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The therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27 days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26 days of treatment. Serum K+ was evaluated after 14 and 27 days of treatment. Urinary Na+, urinary K+, and urinary Na+/K+ ratio were evaluated after 7, 14, and 26 days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC50) for increasing serum K+ to the EC50 for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K+, and decreased urinary Na+ relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5 mg/kg BID while eplerenone did so only at the two highest doses of 50 and 450 mg/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K+ seen in the aldosterone treatment group, with significant increases in serum K+ at the high doses only (5 mg/kg and 450 mg/kg BID, respectively). Additionally, the urinary Na+ and Na+/K+ ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window.

Since December 2019, coronavirus disease 2019 (COVID-19) has been spreading worldwide with devastating immediate or long-term effects on people’s health. Although the lungs are the primary organ affected by COVID-19, individuals infected with SARS-CoV-2 also develop systemic lesions involving multiple organs throughout the body, such as the cardiovascular system. Emerging evidence reveals that COVID-19 could generate myocardial fibrosis, termed “COVID-19-associated myocardial fibrosis.” It can result from the activation of fibroblasts via the renin-angiotensin-aldosterone system (RAAS), transforming growth factor-β1 (TGF-β1), microRNAs, and other pathways, and can also occur in other cellular interactions with SARS-CoV-2, such as immunocytes, endothelial cells. Nonetheless, to gain a more profound insight into the natural progression of COVID-19-related myocardial fibrosis, additional investigations are necessary. This review delves into the underlying mechanisms contributing to COVID-19-associated myocardial fibrosis while also examining the antifibrotic potential of current COVID-19 treatments, thereby offering guidance for future clinical trials of these medications. Ultimately, we propose future research directions for COVID-19-associated myocardial fibrosis in the post-COVID-19 era, such as artificial intelligence (AI) telemedicine. We also recommend that relevant tests be added to the follow-up of COVID-19 patients to detect myocardial fibrosis promptly.

BackgroundPeroxisome proliferator-activated receptor (PPAR) agonists are recognised as a promising treatment for primary biliary cholangitis (PBC). However, the effects and safety of these agonists on PBC remain unexplored. Our study aimed to investigate the efficacy and safety of PPAR agonists in treating PBC.MethodsWe searched Cochrane Library, and Web of Science, PubMed, and Embase databases from inception to 15 March 2024 for randomised controlled studies (RCTs) that enrolled individuals with PBC treated with PPAR agonists compared with placebo. The primary outcomes were biochemical response and normalization of the alkaline phosphatase (ALP) level.ResultsEight RCTs involving 869 participants in total were included. The meta-analysis revealed that compared to placebo, PPAR agonists increased the rate of biochemical response (RR: 5.53; 95% CI: 3.79, 8.06) and normalization of the ALP level (RR: 17.18; 95% CI: 5.61, 52.61). In addition, PPAR agonists can also reduce alanine aminotransferase (ALT) (MD: −12.69 U/L; 95% CI: −18.03, −7.35), aspartate aminotransferase (AST) (MD: −4.18 U/L; 95% CI: −7.28, −1.08), ALP (MD: −142.95 U/L; 95% CI: −167.29, −118.60), γ-glutamyltransferase (GGT) (MD: −63.03 U/L; 95% CI: −92.08, −33.98), and total cholesterol (TC) levels (SMD: −0.71; 95% CI: −1.38, −0.04), and there was no significant difference in overall adverse reactions (RR: 0.99; 95% CI: 0.92, 1.05), serious adverse reactions (RR: 1.10; 95% CI: 0.70, 1.72) between the two groups.ConclusionPPAR agonists are safe and well-tolerated in patients with PBC and are effective in improving the rate of biochemical response and related biomarkers.

NSCLC (non-small cell lung cancer) is one of the most common and lethal malignant tumors, with low 5-year overall survival rate. Curcumol showed antitumor activity in several cancers, but evidence about its effect on NSCLC remains unclear. In the present study, we found that Curcumol markedly inhibited NSCLC cells proliferation, migration and invasion. Endothelial cells are an important part of tumor microenvironment. Tube formation assay and wound healing assay indicated that A549 derived conditioned medium affected HUVECs (human umbilical vein endothelial cells). Mechanistically, Curcumol downregulated the expression of SP1 (specificity protein 1) while upregulated miR-125b-5p, followed by decreasing VEGFA expression in NSCLC cells. Furthermore, overexpression of SP1 partially reversed the inhibitory effect of Curcumol on A549 and H1975 cell viability and VEGFA expression. Inhibition of miR-125b-5p presented similar effect. Interestingly, there was mutual modulation between SP1 and miR-125b-5p. Collectively, our study revealed that Curcumol inhibited cell growth and angiogenesis of NSCLC in vitro and in vivo, possibly through SP1/miR-125b-5p/VEGFA regulatory mechanism. These findings may provide effective therapy strategies for NSCLC treatment.

Green tea (GT) and oolong tea (OLT) are widely consumed beverages, and their preventive and regulatory effects on hypertension have been reported. However, the interventional effects of GT and OLT on hypertension induced by a high-salt diet and its mechanism have not been fully explored. This study evaluated the anti-hypertensive effects of GT and OLT and their underlying mechanisms. The in vivo anti-hypertensive effects of GT and OLT and their capability to prevent hypertension and regulate the intestinal microbiota in Wistar rats fed with a high-salt diet were evaluated. Our results show that GT and OLT supplementations could regulate oxidative stress, inflammation, gene expression, and parameter levels related to blood pressure (BP) and prevent the increase in BP induced by a high-salt diet. Furthermore, both GT and OLT boosted the richness and diversity of intestinal microbiota, increased the abundance of beneficial bacteria and reduced the abundance of harmful bacteria and conditionally pathogenic bacteria, and regulated the intestinal microbial metabolism pathway related to BP. Among them, OLT presented better effects than GT. These findings indicate that GT and OLT can prevent hypertension caused by high-salt diets, which may be due to the regulation of intestinal flora by GT and OLT.

Cognitive diagnostic test design (CDTD) has a direct impact on the pattern match ratio (PMR) of the classification of examinees. It is more helpful to know the quality of a test during the stage of the test design than after the examination is taken. The theoretical construct validity (TCV) is an index of the test quality that can be calculated without testing, and the relationship between the PMR and the TCV will be revealed. The TCV captures the three aspects of the appeal of the test design as follows: (1) the TCV is a measure of test construct validity, and this index will navigate the processes of item construction and test design toward achieving the goal of measuring the intended objectives, (2) it is the upper bound of the PMR of the knowledge states of examinees, so it can predict the PMR, and (3) it can detect the defects of test design, revise the test in time, improve the efficiency of test design, and save the cost of test design. Furthermore, the TCV is related to the distribution of knowledge states and item categories and has nothing to do with the number of items.

Psoriasis is a chronic proliferative skin disorder characterised by abnormal epidermal differentiation. The Fuzhenghefuzhiyang (FZHFZY) formula created by Chuanjian Lu, a master of Chinese medicine in dermatology, has been external used in the Guangdong Provincial Hospital of Chinese Medicine for the treatment of psoriasis, but its mechanisms of action against psoriasis remain poorly understood. This study involved an exploration of the effects of FZHFZY on epidermal differentiation and its underlying mechanisms in interleukin (IL)-17A/IL-22/interferon (IFN)-γ/tumour necrosis factor (TNF)-α–stimulated HaCaT cells and in a mouse model of imiquimod (IMQ)-induced psoriasis. Cell viability was assessed by MTT assay. Epidermal differentiation was detected by reverse-transcription polymerase chain reaction and western blotting. Histological evaluation of the skin tissue was performed via haematoxylin and eosin staining, and the Akt/mTORC1/S6K1 pathway was analysed by western blotting. FZHFZY inhibited proliferation and improved epidermal differentiation in IL-17A/IL-22/IFN-γ/TNF-α–induced HaCaT cells. FZHFZY ameliorated symptoms of psoriasis, regulated epidermal differentiation and inhibited phosphorylation of the Akt/mTORC1/S6K1 pathway in the skin of mice with imiquimod-induced psoriasis. Our results suggest that FZHFZY may exhibit therapeutic action against psoriasis by regulating epidermal differentiation via inhibition of the Akt/mTORC1/S6K1 pathway.

Psoriasis is a chronic proliferative autoimmune dermatologic disease characterised by abnormal angiogenesis. Thus, regulating angiogenesis in the skin is an important treatment strategy for psoriasis. PSORI-CM02, an empirical Chinese medicine formula optimised from Yin Xie Ling, was created by the Chinese medicine specialist, Guo-Wei Xuan. Clinical studies have shown that PSORI-CM02 is safe and effective for the treatment of psoriasis. However, its anti-psoriatic mechanisms remain to be further explored. In this study, we investigated the effects of PSORI-CM02 on angiogenesis in the skin and the underlying mechanisms in IL-17A-stimulated human umbilical vein endothelial cells (HUVECs) and a murine model of imiquimod (IMQ)-induced psoriasis. In vitro, PSORI-CM02 significantly inhibited the proliferation and migration of IL-17A-stimulated HUVECs in a dose-dependent manner. Further, it markedly regulated the antioxidative/oxidative status and inflammation; suppressed the expression of VEGF, VEGFR1, VEGFR2, ANG1, and HIF-1α; and reduced the phosphorylation of MAPK signalling pathway components in IL-17A-stimulated HUVECs. In vivo studies showed that PSORI-CM02 markedly reduced angiogenesis in the skin of mice with IMQ-induced psoriasis, while significantly rebalancing antioxidant/oxidant levels; inhibiting the production of IL-6, TNF-α, IL-17A, and IL-17F; and repressing the synthesis of angiogenic mediators. In addition, PSORI-CM02 markedly reduced the activation of the MAPK signalling pathway in psoriatic skin tissue. Taken together, our results demonstrated that PSORI-CM02 inhibited psoriatic angiogenesis by reducing the oxidative status and inflammation, suppressing the expression of angiogenesis-related molecules, and inhibiting the activation of the MAPK signalling pathway in vitro and in vivo.

Solasonine (SS), a natural glycoalkaloid component, has been shown to have potent inhibitory activity and cytotoxicity against many cancer types. However, the precise mechanisms underlying this, particularly in hepatocellular carcinoma (HCC) are poorly understood. In this study, we showed that SS inhibited growth of HCC cells. Mechanistically, we observed that SS increased the expression of miR-375-3p, whereas reducing levels of long non-coding RNAs (lncRNAs) CCAT1 was noticed in HepG2 HCC and other cells. In addition, we found that SS repressed transcription factors, SP1 and interferon regulatory factor 5 (IRF5), protein expressions. There was a reciprocal interaction among miR-375-3p, CCAT1, and SP1. Moreover, SS inhibited IRF5 promoter activity, which was not observed in cells transfected with excessive expressed SP1 vectors. Interestingly, exogenously expressed IRF5 was shown to reverse expressions of SS-inhibited CCAT1 and induced-miR-375-3p; and neutralized SS-inhibited growth of HCC cells. Similar results were also found in vivo mouse model. Collectively, our results show that SS inhibits HepG2 HCC growth through the reciprocal regulation between the miR-375-3p and lncRNA CCAT1, and this results in transcription factor SP1-mediated reduction of IRF5 expression. The regulations and interactions among miR-375-3p, CCAT1, SP1, and IRF5 axis unveil a novel molecular mechanism underlying the anti-HCC growth by SS. IRF5 may be a potential target for treatment of HCC.

Streptococcus suis (S. suis) ranks among the five most important porcine pathogens worldwide and occasionally threatens human health, particularly in people who come into close contact with pigs or pork products. An S. suis infection induces the formation of neutrophil extracellular traps (NETs) in vitro and in vivo, and the NET structure plays an essential role in S. suis clearance. However, the signaling pathway by which S. suis induces NET formation remains to be elucidated. In the present study, we used a label-free quantitative proteomic analysis of mouse NET formation induced by S. suis or phorbol myristate acetate (PMA), a robust NET inducer. Greater than 50% of the differentially expressed proteins in neutrophils infected by S. suis showed similar changes as observed following PMA stimulation, and PKC, NADPH oxidase, and MPO were required for NET formation induced by both stimuli. Because PMA induced robust NET formation while S. suis (MOI = 2) induced only weak NET formation, the association between the inducer and NET formation was worth considering. Interestingly, proteins involved in peptidase activity showed significant differential changes in response to each inducer. Of these peptidases, MMP-8 expression was obviously decreased in response to PMA, but it was not significantly changed in response to S. suis. A subsequent study further confirmed that MMP-8 activity was inversely correlated with NET formation induced by both stimuli. Therefore, the present study provides potentially important information about the manner by which neutrophils responded to the inducers to form NETs.