To elucidate the bioactive components of Lamiophlomis herba in the treatment of liver fibrosis via plasma pharmacochemistry and network pharmacology.

Lamiophlomis Herba (LH) is a traditional Chinese and Tibetan dual-use herb with hemostatic and analgesic effects, and is widely used in the clinical treatment of traumatic bleeding and pain. In recent years, LH has been proven to treat liver fibrosis (LF), but the chemical components related to the pharmacological properties of LH in the treatment of LF are still unclear. Based on the theory of plasma pharmachemistry, the characteristic components in water extract and drug-containing plasma samples of LH were qualitatively analyzed by UPLC-Q-TOF-MS. The chemical components in plasma were screened and the targets were predicted by network pharmacology. Then, the predicted components and targets were verified in vitro by Elisa and qRT-PCR technology. Finally, the pharmacological effects of LH and its monomeric components were determined by hematoxylin-eosin staining of rat liver. A total of 50 chemical constituents were identified in LH, of which 12 were blood prototypes and 9 were metabolites. In vitro experiments showed that LH and its monomeric components luteolin, shanzhiside methyl ester, loganic acid, loganin, 8-O-acetyl shanzhiside methyl ester could increase the expression of antioxidant genes (NQO-1, HO-1) and decrease the expression of inflammatory genes (IL-6, IL-18), thereby reducing the expression of extracellular matrix-related genes and proteins (COL1A1, COL3A1, LN, α-sma, PC-III, Col-IV). In vivo experiments showed that LH could reduce the area of LF in rats in a dose-dependent manner, and shanzhiside methyl ester and 8-O-acetyl shanzhiside methyl ester may be the main components in pharmacodynamics. These effects may be mediated by LH-mediated Nrf2/NF-κB pathway. This study explored the potential pharmacodynamic components of LH in the treatment of LF, and confirmed that shanzhiside methyl ester and 8-O-acetyl shanzhiside methyl ester play a key role in the treatment of LF with LH.

The potential of EGCG in modulating the oral-gut axis microbiota for treating inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a recurrent chronic intestinal disorder that includes ulcerative colitis (UC) and Crohn's disease (CD). Its pathogenesis involves intricate interactions between pathogenic microorganisms, native intestinal microorganisms, and the intestinal immune system via the oral-gut axis. The strong correlation observed between oral diseases and IBD indicates the potential involvement of oral pathogenic microorganisms in IBD development. Consequently, therapeutic strategies targeting the proliferation, translocation, intestinal colonization and exacerbated intestinal inflammation of oral microorganisms within the oral-gut axis may partially alleviate IBD. Tea consumption has been identified as a contributing factor in reducing IBD, with epigallocatechin gallate (EGCG) being the primary bioactive compound used for IBD treatment. However, the precise mechanism by which EGCG mediates microbial crosstalk within the oral-gut axis remains unclear. In this review, we provide a comprehensive overview of the diverse oral microorganisms implicated in the pathogenesis of IBD and elucidate their colonization pathways and mechanisms. Subsequently, we investigated the antibacterial properties of EGCG and its potential to attenuate microbial translocation and colonization in the gut, emphasizing its role in attenuating exacerbations of IBD. We also elucidated the toxic and side effects of EGCG. Finally, we discuss current strategies for enhancing EGCG bioavailability and propose novel multi-targeted nano-delivery systems for the more efficacious management of IBD. This review elucidates the role and feasibility of EGCG-mediated modulation of the oral-gut axis microbiota in the management of IBD, contributing to a better understanding of the mechanism of action of EGCG in the treatment of IBD and the development of prospective treatment strategies.

Radioiodine-refractory differentiated thyroid cancer: Molecular mechanisms and therapeutic strategies for radioiodine resistance.

Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) is difficult to treat with radioactive iodine because of the absence of the sodium iodide transporter in the basement membrane of thyroid follicular cells for iodine uptake. This is usually due to the mutation or rearrangement of genes and the aberrant activation of signal pathways, which result in abnormal expression of thyroid-specific genes, leading to resistance of differentiated thyroid cancer cells to radioiodine therapy. Therefore, inhibiting the proliferation and growth of RAIR-DTC with multikinase inhibitors and other drugs or restoring its differentiation and then carrying out radioiodine therapy have become the first-line treatment strategies and main research directions. The drugs that regulate these kinases or signaling pathways have been studied in clinical and preclinical settings. In this review, we summarized the major gene mutations, gene rearrangements and abnormal activation of signaling pathways that led to radioiodine resistance of RAIR-DTC, as well as the medicine that have been tested in clinical and preclinical trials.

UPLC-Q-TOF-MS based investigation into the bioactive compounds and molecular mechanisms of Lamiophlomis Herba against hepatic fibrosis.

BACKGROUND: Lamiophlomis Herba (LH) is a valuable traditional medicinal plant found on the Qinghai-Tibetan Plateau that promotes blood circulation, removes blood stasis, and has antibacterial and anti-inflammatory properties. The main components of LH are iridoid glycosides, phenethyl alcohol glycosides, flavonoids, and polysaccharides. PURPOSE: To investigate the mechanism of the anti-liver fibrosis effects of LH and screen for its bioactive compounds. STUDY DESIGN: Screening LH marker components and validating the LH anti-liver fibrosis mechanism. METHODS: The active ingredients of LH were identified using UPLC-Q-TOF-MS, and HotMap combined with principal components analysis (PCA) was used to screen for marker components. Network pharmacology and molecular docking techniques were used to predict the potential anti-fibrotic targets of LH. Immunofluorescence, enzyme-linked immunosorbent assay (ELISA), real-time PCR (RT-PCR), and western blotting were used for experimental validation and mechanistic studies. RESULTS: Fifteen compounds that actively contributed to the cluster were identified as marker compounds. Acteoside, 8-O-acetyl shanzhiside methyl ester (8-O-ASME), Luteolin, Shanzhiside Methyl ester (SME), Loganin, Loganate were the main active components. Network pharmacology and molecular docking studies have shown that LH might improve liver fibrosis, inflammation, and oxidative stress, which might be related to key targets such as PTGS2, MAPK, EGFR, AKT1, SRC, Fn1, Col3a1, Col1a1, and PC-III. The results of ELISA, RT-PCR and western blot experiments showed that Acteoside, 8-O-ASME, Luteolin, SME, Loganin, Loganate, and the LH group could reduce the levels of fibronectin, Col1a1, Col3a1, α-SMA, Col-Ⅳ, LN, and PC-Ⅲ. CONCLUSION: LH improves liver fibrosis induced by HSC-T6 cells and inhibits the deposition of extracellular matrix (ECM) in hepatocytes, resulting in a decrease in the degree of liver fibrosis and a good anti-liver fibrosis effect.

The medicinal value of tea drinking in the management of COVID-19.

Corona Virus Disease 2019 (COVID-19) is presently the largest international public health event, individuals infected by the virus not only have symptoms such as fever, dry cough, and lung infection at the time of onset, but also possibly have sequelae in the cardiovascular system, respiratory system, nervous system, mental health and other aspects. However, numerous studies have depicted that the active ingredients in tea show good antiviral effects and can treat various diseases by regulating multiple pathways, and the therapeutic effects are associated with the categories of chemical components in tea. In this review, the differences in the content of key active ingredients in different types of tea are summarized. In addition, we also highlighted their effects on COVID-19 and connected sequelae, further demonstrating the possibility of developing a formulation for the prevention and treatment of COVID-19 and its sequelae through tea extracts. We have a tendency to suggest forestalling and treating COVID-19 and its sequelae through scientific tea drinking.

Schisandrin B ameliorates acute liver injury by regulating EGFR-mediated activation of autophagy.

OBJECTIVE: To investigate the role and possible molecular mechanism of Schisandrin B-induced cell autophagy in the prevention and treatment of APAP-induced liver injury. METHODS: Molecular docking method was used to predict the interaction between Schisandrin B and the EGFR protein. HepG2 cells were treated with different concentrations of Schisandrin B for 24 h. Schisandrin B-induced autophagy of HepG2 cells was determined using real-time label-free cell analysis (RTCA), flow cytometry, immunofluorescence, PCR, and western blot. Flow cytometry and western blot were used to explore whether Schisandrin B-induced autophagy plays a role in the prevention and treatment of liver injury via the EGFR/TFEB signaling pathway. RESULTS: Schisandrin B treatment of APAP-induced HepG2 cells inhibited the production of TNF-α and IL-1ß. Further, Schisandrin B downregulated EGFR protein expression and activated the EGFR/TFEB signaling pathway. Autophagy inhibition promoted APAP-induced apoptosis of HepG2 cells. Moreover, the protein expression levels of TFEB, LC3 and Beclin-1 were upregulated, whereas those of ATG3 and EGFR were downregulated. CONCLUSION: Schisandrin B can induce autophagy in HepG2 cells. Autophagy may play a role in the prevention and treatment of liver injury via the EGFR/TFEB signaling pathway. Activation of autophagy enhances the effect of Schisandrin B on APAP-induced liver injury.

Potential therapeutic effects and applications of Eucommiae Folium in secondary hypertension.

Eucommiae Folium (EF), a traditional Chinese medicine, has been used to treat secondary hypertension, including renal hypertension and salt-sensitive hypertension, as well as hypertension caused by thoracic aortic endothelial dysfunction, a high-fat diet, and oxidized low-density lipoprotein. The antihypertensive components of EF are divided into four categories: flavonoids, iridoids, lignans, and phenylpropanoids, such as chlorogenic acid, geniposide acid and pinoresinol diglucoside. EF regulates the occurrence and development of hypertension by regulating biological processes, such as inhibiting inflammation, regulating the nitric oxide synthase pathway, reducing oxidative stress levels, regulating endothelial vasoactive factors, and lowering blood pressure. However, its molecular antihypertensive mechanisms are still unclear and require further investigation. In this review, by consulting the relevant literature on the antihypertensive effects of EF and using network pharmacology, we summarized the active ingredients and pharmacological mechanisms of EF in the treatment of hypertension to clarify how EF is associated with secondary hypertension, the related components, and underlying mechanisms. The results of the network pharmacology analysis indicated that EF treats hypertension through a multi-component, multi-target and multi-pathway mechanism. In particular, we discussed the role of EF targets in the treatment of hypertension, including epithelial sodium channel, heat shock protein70, rho-associated protein kinase 1, catalase, and superoxide dismutase. The relevant signal transduction pathways, the ras homolog family member A (RhoA)/Rho-associated protein kinase (ROCK) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/eNOS/NO/Ca2+ pathways, are also discussed.

UPLC-MS analysis and network pharmacology-based investigation into the active ingredients and molecular mechanisms of anti-fatigue of male flowers with Eucommia ulmoides Oliv.

The male flowers of Eucommia ulmoides Oliv. (MFEU) was a natural product that could alleviate fatigue and accelerate fatigue alleviation. Nonetheless, the active ingredients and underlying pharmacological mechanisms remain unknown. This study aimed to decode the active ingredients and potential action mechanisms of MFEU in the therapy of anti-fatigue using an integrated UPLC-MS analysis, network pharmacology approach, and cell experiments. Characterizations of chemical constituents of MFEU extract were identified by UPLC-Q-TOF-MS. The corresponding drug targets were retrieved from the drug target database and used to construct the "composite-target-pathway" network. The Cytoscape was used to identify potential protein targets of these MFEU components, indicating that 24 anti-fatigue compounds in MFEU regulate 18 anti-fatigue-related targets in 10 signaling pathways. The 16 components of MFEU were verified at the cellular level. The results of cell experiments showed that MFEU extract (0.361 µg/ml), Caffeic acid, Deacetylasperulosidic acid, Naringenin, Acanthoside B, Geniposidic acid, Rutin, and Quercetin could promote testosterone secretion on Leydig cells at 50 µM. The MFEU extract and seven compounds in MFEU might play a role in anti-fatigue by participating in the regulation of testosterone secretion. Finally, the results of PCR analysis showed that MFEU promotes the secretion of testosterone, which is related to CYPIIa1 and 17ß-HSD, STAR in the signal pathway of testosterone synthesis. This study provides a basis for further exploring the anti-fatigue mechanism of MFEU, adopting the method of multi-compound and multi-target.

Incremental learning algorithm for large-scale semi-supervised ordinal regression.

As a special case of multi-classification, ordinal regression (also known as ordinal classification) is a popular method to tackle the multi-class problems with samples marked by a set of ranks. Semi-supervised ordinal regression (SSOR) is especially important for data mining applications because semi-supervised learning can make use of the unlabeled samples to train a high-quality learning model. However, the training of large-scale SSOR is still an open question due to its complicated formulations and non-convexity to the best of our knowledge. To address this challenging problem, in this paper, we propose an incremental learning algorithm for SSOR (IL-SSOR), which can directly update the solution of SSOR based on the KKT conditions. More critically, we analyze the finite convergence of IL-SSOR which guarantees that SSOR can converge to a local minimum based on the framework of concave-convex procedure. To the best of our knowledge, the proposed new algorithm is the first efficient on-line learning algorithm for SSOR with local minimum convergence guarantee. The experimental results show, IL-SSOR can achieve better generalization than other semi-supervised multi-class algorithms. Compared with other semi-supervised ordinal regression algorithms, our experimental results show that IL-SSOR can achieve similar generalization with less running time.

Network pharmacology, molecular docking technology integrated with pharmacodynamic study to reveal the potential targets of Schisandrol A in drug-induced liver injury by acetaminophen.

Schisandrae Chinensis Fructus (SCF) was a Traditional Chinese Medicine for protecting liver. However, underlying therapeutic mechanisms of these bioactive lignans from SCF similar hepatoprotective effects against drug-induced liver injury (DILI) by acetaminophen (APAP) are still unclear. This study aims to discover the potential regulation mechanisms of Schisandrol A in the treatment of DILI by APAP. The integrated UPLC-Q-TOF/MS, pharmacodynamic study, histopathological combination with network pharmacology and molecular docking technology were used to explore the potential mechanisms. The results showed that Schisandrol A reduced the level of AST, ALT, MDA, PNP, TNF-α and IL-1ß, increased the levels of the GSH against acute liver failure. Additionally, Schisandrol A could improve the morphological characteristics of DILI by APAP in mice with liver tissue. Molecular docking results had showed that Schisandrol A with high scores when docking with COX-2, ALOX5, CYP2E1, CYP2C9, CYP2C19, EGFR SRC, Nrf2, MAPK14 and MAPK8. The study demonstrated that Schisandrol A could play critical roles in DILI by APAP via regulating TNF signaling pathway, inhibiting oxidative stress, inflammation and inhibiting the activities of cytochrome P450 enzymes, which contributed to searching for leading compounds and the development of new drugs for DILI by APAP.

Modular Assembly of Ordered Hydrophilic Proteins Improve Salinity Tolerance in Escherichia coli.

Most late embryogenesis abundant group 3 (G3LEA) proteins are highly hydrophilic and disordered, which can be transformed into ordered α-helices to play an important role in responding to diverse stresses in numerous organisms. Unlike most G3LEA proteins, DosH derived from Dinococcus radiodurans is a naturally ordered G3LEA protein, and previous studies have found that the N-terminal domain (position 1-103) of DosH protein is the key region for its folding into an ordered secondary structure. Synthetic biology provides the possibility for artificial assembling ordered G3LEA proteins or their analogues. In this report, we used the N-terminal domain of DosH protein as module A (named DS) and the hydrophilic domains (DrHD, BnHD, CeHD, and YlHD) of G3LEA protein from different sources as module B, and artificially assembled four non-natural hydrophilic proteins, named DS + DrHD, DS + BnHD, DS + CeHD, and DS + YlHD, respectively. Circular dichroism showed that the four hydrophile proteins were highly ordered proteins, in which the α-helix contents were DS + DrHD (56.1%), DS + BnHD (53.7%), DS + CeHD (49.1%), and DS + YLHD (64.6%), respectively. Phenotypic analysis showed that the survival rate of recombinant Escherichia coli containing ordered hydrophilic protein was more than 10% after 4 h treatment with 1.5 M NaCl, which was much higher than that of the control group. Meanwhile, in vivo enzyme activity results showed that they had higher activities of superoxide dismutase, catalase, lactate dehydrogenase and less malondialdehyde production. Based on these results, the N-terminal domain of DosH protein can be applied in synthetic biology due to the fact that it can change the order of hydrophilic domains, thus increasing stress resistance.