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BACKGROUND: Coronavirus disease-19 (COVID-19) pneumonia continues to spread in the entire globe with limited medication available. In this study, the active compounds in Chinese medicine (CM) recipes targeting the transmembrane serine protease 2 (TMPRSS2) protein for the treatment of COVID-19 were explored. METHODS: The conformational structure of TMPRSS2 protein (TMPS2) was built through homology modeling. A training set covering TMPS2 inhibitors and decoy molecules was docked to TMPS2, and their docking poses were re-scored with scoring schemes. A receiver operating characteristic (ROC) curve was applied to select the best scoring function. Virtual screening of the candidate compounds (CCDs) in the six highly effective CM recipes against TMPS2 was conducted based on the validated docking protocol. The potential CCDs after docking were subject to molecular dynamics (MD) simulations and surface plasmon resonance (SPR) experiment. RESULTS: A training set of 65 molecules were docked with modeled TMPS2 and LigScore2 with the highest area under the curve, AUC, value (0.886) after ROC analysis selected to best differentiate inhibitors from decoys. A total of 421 CCDs in the six recipes were successfully docked into TMPS2, and the top 16 CCDs with LigScore2 higher than the cutoff (4.995) were screened out. MD simulations revealed a stable binding between these CCDs and TMPS2 due to the negative binding free energy. Lastly, SPR experiments validated the direct combination of narirutin, saikosaponin B1, and rutin with TMPS2. CONCLUSIONS: Specific active compounds including narirutin, saikosaponin B1, and rutin in CM recipes potentially target and inhibit TMPS2, probably exerting a therapeutic effect on COVID-19.
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COVID-19 , Inibidores de Serina Proteinase , Humanos , Tratamento Farmacológico da COVID-19 , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Rutina , Serina Endopeptidases/química , Ressonância de Plasmônio de Superfície , Inibidores de Serina Proteinase/farmacologiaRESUMO
Triple-negative breast cancer (TNBC) is a unique breast cancer subtype characterized by a lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Since TNBC lacks ER, PR, and HER2, there are currently no drugs that specifically target TNBC. Therefore, the development of new drugs or effective treatment strategies to target TNBC has become an urgent clinical need. Research has shown that the application of histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors leads to genomic and epigenomic instability. This, in turn, triggers the activation of pattern recognition receptors (PRRs) and subsequently activates downstream interferon (IFN) signalling pathways. In this study, the bifunctional HDAC and DNMT inhibitor J208 exhibited antitumour activity in TNBC cell lines. J208 effectively induced apoptosis and cell cycle arrest at the G0/G1 phase, inhibiting cell migration and invasion in TNBC. Moreover, this bifunctional inhibitor induced the expression of endogenous retroviruses (ERVs) and elicited a viral mimicry response, which increased the intracellular levels of double-stranded RNA (dsRNA) to activate the innate immune signalling pathway in TNBC. In summary, we demonstrated that the bifunctional inhibitor J208, which is designed to inhibit HDAC and DNMT, has potent anticancer effects, providing a new research basis for reactivating antitumour immunity by triggering innate immune signalling and offering a promising strategy for TNBC treatment.
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Inibidores de Histona Desacetilases , Imunidade Inata , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Humanos , Linhagem Celular Tumoral , Imunidade Inata/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Feminino , Apoptose/efeitos dos fármacos , Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , AnimaisRESUMO
Due to the pathological production of liver disease in utility particularly complexity, the morbidity and mortality of liver disease including viral hepatitis, liver fibrosis/cirrhosis and hepatocellular carcinoma (HCC) are rapidly increasing worldwide. Considering its insidious onset, rapid progression and drug resistance, finding an effective therapy is particularly worthwhile. Phyllanthus urinaria L. (P. urinaria), an ethnic medicine, can be applied at the stages of viral hepatitis, liver fibrosis/cirrhosis and HCC, which demonstrates great potential in the treatment of liver disease. Currently, there are numerous reports on the application of P. urinaria in treating liver diseases, but a detailed analysis of its metabolites and a complete summary of its pharmacological mechanism are still scarce. In this review, the phytochemical metabolites and ethnopharmacological applications of P. urinaria are summarized. Briefly, P. urinaria mainly contains flavonoids, lignans, tannins, phenolic acids, terpenoids and other metabolites. The mechanisms of P. urinaria are mainly reflected in reducing surface antigen secretion and interfering with DNA polymerase synthesis for anti-viral hepatitis activity, reducing hepatic stellate cells activity, inflammation and oxidative stress for anti-liver fibrosis/cirrhosis activity, as well as preventing tumor proliferation, invasion and angiogenesis for anti-HCC activity via relevant signaling pathways. Accordingly, this review provides insights into the future application of natural products in the trilogy of liver diseases and will provide a scientific basis for further research and rational utilization of P. urinaria.
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Capsular polysaccharides derived from Bacteroides species have emerged as potential mitigators of intestinal inflammation in murine models. However, research on capsular polysaccharides from B. uniformis, a Bacteroides species with reduced abundance in colons of patients with ulcerative colitis, remains scarce. In this study, we extracted a neutral polysaccharide component from B. uniformis ATCC8492, termed BUCPS1B, using ultrasonic disruption, ethanol precipitation, and anion exchange chromatography. Structural characterization revealed BUCPS1B as a water-soluble polysaccharide with an α-1,4-glucan main chain adorned with minor substituent sugar residues. BUCPS1B alleviated intestinal inflammation in a mouse model of colitis and induced polarization of macrophages into M2-type. Furthermore, BUCPS1B modulated the gut microbiota composition, increased the abundance of the probiotic Akkermansia muciniphila and altered the gut metabolic profile to promote phenylalanine and short chain fatty acids metabolism. BUCPS1B is therefore a promising candidate to prevent inflammation and augment intestinal health.
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Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by social communication deficiencies and stereotypic behaviors influenced by hereditary and/or environmental risk factors. There are currently no approved medications for treating the core symptoms of ASD. Human fecal microbiota transplantation (FMT) has emerged as a potential intervention to improve autistic symptoms, but the underlying mechanisms are not fully understood. In this study, we evaluated the effects of human-derived FMT on behavioral and multi-omics profiles of the BTBR mice, an established model for ASD. FMT effectively alleviated the social deficits in the BTBR mice and normalized their distinct plasma metabolic profile, notably reducing the elevated long-chain acylcarnitines. Integrative analysis linked these phenotypic changes to specific Bacteroides species and vitamin B6 metabolism. Indeed, vitamin B6 supplementation improved the social behaviors in BTBR mice. Collectively, these findings shed new light on the interplay between FMT and vitamin B6 metabolism and revealed a potential mechanism underlying the therapeutic role of FMT in ASD.IMPORTANCEAccumulating evidence supports the beneficial effects of human fecal microbiota transplantation (FMT) on symptoms associated with autism spectrum disorder (ASD). However, the precise mechanism by which FMT induces a shift in the microbiota and leads to symptom improvement remains incompletely understood. This study integrated data from colon-content metagenomics, colon-content metabolomics, and plasma metabolomics to investigate the effects of FMT treatment on the BTBR mouse model for ASD. The analysis linked the amelioration of social deficits following FMT treatment to the restoration of mitochondrial function and the modulation of vitamin B6 metabolism. Bacterial species and compounds with beneficial roles in vitamin B6 metabolism and mitochondrial function may further contribute to improving FMT products and designing novel therapies for ASD treatment.
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Modelos Animais de Doenças , Transplante de Microbiota Fecal , Vitamina B 6 , Animais , Camundongos , Humanos , Vitamina B 6/metabolismo , Microbioma Gastrointestinal , Masculino , Comportamento Social , Transtorno do Espectro Autista/terapia , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/microbiologia , Transtorno Autístico/terapia , Transtorno Autístico/metabolismo , Transtorno Autístico/microbiologiaRESUMO
OBJECTIVE: To explore the specific pharmacological molecular mechanisms of Kai Xin San (KXS) on treating Alzheimer's disease (AD) based on network pharmacology and experimental validation. METHODS: The chemical compounds of KXS and their corresponding targets were screened using the Encyclopedia of Traditional Chinese Medicine (ETCM) database. AD-related target proteins were obtained from MalaCards database and DisGeNET databases. Key compounds and targets were identified from the compound-target-disease network and protein-protein interaction (PPI) network analysis. Functional enrichment analysis predicted the potential key signaling pathways involved in the treatment of AD with KXS. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, the predicted key signaling pathway was validated experimentally. Positioning navigation and space search experiments were conducted to evaluate the cognitive improvement effect of KXS on AD rats. Western blot was used to further examine and investigate the expression of the key target proteins related to the predicted pathway. RESULTS: In total, 38 active compounds and 469 corresponding targets of KXS were screened, and 264 target proteins associated with AD were identified. The compound-target-disease and PPI networks identified key active ingredients and protein targets. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested a potential effect of KXS in the treatment of AD via the amyloid beta (A ß)-glycogen synthase kinase-3 beta (GSK3 ß)-Tau pathway. Molecular docking revealed a high binding affinity between the key ingredients and targets. In vivo, KXS treatment significantly improved cognitive deficits in AD rats induced by Aß1-42, decreased the levels of Aß, p-GSK3ß, p-Tau and cyclin-dependent kinase 5, and increased the expressions of protein phosphatase 1 alpha (PP1A) and PP2A (P<0.05 or P<0.01). CONCLUSION: KXS exerted neuroprotective effects by regulating the Aß -GSK3ß-Tau signaling pathway, which provides novel insights into the therapeutic mechanism of KXS and a feasible pharmacological strategy for the treatment of AD.
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Doença de Alzheimer , Medicamentos de Ervas Chinesas , Ratos , Animais , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Glicogênio Sintase Quinase 3 beta , Farmacologia em Rede , Simulação de Acoplamento Molecular , Quinase 3 da Glicogênio Sintase/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêuticoRESUMO
Drug resistance to chemotherapy agents presents a major obstacle to the effective treatment of hepatocellular carcinoma (HCC), a common type of liver cancer. Increasing evidence indicates a link between drug resistance and the recurrence of HCC. Polyphyllin I (PPI), a promising pharmaceutical candidate, has shown potential therapeutic advantages in the treatment of sorafenib-resistant hepatocellular carcinoma (SR-HCC cells). In this study, we sought to investigate the mechanism underlying the inhibitory effect of PPI on the invasion and metastasis of SR-HCC cells. Our in vitro studies included scratch wound-healing migration assays and transwell assays to examine PPI's effect on HCC cell migration and invasion. Flow cytometry was employed to analyze the accumulation or efflux of chemotherapy drugs. The results of these experiments demonstrated that PPI increased the susceptibility of HCC to sorafenib while inhibiting SR-HCC cell growth, migration, and invasion. Molecular docking analysis revealed that PPI exhibited a higher binding affinity with GRP78. Western blot analysis and immunofluorescence experiments showed that PPI reduced the expression of GRP78, E-cadherin, N-cadherin, Vimentin, and ABCG2 in SR-HCC cells. Interference with and overproduction of GRP78 in vitro impacted the proliferation, migration, invasion, and metastasis of HCC cells. Further examination revealed that PPI hindered the expression of GRP78 protein, resulting in a suppressive effect on SR-HCC cell migration and invasion. Histological examination of tumor tissue substantiated that administering PPI via gavage to HepG2/S xenograft nude mice inhibited tumor growth and significantly reduced tumor size, as evidenced by xenograft experiments involving nude mice. Hematoxylin and eosin (HE) staining of tumor tissue specimens, along with immunohistochemistry (IHC), were conducted to evaluate the expression levels of Ki67, GRP78, N-cadherin, Vimentin, and ABCG2. The results indicated that PPI administration decreased the levels of proteins associated with metastasis and markers of drug resistance in tumor tissues, impeding tumor growth and spread. Overall, our findings demonstrated that PPI effectively suppressed the viability, proliferation, invasion, and metastasis of SR-HCC cells both in vitro and in vivo by modulating GRP78 activity. These findings provide new insights into the mechanism of PPI inhibition of SR-HCC cell invasion and metastasis, highlighting PPI as a potential treatment option for sorafenib-resistant HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Chaperona BiP do Retículo Endoplasmático , Vimentina/metabolismo , Camundongos Nus , Preparações Farmacêuticas , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Proliferação de Células , Caderinas/metabolismo , Movimento CelularRESUMO
Currently, it remains controversial whether p-phenylenediamine (PPD) is genotoxic. In this study, we evaluated the potential genotoxicity of PPD using the newly-developed Pig-a gene mutation assay. The results of three classical genetic toxicity tests (bacterial reverse mutation assay, mammalian cell chromosomal aberration test, and mammalian erythrocyte micronucleus test) are all positive, suggesting that PPD is potentially genotoxic. In Pig-a assay, Sprague-Dawley rats are orally administered with PPD for 28 consecutive days at three doses (12.5, 25, and 50â¯mg/kg/day). Our result shows that PPD (25 and 50â¯mg/kg/day) dose-dependently increases RETCD59- value over controls on Day 8. RETCD59- keeps increasing to the maximum on Day 15 and then decreases until Day 29. PPD also dose-dependently increase RBCCD59- value on Day 15, which keeps elevating until Day 29. The time-course of RETCD59- and RBCCD59- induced by PPD are similar with that induced by N-ethyl-N-nitrosourea (ENU) treatment for 3 days. Our data suggests that PPD has potential genotoxic effects, and the Pig-a assay is sensitive to assess mutagenicity. However, further investigation of the changes of RETCD59- and RBCCD59- induced by hair dyes containing PPD should be detected by Pig-a assay in occupational exposure population to confirm the safety of PPD usage.