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Danshen-Shanzha Formula (DSF) is a well-known herbal combination comprising Radix Salvia Miltiorrhiza (known as Danshen in Chinese) and Fructus Crataegi (known as Shanzha in Chinese), It has been documented to exhibit considerable benefits for promoting blood circulation and removing blood stasis, and was used extensively in the treatment of atherosclerotic cardiac and cerebral vascular diseases over decades. Despite several breakthroughs achieved in the basic research and clinical applications of DSF over the past decades, there is a lack of comprehensive reviews summarizing its features and research, which hinders further exploration and exploitation of this promising formula. This review aims to provide a comprehensive interpretation of DSF in terms of its ethnopharmacological relevance, preparation methods, chemical constituents, pharmacokinetic properties and pharmacological effects. The related information on Danshen, Shanzha, and DSF was obtained from internationally recognized online scientific databases, including Web of Science, PubMed, Google Scholar, China National Knowledge Infrastructure, Baidu Scholar, ScienceDirect, ACS Publications, Online Library, Wan Fang Database as well as Flora of China. Data were also gathered from documentations, printed works and classics, such as the Chinese Pharmacopoeia, Chinese herbal classics, etc. Three essential avenues for future studies were put forward as follows: a) Develop and unify the standard preparation method of DSF as to achieve optimized pharmacological properties. b) Elucidate the functional mechanisms as well as the rationality and rule for the compatibility art of DSF by focusing on the clinic syndromes together with the subsequent development of preclinic study system in vitro and in vivo with consistent pathological features, pharmacokinetical behaviour and biomarkers. c) Perform more extensive clinical studies towards the advancement of mechanism-based on evidence-based medicine on the safety application of DSF. This review will provide substantial data support and broader perspective for further research on the renowned formula.

Morus alba L., a common traditional Chinese medicine (TCM) with a centuries-old medicinal history, owned various medicinal parts like Mori folium, Mori ramulus, Mori cortex and Mori fructus. Different medical parts exhibit distinct modern pharmacological effects. Mori folium exhibited analgesic, anti-inflammatory, hypoglycemic action and lipid-regulation effects. Mori ramulus owned anti-bacterial, anti-asthmatic and diuretic activities. Mori cortex showed counteraction action of pain, inflammatory, bacterial, and platelet aggregation. Mori fructus could decompose fat, lower blood lipids and prevent vascular sclerosis. The main chemical components in Morus alba L. covered flavonoids, phenolic compounds, alkaloids, and amino acids. This article comprehensively analyzed the recent literature related to chemical components and pharmacological actions of M. alba L., summarizing 198 of ingredients and described the modern activities of different extracts and the bioactive constituents in the four parts from M. alba L. These results fully demonstrated the medicinal value of M. alba L., provided valuable references for further comprehensive development, and layed the foundation for the utilization of M. alba L.

Tumorigenesis and tumor development are closely related to the abnormal regulation of ubiquitination. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), an E3 ubiquitin ligase critical to the ubiquitination process, plays key roles in the regulation of cancer stem cells, as well as tumor cell functions, including cell proliferation, apoptosis, cell cycle regulation, migration, invasion, epithelial–mesenchymal transition (EMT), and tumor drug resistance, by controlling subsequent protein degradation through ubiquitination. NEDD4L primarily functions as a tumor suppressor in several tumors but also plays an oncogenic role in certain tumors. In this review, we comprehensively summarize the relevant signaling pathways of NEDD4L in tumors, the regulatory mechanisms of its upstream regulatory molecules and downstream substrates, and the resulting functional alterations. Overall, therapeutic strategies targeting NEDD4L to treat cancer may be feasible.

Objective: We compared Chinese and American pharmaceutical companies’ corporate social responsibility (CSR) reports to determine their differences and to analyze the possible reasons for them.Methods: We took as a model the top 500 pharmaceutical companies from Torreya’s (a global investment bank) list of the 1,000 most valuable pharmaceutical companies in the world. We then collected the 2020 corporate social responsibility reports of 97 Chinese and 94 American pharmaceutical companies. These reports were analyzed using software such as ROST Content Mining 6.0 and Gephi 0.92.Results: We formed a high-frequency word list, a semantic network diagram, and a high-frequency word centrality scale for the Chinese and American pharmaceutical corporate social responsibility reports. The Chinese pharmaceutical companies’ corporate social responsibility reports formed a layout of “double centers and double themes,” and the text paid more attention to the disclosure of environmental protection information. The American pharmaceutical companies formed a report presentation form of “three centers and two themes,” focusing on corporate social responsibility information disclosures from the perspective of humanistic care.Discussion: The differences in between Chinese and American pharmaceutical companies’ corporate social responsibility reports may be due to different corporate development strategies, regulatory requirements, social demands, and the concept of “corporate citizenship.” This study makes recommendations for Chinese pharmaceutical companies to better fulfill their CSR at three levels: policy-making, company management, and society.

Objective: The aim of this study was to develop a thermosensitive in situ gel (TISG) as an effective rectal delivery platform for delivering Periplaneta americana extracts (PA) to alleviate ulcerative colitis (UC) and explore the underlying molecular mechanism.Materials and methods: Thermosensitive (poloxamer 407) and adhesive polymers (chondroitin sulfate modified carboxymethyl chitosan, CCMTS) were used to construct the in situ gel. CCMTS and aldehyde poloxamer 407 (P407-CHO) were synthesized and chemically cross-linked by Schiff base reaction to formulate thermosensitive in situ gel, which carried Periplaneta americana extracts (PA/CCMTS-P). The cytotoxicity and cellular uptake of CCMTS-P were investigated in lipopolysaccharide (LPS) -induced macrophages by CCK-8 assay. The anti-inflammatory effects of PA/CCMTS-P were studied in lipopolysaccharide-induced RAW264.7 cells and dextran sulfate sodium (DSS)-induced ulcerative colitis mouse models. In addition, the ability of PA/CCMTS-P to restore the intestinal mucosal barrier after rectal administration was evaluated by immunohistochemical analysis (IHC).Results: PA/CCMTS-P was prepared and characterized as gel with a phase-transition temperature of 32.9°C. The results of the in vitro experiments indicated that the hydrogels promoted the cellular uptake of Periplaneta americana extracts without causing any toxicity as compared to the free gel. PA/CCMTS-P showed superior anti-inflammatory activity both in vitro and in vivo, which restored the damaged intestinal mucosal barrier associated by inhibiting necroptosis in dextran sulfate sodium-induced ulcerative colitis models.Conclusion: The findings from our study show that the rectal administration of PA/CCMTS-P holds a promising potential for the treatment of ulcerative colitis.

Ferroptosis is a newly identified form of cell death that differs from autophagy, apoptosis and necrosis, and its molecular characteristics include iron-dependent lipid reactive oxygen species accumulation, mitochondrial morphology changes, and membrane permeability damage. These characteristics are closely related to various human diseases, especially tumors of the nervous system. Glioblastoma is the most common primary malignant tumor of the adult central nervous system, and the 5-year survival rate is only 4%–5%. This study reviewed the role and mechanism of ferroptosis in glioblastoma and the research status and progress on ferroptosis as a potential therapeutic target. The mechanism of ferroptosis is related to the intracellular iron metabolism level, lipid peroxide content and glutathione peroxidase 4 activity. It is worth exploring how ferroptosis can be applied in disease treatment; however, the relation between ferroptosis and other apoptosis methods is poorly understood and methods of applying ferroptosis to drug-resistant tumors are insufficient. Ferroptosis is a promising therapeutic target for glioblastoma. In-depth studies of its mechanism of action in glioblastoma and applications for clinical treatment are expected to provide insights for glioblastoma patients.

A disintegrin and metalloprotease domain family protein 17 (ADAM17) is a new member of renin-angiotensin system (RAS) but its role in the pathogenesis of diabetic cardiomyopathy (DCM) is obscure. To test the hypothesis that ADAM17 knockdown mitigates while ADAM17 overexpression aggravates cardiac fibrosis via regulating ACE2 shedding and myofibroblast transformation in diabetic mice, ADAM17 gene was knocked down and overexpressed by means of adenovirus-mediated short-hairpin RNA (shRNA) and adenovirus vector carrying ADAM17 cDNA, respectively, in a mouse model of DCM. Two-dimensional and Doppler echocardiography, histopathology and immunohistochemistry were performed in all mice and in vitro experiments conducted in primary cardiofibroblasts. The results showed that ADAM17 knockdown ameliorated while ADAM17 overexpression worsened cardiac dysfunction and cardiac fibrosis in diabetic mice. In addition, ADAM17 knockdown increased ACE2 while reduced AT1R expression in diabetic hearts. Mechanistically, ADAM17 knockdown decreased while ADAM17 overexpression increased cardiac fibroblast-to-myofibroblast transformation through regulation of TGF-β1/Smad3 signaling pathway. In conclusion, ADAM17 knockdown attenuates while ADAM17 overexpression aggravates cardiac fibrosis via regulating ACE2 shedding and myofibroblast transformation through TGF-β1/Smad3 signaling pathway in diabetic mice. Targeting ADAM17 may provide a promising approach to the prevention and treatment of cardiac fibrosis in DCM.

Introduction: Chronic inflammation is the core mechanism of the development of chronic obstructive pulmonary disease (COPD). Corticosteroid resistance in COPD limits its anti-inflammatory potency. p38 MAPKIs were suggested as an alternative to corticosteroids despite the fact that there is currently no systematic review evaluating existing evidence.Methods: This randomized controlled trials (RCT)-based systematic review with meta-analysis was conducted following the PRISMA statement. RCTs were searched and screened from 8 databases. Three types of data, including basic information of included studies, pre-defined outcome data, and quality assessment information were extracted. Pooling values and associated 95 % confidence intervals were deemed as statistically significant only when two-tailed p values were smaller than 0.05.Results: This study included 10 RCTs with a total population of 1,751 [age, mean (SD) = 64.39 (8.06)]. Safety and several efficacy indicators of lung function, inflammatory biomarkers, and quality of life were meta-analyzed. Despite the improvement of post-bronchodilator-forced vital capacity (FVC), no difference between p38 MAPKIs and placebo was found in both safety and efficacy.Conclusion: Compared with placebo, p38 MAPKIs are safe but did not show any significant effects in the COPD population. Results of this study should be regarded with caution due to the small number of included studies and heterogeneity from combining different p38 MAPKIs as a whole.Systematic Review registration: PROSPERO #CRD42022302890.

EPM2A encodes a dual specificity phosphatase and has been proven to be a potential biomarker in several cancers but has not been mentioned in prostate cancer (PCA). We investigated the prognostic and therapeutic value of EPM2A in PCA. The TCGA-PRAD cohort was collected to evaluate the differential expression, prognostic value, immunocyte infiltration and drug sensitivity of EPM2A in PCA. We constructed a nomogram model to predict the recurrence probability for PCA patients. Immunohistochemistry was used to validate the different transcript levels of EPM2A between tumor and normal tissues. A real-world AHMU-PC cohort was employed for validation. The results showed decreased expression of EPM2A in 95.65% of tumor tissues and was related to their prognosis, especially PCA (p = 0.008, HR = 0.57, 95% CI: 0.371–0.863). Further multiple analysis by adjusting clinical features revealed that EPM2A acted as an independent prognostic factor (p = 0.014, HR = 0.589, 95% CI: 0.386–0.898). Pathway enrichment analysis showed variable signaling activation between high EPM2A expression patients (HEXP) and low EPM2A expression patients (LEXP). The HEXP group contained higher infiltration of immunocytes than the LEXP group, as well as high levels of PD-1, PD-L1 and PD-L2, while LEXP patients were more sensitive to cisplatin, paclitaxel and bicalutamide therapy. The nomogram containing the EPM2A group, T stage and Gleason score showed a preferable prognostic value (AUC = 0.755; Hosmer‒Lemeshow, p = 0.486). In validation, we confirmed the lower transcript level of EPM2A in PCA than in normal tissues (120.5 ± 2.159 vs. 138.3 ± 1.83, p = 0.035) and correlated it with the expression level of PD-1 (R = 0.283). Among the 66 patients from the AHMU-PC cohort, we further validated the function of EPM2A in PCA patients. HEXP patients had longer recurrence-free survival times (1207 ± 110 vs. 794.2 ± 97.02, p = 0.0063) and favorable prognoses (HR: 0.417, 95% CI: 0.195–0.894, p = 0.0245). Collectively, we identified the prognostic value of EPM2A in PCa via a bioinformatics method. Patients with higher EPM2A may be more sensitive to immunotherapy, and patients with lower EPM2A were more suitable for bicalutamide, cisplatin and paclitaxel therapy.

Renal tubulointerstitial fibrosis (TIF), characterized by epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells, is the typical pathological alteration in diabetic nephropathy. Gentiopicroside (GPS), a natural compound with anti-inflammatory activity, has been demonstrated to alleviate glomerulosclerosis, whereas whether GPS inhibits TIF via regulating inflammation remains unclear. In this study, diabetic db/db mice and high glucose (HG)-stimulated renal tubular epithelial cells (NRK-52E) were applied to explore the effects and mechanisms of GPS on TIF. The results in vivo showed that GPS effectively improves glycolipid metabolism disorder, renal dysfunction, and TIF. In particular, GPS treatment reversed the abnormal expressions of EMT marker proteins including elevated α-smooth muscle actin and vimentin and decreased E-cadherin in the kidney of db/db mice. Moreover, GPS treatment also inhibited protein expressions of angiotensinⅡ type 1 receptor (AT1R) and CK2α and the activation of the NF-κB pathway. Importantly, the aforementioned effects of GPS acted in vivo were further observed in vitro in HG-stimulated NRK-52E cells, which were independent of its effects on glucose and lipid-lowering activity but were reversed by AT1R over-expression. Together, our results indicate that GPS that directly inhibits the CK2/NF-κB inflammatory signaling pathway via AT1R may also contribute to the amelioration of TIF in diabetes.

High blood pressure (BP) plays an important role in the pathogenesis and development of cardiovascular diseases and multi-organ damages. Music has been well known to elicit emotional changes, such as anxiolytic effects. However, whether music therapy lowers BP in spontaneously hypertensive rats (SHR) and the potential mechanism remains unknown. SHRs were, respectively exposed to white noise (WN), Western classical music (WM), Chinese classical music (CCM), rock music (RM), and bisoprolol treatment. WN and WM did not lower systemic BP, but CCM and RM significantly lowered BPs in SHRs. The effects of CCM therapy on lowering systemic BPs is comparable to that of bisoprolol at the dose of low to medium. Combination of CCM treatment with bisoprolol further improved systemic BPs and myocardial hypertrophy in SHRs, compared to CCM treatment or bisoprolol alone. Furthermore, IHC and WB analysis indicated that CCM therapy inhibited the β1/cAMP/PKA and α1/PLC/PKC signalings, but didn’t alter the β2/PI3K/Akt signaling. Above all, CCM therapy lowers systemic BPs and alleviates myocardial hypertrophy in hypertensive rats, which may be caused by the inhibitions of β1/cAMP/PKA and α1/PLC/PKC signalings.

Intestinal flora plays an important role in atherosclerosis. Tongxinluo, as a multi-target Chinese medicine to improve atherosclerosis, whether it can improve atherosclerosis by affecting the intestinal flora is worth exploring. We established a vulnerable plaque model of atherosclerosis in New Zealand white rabbits by high cholesterol diet and balloon injury (HCB), and performed Tongxinluo intervention. We detected the level of inflammation by immunohistochemistry, Western Blot, and ELISA, analyzed plaque characteristics by calculating the vulnerability index, and analyzed the changes of gut microbiota and metabolites by 16S rRNA gene sequencing and untargeted metabolomic sequencing. The results showed that Tongxinluo intervention improved plaque stability, reduced inflammatory response, inhibited NLRP3 inflammatory pathway, increased the relative abundance of beneficial bacteria such as Alistipes which reduced by HCB, and increased the content of beneficial metabolites such as trans-ferulic acid in feces. Through correlation analysis, we found that some metabolites were significantly correlated with some bacteria and some inflammatory factors. In particular, the metabolite trans-ferulic acid was also significantly positively correlated with plaque stability. Our further studies showed that trans-ferulic acid could also inhibit the NLRP3 inflammatory pathway. In conclusion, Tongxinluo can improve plaque stability and reduce inflammation in atherosclerotic rabbits, which may be achieved by modulating intestinal flora and intestinal metabolism. Our study provides new views for the role of Tongxinluo in improving atherosclerotic vulnerable plaque, which has important clinical significance.

The Fuyou (Fy) formula is an in-hospital preparation consisting of traditional Chinese medicine (TCM) that has been used for treating precocious puberty (PP) for more than 20 years. In this study, we aimed to clarify the effect of the Fy formula and its major components on PP. To confirm the effect of the Fy formula on the release of hypothalamic gonadotropin-releasing hormone (GnRH), GT1-7 cells were treated with estrogen to build the model group and subsequently treated with the Fy formula and its major components to explore their effects on the secretion of GnRH. The level of GnRH in GT1-7 cells was determined using enzyme-linked immunosorbent assay. The results illustrated that, compared to the model group, the Fy formula inhibited the release of GnRH. In addition, the expression levels of proteins related to GnRH secretion, including GnRH, gonadotropin-releasing hormone receptor (GnRHR), Kiss-1 metastasis-suppressor (Kiss1), G-protein coupled receptor 54 (GPR54), estrogen receptor α (ERα), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-1 receptor (IGF-1R), were detected by real-time polymerase chain reaction (RT-qPCR). The results demonstrated that the Fy formula significantly reduced the level of GnRH secretion in the GT1-7 cell lines compared with the model group. Moreover, it significantly downregulated the expression of GnRH, GnRHR, Kiss1, GPR54, ERα, IGF-1, and IGF-1R. In summary, our results indicate that the Fy formula and its major components may inhibit the effects of estrogen, which alleviates PP through transcriptional regulation of target genes.

The KRAS-G12C inhibitor ARS-1620, is a novel specific covalent inhibitor of KRAS-G12C, possessing a strong targeting inhibitory effect on KRAS-G12C mutant tumors. Overexpression of ATP-binding cassette super-family B member 1 (ABCB1/P-gp) is one of the pivotal factors contributing to multidrug resistance (MDR), and its association with KRAS mutations has been extensively studied. However, the investigations about the connection between the inhibitors of mutant KRAS and the level of ABC transporters are still missing. In this study, we investigated the potential drug resistance mechanism of ARS-1620 associated with ABCB1. The desensitization effect of ARS-1620 was remarkably intensified in both drug-induced ABCB1-overexpressing cancer cells and ABCB1-transfected cells as confirmed by cell viability assay results. This desensitization of ARS-1620 could be completely reversed when co-treated with an ABCB1 reversal agent. In mechanism-based studies, [3H] -paclitaxel accumulation assay revealed that ARS-1620 could be competitively pumped out by ABCB1. Additionally, it was found that ARS-1620 remarkably stimulated ATPase activity of ABCB1, and the HPLC drug accumulation assay displayed that ARS-1620 was actively transported out of ABCB1-overexpressing cancer cells. ARS-1620 acquired a high docking score in computer molecular docking analysis, implying ARS-1620 could intensely interact with ABCB1 transporters. Taken all together, these data indicated that ARS-1620 is a substrate for ABCB1, and the potential influence of ARS-1620-related cancer therapy on ABCB1-overexpressing cancer cells should be considered in future clinical applications.

Post-stroke depression (PSD) is the most common non-cognitive neuropsychiatric complication after stroke, and about a third of patients with stroke have depression. Although a great deal of effort has been made to treat PSD, the efficacy thereof has not been satisfactory, due to the complex pathological mechanism underlying PSD. In Traditional Chinese Medicine (TCM) theory, PSD is considered to be a combination of “stroke” and “Yu Zheng.” The holistic, multi-drug, and multi-objective nature of TCM is consistent with the treatment concept of systems medicine for PSD. TCM has a very long history of being used to treat depression, and various TCM prescriptions have been clinically proven to be effective in improving depression. Among the numerous prescriptions for treating depression, Shugan Jieyu capsule (SG) is one of the classic prescriptions. Additionally, clinical studies have increasingly confirmed that using SG alone or in combination with Western medicine can significantly improve the psychiatric symptoms of PSD patients. Here, we reviewed the mechanism of antidepressant action of SG and its targets in PSD pathologic systems. This review provides further insights into the pharmacological mechanism, drug interaction, and clinical application of TCM prescriptions, as well as a basis for the development of new drugs to treat PSD.

Background: Ulcerative colitis (UC) is a chronic recurrent disease of unknown etiology. Recently, it has been reported that autophagy-related gene polymorphism is closely associated with increased risk of UC, and the therapeutic effect of some UC drugs is mediated by regulating autophagy pathways. This study aims to identify pivotal autophagy-related regulators in UC pathogenesis and provide novel molecular targets for the treatment of active UC.Methods: Gene expression profiles and clinical information of active UC patients were obtained from GEO databases. CIBERSORT was adopted to evaluate the immune cell infiltration. We used weighted gene co-expression network analysis (WGCNA) and differential expression analysis to identify the pivotal modules and genes associated with active UC. Subsequently, we conducted validation in the validation set and explored its relationship with commonly used UC therapeutics.Results: 36 healthy controls and 46 active UC patients have been obtained from the training set of GSE53306, GSE87466, and GSE134025. There were 423 differentially expressed genes (DEGs) found, which dramatically enriched in autophagy-related pathways. And more infiltration of mast cells, activated T cells, dendritic cells, and M1 macrophages were observed in the intestinal mucosa of active UC, while more infiltration of resting immune cells and M2 macrophages in healthy controls. WGCNA indicated that the turquoise and blue modules were the critical modules. CASP1, SERPINA1, and CCL2 have been identified as the hub autophagy-related genes of active UC, after combining DEGs and 232 autophagy-related genes from HADb with the genes of turquoise and blue modules, respectively. We further verified that CASP1, SERPINA1, and CCL2 were positively associated with active UC and served as an autophagy-related biomarker for active UC. Moreover, increased SERPINA1 in the involved intestinal mucosa was reduced in patients with active UC who responded to golimumab or glucocorticoid therapy. But, neither CASP1, SERPINA1, and CCL2 were changed by treatment of 5-aminosalicylic acid (5-ASA) and azathioprine.Conclusion: CASP1, SERPINA1, and CCL2 are autophagy-related hub genes of active UC. And SERPINA1 may serve as a new pharmacological autophagy regulator of UC, which provides a new target for the use of small molecules targeting autophagy in the treatment of active UC.

Background: Although the predominant airway inflammation in chronic obstructive pulmonary disease (COPD) is neutrophilic, approximately 20–40% of COPD patients present with eosinophilic airway inflammation. Compared with non-eosinophilic COPD patients, eosinophilic COPD patients are characterized by a greater number of total exacerbations and higher hospitalization rates. Furthermore, anti-interleukin-5 (IL-5) therapy, consisting of monoclonal antibodies (mAbs) targeting IL-5 or IL-5 receptor α (IL-5Rα), has been proven to be effective in severe eosinophilic asthma. This meta-analysis aimed to determine the efficacy and safety of anti-IL-5 therapy in eosinophilic COPD.Methods: We searched the PubMed, Web of Science, Embase, and Cochrane Library databases from inception to August 2020 (updated in June 2021) to identify studies comparing anti-IL-5 therapy (including mepolizumab, benralizumab, and reslizumab) with placebo in eosinophilic COPD patients.Results: Anti-IL-5 therapy was associated with a decrease in acute exacerbation rate (RR 0.89; 95% CI 0.84 to 0.95, I2 = 0%) and the severe adverse events (RR 0.90; 95% CI 0.84 to 0.97, I2 = 0%). However, no significant improvement was observed in pre-bronchodilator forced expiratory volume in 1 s (FEV1) (WMD 0.01; 95% CI −0.01 to 0.03, I2 = 25.9%), SGRQ score (WMD −1.17; 95% CI −2.05 to −0.29, I2 = 0%), and hospital admission rate (RR 0.91; 95% CI 0.78 to 1.07, I2 = 20.8%).Conclusion: Anti-IL-5 therapy significantly reduced the annual acute exacerbation rate and severe adverse events in eosinophilic COPD patients. However, it did not improve lung function, quality of life, and hospitalization rate.

Objective: The iridoid glycosides were extracted and separated from Osmanthus fragrans seeds, and the potential protective effect of Osmanthus fragrans seed extract on concanavalin A-induced immune liver injury in mice was studied.Methods:Osmanthus fragrans seeds were extracted by 95% ethanol reflux. Then, the iridoid glycosides were enriched by extraction refined through petroleum ether (60°C–90°C), ethyl acetate, and water-saturated n-butanol in sequence, so as to purify the n-butanol part (Osmanthus fragrans seed’s n-butanol extraction, OFSN) by macroporous resin. Specnuezhenide and Nuezhenoside G13 were used as the reference substances to determine the concentration of iridoid glycosides by HPLC. On this basis, a mouse immune liver injury model was established by tail intravenous concanavalin A (20 mg/kg); the contents of serum ALT, AST, IFN-γ, and TNF-α and the contents of liver tissue MDA and SOD were determined; the pathological changes of the liver by HE staining were observed; and the expression levels of p38MAPK and p-p38mapk in liver tissue were detected by WB.Results: The linearity, precision, repeatability, recovery, and stability of HPLC all met the requirements by validating with the methodology. The contents of Specnuezhenide and Nuezhenoside G13 in the n-butanol extracts were 39.20% and 39.88%, respectively. Actually, their contents can reach up to 82.56% and 87.9% after being purified by macroporous resin. The results of animal experiments show that OFSN could significantly reduce the liver and spleen index, reduce the ALT and AST contents in plasma and the MDA content in liver tissue, and then increase the SOD content. Besides, OFSN could also reduce the plasma IFN-γ and TNF-α levels. The HE staining result indicates that the pathological changes in the liver tissues of mice treated with OFSN are alleviated to different degrees while the WB result suggests that OFSN could significantly inhibit the expression of p-p38mapk.Conclusion:Osmanthus fragrans seeds are rich in iridoid glycosides, which has a good protective effect on mouse immune liver injury caused by concanavalin A. The mechanism may be related to inhibiting the phosphorylation of p38MAPK, inhibiting the release of inflammatory mediators, improving the antioxidant capacity of liver cells, and weakening the occurrence of lipid peroxidation.

Sodium dehydroacetate (Na-DHA), a fungicide used in food, feed, cosmetics, and medicine, has been found to cause coagulation aberration accompanied by the inhibition of vitamin K epoxide reductase (VKOR) in the liver in rats. VKOR complex 1 (VKORC1) and VKORC1 like-1 (VKORC1L1) are two homologous VKOR proteins. Little information is available on the effect of Na-DHA on VKORC1L1 in the liver or VKORC1/VKORC1L1 in extrahepatic tissue and sex differences in Na-DHA metabolism. In the present study, after administration of 200 mg/kg Na-DHA by gavage, significant inhibition of VKORC1 or VKORC1L1 expression in tissues, as well as prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), were observed. The PT/APTT in the Na-DHA-exposed males were 1.27- to 1.48-fold/1.17- to 1.37-fold, while the corresponding values in the Na-DHA-exposed females were 1.36- to 2.02-fold/1.20- to 1.70-fold. Serum or tissue Na-DHA concentrations were significantly higher in females than in males. The pharmacokinetic parameters (t1/2, Cmax, AUC0∼24 h, and MRT0∼24 h) of Na-DHA in female rats were significantly higher than those in male rats. Furthermore, cytochrome P450 (CYP) activity was investigated using the cocktail probe method. The results revealed that Na-DHA exhibited an inductive effect on CYP1A2, 2D1/2, and 3A1/2 activities by changing the main pharmacokinetic parameters of probe drugs in male rats. However, no significant change in CYP2E1 activity was found. There were sex differences in the metabolism and coagulation in rats exposed to Na-DHA. The lower metabolism and higher blood Na-DHA concentration in females may be the reasons for higher coagulation sensitivity in female rats.

As an important part of complementary and alternative medicine, traditional Chinese medicine (TCM) has been applied to treat a host of diseases for centuries. Over the years, with the incidence rate of human colorectal cancer (CRC) increasing continuously and the advantage of TCM gradually becoming more prominent, the importance of TCM in both domestic and international fields is also growing with each passing day. However, the unknowability of active ingredients, effective substances, and the underlying mechanisms of TCM against this malignant tumor greatly restricts the translation degree of clinical products and the pace of precision medicine. In this review, based on the characteristics of TCM and the oral administration of most ingredients, we herein provide beneficial information for the clinical utilization of TCM in the prevention and treatment of CRC and retrospect the current preclinical studies on the related active ingredients, as well as put forward the research mode for the discovery of active ingredients and effective substances in TCM, to provide novel insights into the research and development of innovative agents from this conventional medicine for CRC treatment and assist the realization of precision medicine.

Background: The response time-course information of biologics and small targeted molecules for the treatment of moderate to severe plaque psoriasis which helps clinicians to understand the onset of action and maintenance of effect are unclear. Quantitative information about the efficacy comparation of different systemic agents are needed.Methods: Model-based meta-analysis was conducted and longitudinal models were developed by applying two clinical end points commonly reported in the clinical trials of psoriasis: the proportion of patients achieving ≥75% reduction from baseline Psoriasis Area and Severity Index score (PASI75) and the proportion of patients achieving ≥90% reduction from baseline Psoriasis Area and Severity Index score (PASI90).Results: A total of 80 trials of thirteen biological agents and four small targeted molecules covering 235 treatment arms and 40323 patients with moderate to severe plaque psoriasis were included in this analysis. The drugs were divided into five classes of biologics and three classes of small molecules. Two longitudinal models of PASI75 and PASI90 were used to describe the time-varying drug effect and dose-effect relationship. The typical response-time courses for PASI75 and PASI90 increased over time and finally reached to the platform. For PASI75 end point at week 12, of all the therapeutic drugs, risankizumab administered as 150 mg at week 0, week 4, and q12w showed the most efficacious with PASI75 was 85.95% (95%CI, 75.71–92.60%), followed by ixekizumab administered as 160 mg at week 0, and q4w with PASI75 was 85.9% (95%CI, 76.12–92.79%). As for PASI90 end point at week 12, ixekizumab 160 mg at week 0, and q4w showed the greatest percentage of person achieved PASI90 (67.2%; 95%CI, 49.91–77.2%), followed by risankizumab 150 mg at week 0, week 4, and q12w (65.5%; 95%CI, 47.8–75.7%). What’s more, the risankizumab provided the highest response of PASI90 at week 16 and week 24.Conclusions: This study provided a quantitative efficacy comparation of 17 systemic agents for psoriasis in term of efficacy only and that safety was not considered. Risankizumab and ixekizumab showed superiority for both the two end points.

Vascular dementia (VD) is one of the most common forms of dementia, referring to a group of symptoms that mainly manifest as advanced neurocognitive dysfunction induced by cerebrovascular disease (CVD). A significant number of studies have shown that traditional Chinese medicine (TCM) has a clinical impact on VD and thus has promising prospects. There have been many discussions regarding the pharmacological mechanisms involved in treatment of the kidney, elimination of turbidity, and promotion of blood circulation. TCM has a prominent effect on improving patients’ cognitive function and quality of life. In this review, we summarize the pathogenesis of VD in modern medicine and TCM, traditional prescriptions, single-agent effective ingredients and their pharmacological mechanisms for treating VD, highlight TCM’s characteristics, and discuss TCM’s multi-targeted mechanism for the treatment of VD.

Fu-you formula (FY), a Traditional Chinese Medicine (TCM) formula composed of 12 herbs, as an in-hospital preparation, has been used treat to precocious puberty (PP) for decades. However, the lack of phytochemical characterization and mechanism of FY remains the main limitation for its spreading. In this study, we analyze the components and mechanisms of FY in PP, based on the integrated pharmacology. Investigated main constituents, targets, pathways of FY by using an integrative pharmacology, and recognized main constituents by HPLC-MS/MS. Then, observed the levels of Follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogen (E2) in danazol-induced PP in Sprague–Dawley (SD) rats. Lastly, retrospective study analyzed the clinical data of 575 patients who were diagnosed PP, treated by the FY, and followed-up in our hospital from 2014–2020. The result that total of 116 important candidate targets were selected based on pharmacological analysis. Selected the top 10 values key targets such as the estrogen receptor alpha (ESR1) and insulin-like growth factor 1 (IGF1), were localized and the related gene functions were determined. Gene functions were associated with biological regulation, a cellular process, or signaling pathway, such as the Estrogen signaling pathway, MAPK signaling pathway and PI3K-Akt signaling pathway. By recognizing the five compounds related to the ESR1 and IGF1, which are Quercetin, kaempferol, Luteolin, Apigenin, and Emodin. The results of the molecular docking study further showed that the flavonoids had a strong binding affinity for ESR1 and IGF1 after docking into the crystal structure. The results showed that the FY could effectively reduce E2, LH, and FSH levels in SD rats. Furthermore, the results of the retrospective analysis of medical records showed that the FY could remarkably reduce E2 levels in girls with PP.

The purpose of this study was to explore the effect of the traditional Chinese medicine Fuyou formula on precocious puberty (PP). The Fy formula may exert an effect in female rats with PP and GT-7 cells through the GPR54/GnRH signaling pathway. To confirm the effect of the Fy formula on PP through the GPR54/GnRH signaling pathway, we first treated GT1-7 cells with the Fy formula and observed changes in the expression of related genes and proteins and in GnRH secretion. Then, we randomly divided young female Sprague-Dawley rats into the control group, model group, leuprorelin group and the Fy formula group. A PP model was established by injection of danazol on postnatal day 5, and the Fy formula was administered on PND15. The time of vaginal opening, the wet weights of the ovary and uterus, serum hormone levels and the expression of hypothalamic-related genes were observed. We found that the Fy formula delayed vaginal opening, decreased the wet weights and coefficients of the ovary and uterus, decreased the levels of serum hormones (E2, follicle-stimulating hormone and luteinizing hormone) and the cellular GnRH level, and downregulated the gene expression of Kiss1, GPR54 and GnRH in the hypothalamus and the gene and protein expression of GPR54 and GnRH in GT1-7 cells. In conclusion, the Fy formula may alleviate PP via the GPR54/GnRH signaling pathway.

Objective: This study aimed to develop a parent-metabolite joint population pharmacokinetic model to characterize the pharmacokinetic (PK) profile for phosphocreatine (PCr) and its metabolite creatine (Cr) in children with myocarditis and to use this model to study the PK profile of different dosing schemes.Methods: One hundred pediatric patients with myocarditis were enrolled. Blood samples were collected at baseline and approximately 30, 40 or 50, 75, and 180 min after a single dose of phosphocreatine sodium. Plasma PCr and Cr concentrations were determined using an HPLC-MS/MS method. A nonlinear mixed effect model approach was used to build the population pharmacokinetic model. After validation, the model was used for simulations to evaluate the PK profile of different dosing schemes.Results: A total of 997 plasma concentrations (498 for PCr and 499 for Cr) were included in the analysis. A four-compartment chain model (central and peripheral compartments for both PCr and Cr) with the first-order elimination adequately characterized the in vivo process of PCr and Cr. Allometric scaling based on bodyweight was applied to the PK parameters. The covariate analysis identified that the glomerular filtration rate (GFR) was strongly associated with Cr clearance. Bootstrapping and visual predictive checks suggested that a robust and reliable pharmacokinetic model was developed. The simulation results showed that PCr had no accumulation in vivo. With the infusion of PCr, the concentration of Cr increased rapidly.Conclusion: A joint population pharmacokinetic model for PCr and Cr in pediatric patients with myocarditis was successfully developed for the first time.

Our previous study proved that paeonol (Pae) could lower blood glucose levels of diabetic mice. There are also a few reports of its potential use for diabetes treatment. However, the role of Pae in regulating glucose and lipid metabolism in diabetes remains largely unknown. Considering the critical role of serine/threonine kinase B (Akt) in glucose and lipid metabolism, we explored whether Pae could improve glucose and lipid metabolism disorders via Akt. Here, we found that Pae attenuated fasting blood glucose, glycosylated serum protein, serum cholesterol and triglyceride (TG), hepatic glycogen, cholesterol and TG in diabetic mice. Moreover, Pae enhanced glucokinase (GCK) and low-density lipoprotein receptor (LDLR) protein expressions, and increased the phosphorylation of Akt. In insulin-resistant HepG2 cells, Pae increased glucose uptake and decreased lipid accumulation. What’s more, Pae elevated LDLR and GCK expressions as well as Akt phosphorylation, which was consistent with the in vivo results. Knockdown and inhibition experiments of Akt revealed that Pae regulated LDLR and GCK expressions through activation of Akt. Finally, molecular docking assay indicated the steady hydrogen bond was formed between Pae and Akt2. Experiments above suggested that Pae ameliorated glucose and lipid metabolism disorders and the underlying mechanism was closely related to the activation of Akt.

Stroke is the second leading cause of death and the leading cause of long-term disability in the world. There is an urgent unmet need to develop a range of neuroprotective strategies to restrain the damage that occurs in the hours and days following a stroke. Storax, a natural resin extracted from injuring Liquidambar orientalis Mill, has been used to treat acute stroke in traditional Chinese medicine for many centuries. Storax has demonstrated the neuroprotective effects in cerebrovascular diseases. However, the neuroprotective mechanisms activated by storax in ischemia/reperfusion-injured astrocytes have not been elucidated. In this study, we established an oxygen-glucose deprivation/reoxygenation (OGD/R)-induced astrocytes injury model to investigate the effects of storax on OGD/R-induced astrocytes injury and potential mechanisms. Experimental results showed that storax alleviated expression of inflammatory cytokines and protected primary cortical astrocytes injured by OGD/R. Furthermore, storax could inhibit NF-κB activation in injured astrocytes by OGD/R and inhibition of NF-κB with Bay-11-7082 obscured the neuroprotective effects of storax. In conclusion, storax alleviated expression of inflammatory cytokines and protected primary cortical astrocytes injured by OGD/R, which was partially mediated by NF-κB signaling pathway activation.

(-)-Epigallocatechin-3-gallate (EGCG), which is the most abundant catechin in green tea, has many potential health benefits, including decreased weight gain and/or adipose tissue weight. Suggested mechanisms for body weight reduction by EGCG include: (1) a decrease in calorie intake and (2) activation of AMPK in liver, skeletal muscle, and white adipose tissue. However, only one study supports the AMPK hypothesis. To determine the role of AMPK in EGCG-induced reduction of body weight, we administrated 50 mg/kg and 100 mg/kg per day to mice, together with a high-fat diet (HFD), for 20 weeks. EGCG had a significant effect on obesity and decrease in epididymal adipose tissue weight, and also affected serum lipid characteristics, including triglyceride, cholesterol (CHOL), and high- and low-density lipoprotein CHOL (HDL-C, LDL-C) concentrations. In addition, EGCG increased the excretion of free fatty acids from feces. By measuring the mRNA expression levels of genes involved in lipid metabolism, we found that EGCG inhibited the expression of genes involved in the synthesis of de novo fatty acids (acc1, fas, scd1, c/ebpβ, pparγ, and srebp1) and increased the expression of genes associated with lipolysis (hsl) and lipid oxidization in white adipose tissue, in both the HFD and the EGCG groups. However, EGCG significantly increased the expression of genes involved in the synthesis of de novo fatty acids compared with the HFD group. Increased AMPK activity was found in both subcutaneous and epididymal adipose tissues. In conclusion, EGCG can decrease obesity and epididymal white adipose tissue weight in mice, only partially via activation of AMPK.

Objective: Diabetic nephropathy (DN) is a serious complication that may occur during the later stages of diabetes, and can be further exacerbated by podocyte damage. Piperazine ferulate (PF) has well-defined nephroprotective effects and is used clinically in the treatment of chronic nephritis and other kidney diseases. However, the renoprotective effects and mechanisms of PF on DN are not clear. This study aims to investigate the protective effect of PF on DN and its mechanism of action, to inform the clinical application of PF in DN treatment. Methods: Network pharmacology was performed to predict themechanism of action of PF in DN. Male Sprague Dawley rats were intraperitoneally injected with STZ (60 mg/kg) to establish a DN model, and then assessed for renal injury after 12 weeks of administration. In vitro, rat podocytes were treated with 25 mmol/L glucose and cultured for 24 h, followed by an assessment of cell injury. Results: Our results showed that PF significantly improved renal function, reduced renal pathological changes, decreased inflammatory response, and alleviated podocyte damage in DN rats. PF also attenuated glucose-induced podocyte injury in vitro. Regarding molecular mechanisms, our study demonstrated that PF downregulated the expression of genes and proteins related to AGE-RAGE-mediated inflammatory signaling. Conclusion: In summary, PF exerts its renoprotective effects by decreasing inflammation and protecting against podocyte injury through the inhibition of the AGE/RAGE/NF-κB/NLRP3 pathway. Overall, these data support the clinical potential of PF as a renoprotective agent in DN. [ABSTRACT FROM AUTHOR]

Background: Several taxane-based chemotherapy regimens are effective in the treatment of gastric cancer; nevertheless, their comparative efficacy and safety remain disputed. This network meta-analysis (NMA) was designed to compare the efficacy and safety of different taxane-based chemotherapy regimens against gastric cancer.Methods: A comprehensive search was conducted to identify all relevant randomized controlled trials (RCTs) in multiple electronic databases. A Bayesian NMA was performed to combine the direct and indirect evidence and estimate the comparative efficacy and safety of different taxane-based chemotherapy regimens simultaneously by utilizing WinBUGS 1.4.3 and Stata 13.1 software. The efficacy outcomes included overall survival rate (OS), progression-free survival (PFS), and overall response rate (ORR), and the safety outcomes were adverse reactions (ADRs), namely, neutropenia, leucopenia, vomiting, and fatigue.Results: A total of 37 RCTs were identified involving 7,178 patients with gastric cancer, and 10 taxane-based chemotherapy regimens (RT, T, TC, TCF, TF, TO, TOF, mTCF, mTF, and mTOF) were collected in gastric cancer therapy. According to the results of cluster analysis, compared with other taxane-based chemotherapy regimens, the regimens of TOF, mTCF, and TF were associated with the most favorable clinical efficacy in improving OS, PFS, and ORR. On the other hand, the regimens of T and mTF had the potential to be the most tolerable and acceptable therapeutic alternative in terms of ADRs.Conclusions: The current NMA provides the evidence that the combination of taxanes (paclitaxel or docetaxel) and fluorouracil is associated with the most preferable and beneficial option for patients with gastric cancer, although additional results from multicenter trials and high-quality studies will be pivotal for supporting our findings.