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Cuproptosis is a recently reported new mode of programmed cell death which might be a potential co-pathogenesis of three kinds of primary cardiomyopathy. However, no investigation has reported a clear relevance between primary cardiomyopathy and cuproptosis. In this study, the differential cuproptosis-related genes (CRGs) shared by three kinds of primary cardiomyopathy were identified in training sets. As a result, four CRGs shared by three kinds of primary cardiomyopathy were acquired and they were mainly related to biological processes such as cell death and immuno-inflammatory response through differential analysis, correlation analysis, GSEA, GSVA and immune cell infiltration analysis. Then, three key CRGs (K-CRGs) with high diagnostic value were identified by LASSO regression. The results of nomogram, machine learning, ROC analysis, calibration curve and decision curve indicated that the K-CRGs exhibited outstanding performance in the diagnosis of three kinds of primary cardiomyopathy. After that, in each disease, two molecular subtypes clusters were distinguished. There were many differences between different clusters in the biological processes associated with cell death and immunoinflammation and K-CRGs had excellent molecular subtype identification efficacy. Eventually, results from validation datasets and in vitro experiments verified the role of K-CRGs in diagnosis of primary cardiomyopathy, identification of primary cardiomyopathic molecular subtypes and pathogenesis of cuproptosis. In conclusion, this study found that cuproptosis might be the potential common pathogenesis of three kinds of primary cardiomyopathy and K-CRGs might be promising biomarkers for the diagnosis and molecular subtypes identification of primary cardiomyopathy.

Total flavones of Abelmoschus manihot L. Medic (TFA) is the major active component isolated from Chinese herb Abelmoschus manihot L. Medic. TFA has shown neuroprotective effect against cerebral ischemia injury in rats and rabbits. However, the effects of TFA on hind-limb ischemia and the underlying mechanisms remain unclear. Therefore, in the present study, we used a rat hind-limb ischemia model to investigate protective effect of TFA against limb ischemia injury. The rat model of hind-limb ischemia was established. Treatment groups received TFA at two different doses (160 and 40mg/kg) daily for 10 days. Sham operated control group and model group received saline. At the end the rats were sacrificed, hindlimb tissues were stained with Haematoxylin-Eosin and Masson's trichrome. RNA and protein were extracted from tissues for PCR and Western blot analysis. The results showed that TFA reduced lower limb ischemic injury, recovered tissue volume and diminished fibrosis and muscle degeneration. Mechanistically, we showed that TFA increased the expression of anti-apoptotic factor such as Bcl-2 and survivin, decreased the expression of pro-apoptotic factor such as Caspase 3, Bax and Bak and inhibited the activation of caspase 3 and 9. In summary, this study proves new evidence that TFA protects hind-limb against ischemia injury by inhibiting apoptosis and could be a promising therapeutic agent for acute lower extremity ischemia.

The purpose of this study was to observe the effects of salvianolic acid A (SAA) pretreatment on the myocardium during ischemia/reperfusion (I/R) and to illuminate the interrelationships among dual specificity protein phosphatase (DUSP) 2/4/16, ERK1/2 and JNK pathways during myocardial I/R, with the ultimate goal of elucidating how SAA exerts cardioprotection against I/R injury (IRI). Wistar rats were divided into the following six groups: control group (CON), I/R group, SAA+I/R group, ERK1/2 inhibitor PD098059+I/R group (PD+I/R), PD+SAA+I/R group, and JNK inhibitor SP600125+I/R group (SP+I/R). The cardioprotective effects of SAA on the myocardium during I/R were investigated with a Langendorff device. Heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), maximum rate of ventricular pressure rise and fall (±dp/dtmax), myocardial infarction areas (MIA), lactate dehydrogenase (LDH), and cardiomyocytes apoptosis were monitored. To determine the crosstalk betwee JNK and ERK1/2 via DUSP2/4/16 with SAA pretreatment, siRNA-DUSP2/4/16 were performed. The expression levels of Bcl-2, Bax, caspase 3, p-JNK, p-ERK1/2 and DUSP2/4/16 in cardiomyocytes were assayed by Western blot. Our results showed that LDH, MIA and cell apoptosis were decreased, and various parameters of heart function were improved by SAA pretreatment and SP application. In the I/R group, the expression levels of p-ERK1/2 and DUSP4/16 were not significantly different compared with the CON group, however, the protein expression levels of p-ERK1/2, Bcl-2 and DUSP4/16 were higher, while p-JNK, Bax, caspase 3 and DUSP2 levels were reduced among the SAA+I/R, PD+SAA+I/R and SP+I/R groups. The above indices were not significantly different between the SAA+I/R and SP+I/R groups. Compared with the SAA+I/R group, p-ERK1/2 was increased and p-JNK was decreased in the SAA+si-DUSP2+I/R, however, p-ERK was downregulated and p-JNK was upregulated in SAA+si-DUSP4+I/R group. SAA exerts an anti-apoptotic role against myocardial IRI by inhibiting DUSP2-mediated JNK dephosphorylation and activating DUSP4/16-mediated ERK1/2 phosphorylation.

Baicalin has been acknowledged for its anti-inflammatory properties. However, its potential impact on osteoarthritis (OA) has not yet been explored. Therefore, our study aimed to examine the effects of Baicalin on OA, both in laboratory and animal models. To evaluate its efficacy, human chondrocytes affected by OA were treated with interleukin-1β and/or Baicalin. The effects were then assessed through viability tests using the cell counting kit-8 (CCK-8) method and flow cytometry. In addition, we analyzed the expressions of various factors such as FOXO1, autophagy, apoptosis, and cartilage synthesis and breakdown to corroborate the effects of Baicalin. We also assessed the severity of OA through analysis of tissue samples. Our findings demonstrate that Baicalin effectively suppresses inflammatory cytokines and MMP-13 levels caused by collagenase-induced osteoarthritis, while simultaneously preserving the levels of Aggrecan and Col2. Furthermore, Baicalin has been shown to enhance autophagy. Through the use of FOXO1 inhibitors, lentivirus-mediated knockdown, and chromatin immunoprecipitation, we verified that Baicalin exerts its protective effects by activating FOXO1, which binds to the Beclin-1 promoter, thereby promoting autophagy. In conclusion, our results show that Baicalin has potential as a therapeutic agent for treating OA (Clinical Trial Registration number: 2023-61). [ABSTRACT FROM AUTHOR]

Jiawei Yanghe Decoction (JWYHD) is a widely used traditional Chinese medicine prescription in the clinical setting for the treatment of autoimmune diseases. Many studies showed that JWYHD has anti-tumor activities in cell and animal models. However, the anti-breast cancer effects of JWYHD and the underlying mechanisms of action remain unknown. This study aimed to determine the anti-breast cancer effect and reveal the underlying mechanisms of action i n vivo, in vitro and in silico. Orthotopic xenograft breast cancer mouse model and inflammatory zebrafish model were used to observe the anti-tumor effect and immune cell regulation of JWYHD. Moreover, the anti-inflammatory effect of JWYHD were evaluated by the expression of RAW 264.7 cells. JWYHD active ingredients were obtained by UPLC-MS/MS and potential targets were screened by network pharmacology. The therapeutic targets and signaling pathways predicted by computer were assessed by Western blot, real-time PCR (RT-PCR), immunohistochemistry (IHC) staining, and Enzyme-linked immunosorbent assays (ELISA) to explore the therapeutic mechanism of JWYHD against breast cancer. At last, Colivelin and Stattic were used to explore the effect of JWYHD on JAK2/STAT3 pathway. JWYHD significantly decreased the tumor growth in a dose-dependent manner in the orthotopic xenograft breast cancer mouse model. Flow cytometry and IHC results indicated that JWYHD decreased the expressions of M2 macrophages and Treg while increasing M1 macrophages. Meanwhile, ELISA and Western blot results showed a decrease in IL-1β, IL-6, TNFα, PTGS2 and VEGFα in tumor tissue of JWYHD groups. The results were also verified in LPS-induced RAW264.7 cells and zebrafish inflammatory models. TUNEL assay and IHC results showed that JWYHD significantly induced apoptosis. Seventy-two major compounds in JWYHD were identified by UPLC-MS/MS and Network pharmacology. It was found that the significant binding affinity of JWYHD to TNFα, PTGS2, EGFR, STAT3, VEGFα and their expressions were inhibited by JWYHD. IHC and Western blot analysis showed that JWYHD could decrease the expression of JAK2/STAT3 pathway. Furthermore, Colivelin could reverse the decrease effect of JWYHD in vitro. JWYHD exerts a significant anti-tumor effect mainly by inhibiting inflammation, activating immune responses and inducing apoptosis via the JAK2/STAT3 signaling pathway. Our findings provide strong pharmacological evidence for the clinical application of JWYHD in the management of breast cancer. JWYHD inhibited the release of inflammatory cytokines such as IL-1β, IL-6, TNFα, and PTGS2, promoted immune cell activation, and impaired tumor microenvironment in orthotopic xenograft breast cancer mouse model. JWYHD reduced the inflammatory responses and induced breast cancer cells apoptosis by inhibiting the activation of JAK2/STAT3 signaling pathway. [Display omitted] • Jiaweiyanghe Decoction (JWYHD) achieves significant anti-tumor activity in the orthotopic xenograft breast cancer mouse model. • JWYHD does not affect breast cancer cell proliferation in vitro. • JWYHD display a strong anti-inflammation effect both in vivo, in vitro and in silico. • Orthotopic xenograft mouse model and inflammatory zebrafish model were used in this experiment. • High-throughput and molecular docking are used to screen active components and immune-related potential targets in JWYHD. [ABSTRACT FROM AUTHOR]