of α-synuclein and inclusion formation of huntingtin, via AMPK-mTOR dependent autophagy induction. Both hederagenin and α-hederin induce autophagy and promote the degradation of neurodegenerative mutant disease proteins in vitro, suggesting the therapeutic roles of HH in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs), widely expressed in the human central nervous system (CNS), perform numerous physiological functions and play a significant role in the pathogenesis of diseases. Consequently, identifying key therapeutic GPCRs targets for CNS-related diseases is garnering immense interest in research labs and pharmaceutical companies. However, using GPCRs drugs for treating neurodegenerative diseases has limitations, including side effects and uncertain effective time frame. Recognizing the rich history of herbal treatments for neurological disorders like stroke, Alzheimer's disease (AD), and Parkinson's disease (PD), modern pharmacological research is now focusing on the understanding of the efficacy of traditional Chinese medicinal herbs and compounds in modulating GPCRs and treatment of neurodegenerative conditions. This paper will offer a comprehensive, critical review of how certain natural products and compounds target GPCRs to treat neurological diseases. Conducting an in-depth study of herbal remedies and their efficacies against CNS-related disorders through GPCRs targeting will augment our strategies for treating neurological disorders. This will not only broaden our understanding of effective therapeutic methodologies but also identify the root causes of altered GPCRs signaling in the context of pathophysiological mechanisms in neurological diseases. Moreover, it would be informative for the creation of safer and more effective GPCR-mediated drugs, thereby establishing a foundation for future treatment of various neurological diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

In future regenerative medicine, far-infrared radiation (FIR) may be an essential component of optical therapy. Many studies have confirmed or validated the efficacy and safety of FIR in various diseases, benefiting from new insights into FIR mechanisms and the excellent performance of many applications. However, the lack of consensus on the biological effects and therapeutic parameters of FIR limits its practical applications in the clinic. In this review, the definition, characteristics, and underlying principles of the FIR are systematically illustrated. We outline the therapeutic parameters of FIR, including the wavelength range, power density, irradiation time, and distance. In addition, the biological effects, potential molecular mechanisms, and preclinical and clinical applications of FIR are discussed. Furthermore, the future development and applications of FIR are described in this review. By applying optimal therapeutic parameters, FIR can influence various cells, animal models, and patients, eliciting diverse underlying mechanisms and offering therapeutic potential for many diseases. FIR could represent a superior alternative with broad prospects for application in future regenerative medicine. [Display omitted] [ABSTRACT FROM AUTHOR]

• Twelve semi-synthetic derivatives of prenylated isoflavones 5 - 16 were designed and synthesized. • Derivatives were evaluated via human recombinant BACE-1 inhibition and cytotoxicity assay. • 7 , 8 and 13 were found to be the most active candidates. • These compounds were targeted for the BACE-1 enzyme and P-glycoprotein (P-gp) in docking studies. • 7 enhance the activity of P-glycoprotein (P-gp) on A549 cancer cells. BACE-1 is considered to be one of the targets for prevention and treatment of Alzheimer's disease (AD). We here report a novel class of semi-synthetic derivatives of prenylated isoflavones, obtained from the derivatization of natural flavonoids from Maclura pomifera. In vitro anti-AD effect of the synthesized compounds were evaluated via human recombinant BACE-1 inhibition assay. Compound 7 , 8 and 13 were found to be the most active candidates which demonstrates good correlation between the computational docking and pharmacokinetic predictions. Moreover, cytotoxic studies demonstrated that the compounds are not toxic against normal and cancer cell lines. Among these three compounds, compound 7 enhance the activity of P-glycoprotein (P-gp) on A549 cancer cells and increases the activity of P-gp ATPase with a possible role on the efflux of amyloid-β across the blood- brain barrier. In conclusion, the present findings may pave the way for the discovery of a novel class of compounds to prevent and/or treat AD. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Eleven dauricine derivatives were synthesized. • Four compounds displayed significant cytotoxicity against five cancer cells. • Four derivatives are validated to induce autophagy-dependent cell death in HeLa cancer cells. Abstract Eleven dauricine derivatives were synthesized and evaluated for their anti-cancer effect in different cancer cells and their autophagic activity in HeLa model cell. Among these newly synthesized compounds, carbamates 2a , 2b , carbonyl ester 3a and sulfonyl ester 4a exhibited potent cytotoxic effects on tested cancer cells with IC 50 values ranged from 2.72 to 12.53 μM, which were more potent than that of dauricine (higher than 15.53 μM). The above four derivatives are validated to induce autophagy-dependent cell death in HeLa cancer cells. These findings offer us a promising source for generating novel autophagic enhancers for anti-cancer therapy. [ABSTRACT FROM AUTHOR]

Tricin, a natural nontoxic flavonoid distributed in grasses and euphorbia plants, has been reported to scavenge free radicals, possess anti-inflammatory and antioxidative effects. However, its autophagic effect on Parkinson's disease (PD) has not been elucidated. By adopting cellular and C. elegans models of PD, the autophagic effect of tricin was identified based on the level of autophagy markers (LC3-II and p62). Besides, the pharmacological effects on neurotransmitters (dopamine), inflammatory cytokines (IFN γ, TNFα, MCP-1, IL-10, IL-6 and IL-17A), histology (hematoxylin & eosin and Nissl staining) and behavioural pathology (open-field test, hindlimb clasping, Y-maze, Morris water-maze and nest building test) were also confirmed in the A53T-α-synuclein transgenic PD mouse model. Further experiments demonstrated that tricin induced autophagic flux and lowered the level of α-synuclein through AMPK-p70s6K- and ATG7-dependent mechanism. Compared to the existing clinical PD drugs, tricin mitigated pathogenesis and symptoms of PD with no observable side effects. In summary, tricin is proposed as a potential adjuvant remedy or nutraceutical for the prevention and treatment of PD. [Display omitted] [ABSTRACT FROM AUTHOR]

Drug resistance in cancer has been classified as innate resistance or acquired resistance, which were characterized by apoptotic defects and ABC transporters overexpression respectively. Therefore, to preclude or reverse these resistance mechanisms could be a promising strategy to improve chemotherapeutic outcomes. In this study, a natural product from Osage Orange , pomiferin, was identified as a novel autophagy activator that circumvents innate resistance by triggering autophagic cell death via SERCA inhibition and activation of the CaMKKβ-AMPK-mTOR signaling cascade. In addition, pomiferin also directly inhibited the P-gp (MDR1/ABCB1) efflux and reversed acquired resistance by potentiating the accumulation and efficacy of the chemotherapeutic agent, cisplatin. In vivo study demonstrated that pomiferin triggered calcium-mediated tumor suppression and exhibited an anti-metastatic effect in the LLC-1 lung cancer-bearing mouse model. Moreover, as an adjuvant, pomiferin potentiated the anti-tumor effect of the chemotherapeutic agent, cisplatin, in RM-1 drug-resistant prostate cancer-bearing mouse model by specially attenuating ABCB1-mediated drug efflux, but not ABCC5, thereby promoting the accumulation of cisplatin in tumors. Collectively, pomiferin may serve as a novel effective agent for circumventing drug resistance in clinical applications. [Display omitted] Schematic diagram of the proposed molecular targets and mechanisms of pomiferin in induction of autophagic cell death and inhibition of P-glycoprotein. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder which is associated with the dysregulation of autoimmune response. In recent years, early diagnosis, aggressive treatment and alternative therapeutic options of disease-modifying anti-rheumatic drugs (DMARDs) markedly improve both the management and long-term prognosis of RA. Since the discovery of non-coding RNA (ncRNA) including microRNA (miRNA), long non-coding RNA (lncRNA) and others, their altered expressions have been unraveled to be deregulated in various diseases including RA. Several lines of evidence are emerging that ncRNA may contribute to the pathogenesis, disease progression and treatment of RA. For example, SNP rs2850711 within lnc00305 was indicated to associate with RA development susceptibility, whereas a higher level of miR-10a represented a good response to methotrexate (MTX) treatment in RA patients. In the aspect of refractory RA, ncRNA also plays an important role by affecting or regulating drug sensitivity in RA patients. Of note, lower expression of miR-20a in rheumatoid arthritis synovial fibroblast (RASFs) was demonstrated to activate the Janus Kinase (JAK)- signal transducer and activator of transcription 3(STAT3)-mediated inflammation, thereby promoting cell proliferation and apoptosis-resistant. In this review, we have illustrated the changes of ncRNAs and their underlying mechanisms in the whole developing period of RA pathogenesis and disease progression, as well as highlighted the novel therapeutic targets/strategies and bio-markers for RA therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Patchouli Essential Oil (PEO) has been used as a scent for various healing purposes since the ancient Egyptian period. The primary source of the oil is Pogostemon cablin (PC), a medicinal plant for treating gastrointestinal symptoms. However, the pharmacological function has not been addressed. Here, we report the cancer prevention and gut microbiota (GM) modulating property of PEO and its derivatives patchouli alcohol (PA) and pogostone (PO) in the Apc Min /+ colorectal cancer mice model. We found that PEO, PA, and PO significantly reduced the tumor burden. At the same time, it strengthened the epithelial barrier, evidenced by substantially increasing the number of the goblet and Paneth cells and upregulation of tight junction and adhesion molecules. In addition, PEO, PA, and PO shifted M1 to M2 macrophage phenotypes and remodeled the inflammatory milieu of Apc Min /+ mice. We also found suppression of CD4+CD25+ and stimulation CD4+ CD8+ cells in the spleen, blood, mesenteric lymph nodes (MLNs), and Peyer's patches (PPs) of the treated mice. The composition of the gut microbiome of the drug-treated mice was distinct from the control mice. The drugs stimulated the short-chain fatty acids (SCFAs)-producers and the key SCFA-sensing receptors (GPR41, GPR43, and GPR109a). The activation of SCFAs/GPSs also triggered the alterations of PPAR-γ, PYY, and HSDCs signaling mediators in the treated mice. Our work showed that PEO and its derivatives exert potent anti-cancer effects by modulating gut microbiota and improving the intestinal microenvironment of the ApcM min /+ mice. [Display omitted] [ABSTRACT FROM AUTHOR]

Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which enter the host cells through the interaction between its receptor binding domain (RBD) of spike glycoprotein with angiotensin-converting enzyme 2 (ACE2) receptor on the plasma membrane of host cell. Neutralizing antibodies and peptide binders of RBD can block viral infection, however, the concern of accessibility and affordability of viral infection inhibitors has been raised. Here, we report the identification of natural compounds as potential SARS-CoV-2 entry inhibitors using the molecular docking-based virtual screening coupled with bilayer interferometry (BLI). From a library of 1871 natural compounds, epigallocatechin gallate (EGCG), 20(R)-ginsenoside Rg3 (RRg3), 20(S)-ginsenoside Rg3 (SRg3), isobavachalcone (Ibvc), isochlorogenic A (IscA) and bakuchiol (Bkc) effectively inhibited pseudovirus entry at concentrations up to 100 μM. Among these compounds, four compounds, EGCG, Ibvc, salvianolic acid A (SalA), and isoliensinine (Isl), were effective in inhibiting SARS-CoV-2-induced cytopathic effect and plaque formation in Vero E6 cells. The EGCG was further validated with no observable animal toxicity and certain antiviral effect against SARS-CoV-2 pseudovirus mutants (D614G, N501Y, N439K & Y453F). Interestingly, EGCG, Bkc and Ibvc bind to ACE2 receptor in BLI assay, suggesting a dual binding to RBD and ACE2. Current findings shed some insight into identifications and validations of SARS-CoV-2 entry inhibitors from natural compounds. [Display omitted] [ABSTRACT FROM AUTHOR]

With the increase in human lifespan, population aging is one of the major problems worldwide. Aging is an irreversible progressive process that affects humans via multiple factors including genetic, immunity, cellular oxidation and inflammation. Progressive neuroinflammation contributes to aging, cognitive malfunction, and neurodegenerative diseases. However, precise mechanisms or drugs targeting age-related neuroinflammation and cognitive impairment remain un-elucidated. Traditional herbal plants have been prescribed in many Asian countries for anti-aging and the modulation of aging-related symptoms. In general, herbal plants' efficacy is attributed to their safety and polypharmacological potency via the systemic manipulation of the body system. Radix polygalae (RP) is a herbal plant prescribed for anti-aging and the relief of age-related symptoms; however, its active components and biological functions remained un-elucidated. In this study, an active methanol fraction of RP containing 17 RP saponins (RPS), was identified. RPS attenuates the elevated C3 complement protein in aged mice to a level comparable to the young control mice. The active RPS also restates the aging gut microbiota by enhancing beneficial bacteria and suppressing harmful bacteria. In addition, RPS treatment improve spatial reference memory in aged mice, with the attenuation of multiple molecular markers related to neuroinflammation and aging. Finally, the RPS improves the behavior and extends the lifespan of C. elegans , confirming the herbal plant's anti-aging ability. In conclusion, through the mouse and C. elega s models, we have identified the beneficial RPS that can modulate the aging process, gut microbiota diversity and rectify several aging-related phenotypes. [Display omitted] [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease which affects about 0.5–1% of people with symptoms that significantly impact a sufferer's lifestyle. The cells involved in propagating RA tend to display pro-inflammatory and cancer-like characteristics. Medical drug treatment is currently the main avenue of RA therapy. However, drug options are limited due to severe side effects, high costs, insufficient disease retardation in a majority of patients, and therapeutic effects possibly subsiding over time. Thus there is a need for new drug therapies. Endoplasmic reticulum (ER) stress, a condition due to accumulation of misfolded proteins in the ER, and subsequent cellular responses have been found to be involved in cancer and inflammatory pathologies, including RA. ER stress protein markers and their modulation have therefore been suggested as therapeutic targets, such as GRP78 and CHOP, among others. Some current RA therapeutic drugs have been found to have ER stress-modulating properties. Traditional Chinese Medicines (TCMs) frequently use natural products that affect multiple body and cellular targets, and several medicines and/or their isolated compounds have been found to also have ER stress-modulating capabilities, including TCMs used in RA treatment by Chinese Medicine practitioners. This review encourages, in light of the available information, the study of these RA-treating, ER stress-modulating TCMs as potential new pharmaceutical drugs for use in clinical RA therapy, along with providing a list of other ER stress-modulating TCMs utilized in treatment of cancers, inflammatory diseases and other diseases, that have potential use in RA treatment given similar ER stress-modulating capacity. [Display omitted] [ABSTRACT FROM AUTHOR]

We previously reported the neuroprotective effects of icariin in rat cortical neurons. Here, we present a study on icariin's anti-aging effect in 24-month aged mice by treating them with a single daily dose of 100 mg/kg of icariin for 15 consecutive days. Icariin treatment improved motor coordination and learning skills while lowered oxidative stress biomarkers in the serum, brain, kidney, and liver of the aged mice. In addition, icariin improved the intestinal integrity of the aged mice by upregulating tight junction adhesion molecules and the Paneth and goblet cells, along with the reduction of iNOS and pro-inflammatory cytokines (IL-1β, TNF-α, IL-2 and IL-6, and IL-12). Icariin treatments also significantly upregulated aging-related signaling molecules, Sirt 1, 3 & 6, Pot1α, BUB1b, FOXO1, Ep300, ANXA3, Calb1, SNAP25, and BDNF in old mice. Through gut microbiota (GM) analysis, we observed icariin-associated improvements in GM composition of aged mice by reinstating bacteria found in the young mice, while suppressing some bacteria found in the untreated old mice. To clarify whether icariin's anti-aging effect is rooted in the GM, we performed fecal microbiota transfer (FMT) from icariin-treated old mice to the old mice. FMT-recipients exhibited similar improvements in the rotarod score and age-related biomarkers as observed in the icariin-treated old mice. Equal or better improvement on the youth-like features was noticed when aged mice were FMT with feces from young mice. Our study shows that both direct treatments with icariin and fecal transplant from the icariin-treated aged mice produce similar anti-aging phenotypes in the aged mice. We prove that GM plays a pivotal role in the healing abilities of icariin. Icariin has the potentials to be developed as a medicine for the wellness of the aged adults. [Display omitted] [ABSTRACT FROM AUTHOR]

Schematic diagram of the proposed molecular targets and mechanisms of celastrol in induction of autophagic cell death and inhibition of P-glycoprotein. Multidrug resistance (MDR) represents an obstacle in anti-cancer therapy. MDR is caused by multiple mechanisms, involving ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), which reduces intracellular drug levels to sub-therapeutic concentrations. Therefore, sensitizing agents retaining effectiveness against apoptosis- or drug-resistant cancers are desired for the treatment of MDR cancers. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump is an emerging target to overcome MDR, because of its continuous expression and because the calcium transport function is crucial to the survival of tumor cells. Previous studies showed that SERCA inhibitors exhibit anti-cancer effects in Bax-Bak-deficient, apoptosis-resistant and MDR cancers, whereas specific P-gp inhibitors reverse the MDR phenotype of cancer cells by blocking efflux of chemotherapeutic agents. Here, we unraveled SERCA and P-gp as double targets of the triterpenoid, celastrol to reverse MDR. Celastrol inhibited both SERCA and P-gp to stimulate calcium-mediated autophagy and ATP depletion, thereby induced collateral sensitivity in MDR cancer cells. In vivo studies further confirmed that celastrol suppressed tumor growth and metastasis by SERCA-mediated calcium mobilization. To the best of our knowledge, our findings demonstrate collateral sensitivity in MDR cancer cells by simultaneous inhibition of SERCA and P-gp for the first time. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Our previous studies have proven that Trillium tschonoskii Maxim. (TTM), a traditional Chinese medicine, possesses potent anti-tumor effect. However, the detailed components and molecular mechanism of TTM in anti-NSCLC are still unknown. In the present experiment, polyphyllin VI (PPVI) was successfully isolated from TTM with guidance of the anti-proliferative effect in A549 cells, and the cell death of PPVI treated A549 and H1299 cells was closely linked with the increased intracellular ROS levels. In addition, PPVI induced apoptosis by promoting the protein expression of Bax/Bcl2, caspase-3 and caspase-9, and activated autophagy by improving LC3 II conversion and GFP-LC3 puncta formation in A549 and H1299 cells. The mechanism study found that the activity of mTOR which regulates cell growth, proliferation and autophagy was significantly suppressed by PPVI. Accordingly, the PI3K/AKT and MEK/ERK pathways positively regulating mTOR were inhibited, and AMPK negatively regulating mTOR was activated. In addition, the downstream of mTOR, ULK1 at Ser 757 which downregulates autophagy was inhibited by PPVI. The apoptotic cell death induced by PPVI was confirmed, and it was significantly suppressed by the overexpression of AKT, ERK and mTOR, and the induced autophagic cell death which was depended on the Atg7 was decreased by the inhibitors, such as LY294002 (LY), Bafilomycin A1 (Baf), Compound C (CC) and SBI-0206965 (SBI). Furthermore, the mTOR signaling pathway was regulated by the increased ROS as the initial signal in A549 and H1299 cells. Finally, the anti-tumor growth activity of PPVI in vivo was validated in A549 bearing athymic nude mice. Taken together, our data have firstly demonstrated that PPVI is the main component in TTM that exerts the anti-proliferative effect by inducing apoptotic and autophagic cell death in NSCLC via the ROS-triggered mTOR signaling pathway, and PPVI may be a promising candidate for the treatment of NSCLC in future. [ABSTRACT FROM AUTHOR]