In vivo proximity proteomics uncovers palmdelphin (PALMD) as a Z-disc-associated mitigator of isoproterenol-induced cardiac injury.

Z-discs are core ultrastructural organizers of cardiomyocytes that modulate many facets of cardiac pathogenesis. Yet a comprehensive proteomic atlas of Z-disc-associated components remain incomplete. Here, we established an adeno-associated virus (AAV)-delivered, cardiomyocyte-specific, proximity-labeling approach to characterize the Z-disc proteome in vivo. We found palmdelphin (PALMD) as a novel Z-disc-associated protein in both adult murine cardiomyocytes and human pluripotent stem cell-derived cardiomyocytes. Germline and cardiomyocyte-specific Palmd knockout mice were grossly normal at baseline but exhibited compromised cardiac hypertrophy and aggravated cardiac injury upon long-term isoproterenol treatment. By contrast, cardiomyocyte-specific PALMD overexpression was sufficient to mitigate isoproterenol-induced cardiac injury. PALMD ablation perturbed the transverse tubule (T-tubule)-sarcoplasmic reticulum (SR) ultrastructures, which formed the Z-disc-associated junctional membrane complex (JMC) essential for calcium handling and cardiac function. These phenotypes were associated with the reduction of nexilin (NEXN), a crucial Z-disc-associated protein that is essential for both Z-disc and JMC structures and functions. PALMD interacted with NEXN and enhanced its protein stability while the Nexn mRNA level was not affected. AAV-based NEXN addback rescued the exacerbated cardiac injury in isoproterenol-treated PALMD-depleted mice. Together, this study discovered PALMD as a potential target for myocardial protection and highlighted in vivo proximity proteomics as a powerful approach to nominate novel players regulating cardiac pathogenesis.

The NLRP3 inflammasome in depression: Potential mechanisms and therapies.

Increasing evidence suggests that the failure of clinical antidepressants may be related with neuroinflammation. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is an intracellular multiprotein complex, and has been considered as a key contributor to the development of neuroinflammation. Inhibition of NLRP3 inflammasome is an effective method for depression treatment. In this review, we summarized current researches highlighting the role of NLRP3 inflammasome in the pathology of depression. Firstly, we discussed NLRP3 inflammasome activation in patients with depression and animal models. Secondly, we outlined the possible mechanisms driving the activation of NLRP3 inflammasome. Thirdly, we discussed the pathogenetic role of NLRP3 inflammasome in depression. Finally, we overviewed the current and potential antidepressants targeting the NLRP3 inflammasome. Overall, the inhibition of NLRP3 inflammasome activation may be a potential therapeutic strategy for inflammation-related depression.

Jolkinolide B alleviates renal fibrosis via anti-inflammation and inhibition of epithelial-mesenchymal transition in unilateral ureteral obstruction mice.

Renal fibrosis is a critical pathological process lead to a progressive loss of renal function. Jolkinolide B (JB) is a natural compound with anti-inflammatory activity from Euphorbia fischeriana Steud. The study evaluated the effect of JB on renal fibrosis in mice with unilateral ureteral obstruction (UUO). The results showed that JB could decrease renal fibrotic area, reduce phosphorylation of NF-κB p65 and the release of TNF-α, IL-6 and IL-1ß, restore the expression of vementin, α-SMA and E-cadherin, as well as TGF-ß1 and p-smad2/3. In conclusion, JB might reduce renal fibrosis by inhibiting inflammation induced by NF-κB pathway and EMT mediated by TGF-ß1/Smad pathway.

Recent advances in functional conservation and divergence of recombinase RAD51 and DMC1.

Meiosis is a specialized cell division that occurs in reproductive cells during sexual reproduction. It contains once DNA replication following nucleus division twice, thus producing haploid gametes. Fusion of male and female gametes restores genome to the diploid level, which not only ensures the genome stability between generations during sexual reproduction, but also leads to genetic diversity among offspring. Meiosis homologous recombination (HR) is one of the crucial events during meiotic prophase I, and it not only ensures the subsequently faithful segregation of homologous chromosomes (homologs), but also exchanges genetic information between homologs with greatly increasing the genetic diversity of progeny. RAD51 (RADiation sensitive 51) and DMC1 (disruption Meiotic cDNA 1) are essential recombinases for the HR process, and have certain commonalities and differences. In this review, we summarize and compare the conserved and differentiated features of RAD51 and DMC1 in terms of origin, evolution, structure, and function, we also provide an outlook on future research directions to further understand and study the molecular mechanisms in regulation of meiotic recombination.

[Pharmacodynamic substances and therapeutic potential of Wuji Pills:based on UPLC-Q-TOF-MS/MS and network pharmacology].

As a classic prescription, Wuji Pills is composed of Coptidis Rhizoma, Euodiae Fructus Preparata, and stir-fried Paeo-niae Radix Alba at the ratio of 6∶1∶6. The practical application of it is limited compared with other famous Chinese medicine prescriptions. Only one company produces Wuji Pills in China. In this study, ultra-performance liquid chromatography quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS/MS) was used to analyze and identify 26 identical compounds from Wuji Pills and drug-containing plasma of rats. Based on these components, 46 potential targets were screened out with network pharmacology methods, followed by the component-target network construction, Gene Ontology(GO) term enrichment, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment, and disease prediction. It was concluded that Wuji Pills acted on core targets such as PTGS2, PTSG1, NCOA2, HSP9 OAD1, and RXRA through magnoflorine, hydroxyevodiamine, daucosterol, and berberine and exerted pharmacodynamic effects through various pathways such as calcium ion signaling pathway, phosphatidylinositol-3-kinase-protein kinase B(PI3 K-Akt) signaling pathway, and vascular endothelial growth factor(VEGF) signaling pathway. Thus, Wuji Pills has therapeutic potential for Alzheimer's disease, diabetes mellitus, myocardial ischemia, and other diseases in addition to the conventional disease(irritable bowel syndrome, IBS). The above research results can provide a reference for the comprehensive interpretation of the pharmacodynamic basis of Wuji Pills and the expansion of clinical application. At the same time, a lot of components in serum and the in vivo transformed and metabolized components of Wuji Pills have similar structure and relative molecular weight. In theory, these components may show additive effects and the competitive/antagonistic effects on the same target. According to the hypothesis of "additive effect of multiple components for a single target" in traditional Chinese medicine, multiple similar components may exert the additive effects on local targets. This study can partly prove the scientificity of this hypothesis and provide laboratory evidence.

Loganin improves chronic unpredictable mild stress-induced depressive-like behaviors and neurochemical dysfunction.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornus officinalis Sieb. et Zucc., is a valuable herb commonly used in Chinese medicine clinics. Loganin is a major iridoid glycoside obtained from the traditional Chinese herb Corni Fructus. Loganin, which has been shown to improve depression-like behavior in mice exposed to acute stress, is probably a potential antidepressant candidate. AIM OF THE STUDY: Loganin was evaluated for its effect on chronic unpredictable mild stress (CUMS) induced depressive-like mice, and its action mechanisms were explored. MATERIALS AND METHODS: ICR mice were subjected to the CUMS stimulation method to induce depression. The therapeutic effect of loganin on depressive-like behavior was evaluated by a series of behavioral tests such as sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST) and open-field test (OFT). In addition, the serum levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were measured using ELISA. The levels of monoamine neurotransmitters were detected by high performance liquid chromatography-electrochemical detection (HPLC-ECD). The levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were measured using western blot analysis. RESULTS: The results showed that CUMS induced depressive-like behaviors in mice, as indicated by behavioral tests. Administration of loganin increased the sucrose preference in SPT, as well as decreased the immobility time in FST and TST. Loganin could also improve food intake, and increased crossing times in the OFT. In mechanism, loganin restored the secretion of monoamine neurotransmitters, ACTH and CORT to normal levels. In addition, loganin elevated the expression of BDNF in the hippocampus. In conclusion, loganin exerts antidepressant-like effects in CUMS model mice through modulating monoamine neurotransmitters, ACTH, CORT and BDNF. CONCLUSION: Loganin effectively ameliorated depressive-like symptoms in CUMS-exposed mice by increasing 5-hydroxytryptamine (5-HT) and dopamine (DA) levels, alleviating hypothalamic-pituitary-adrenal (HPA) axis dysfunction, and increasing BDNF expression. In conclusion, the findings of the current study extensive evidence for the application of loganin in stress-associated disorders, specifically targeting depression.

Epimedii Herba: An ancient Chinese herbal medicine in the prevention and treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, progressive inflammatory and systemic autoimmune disease resulting in severe joint destruction, lifelong suffering and considerable disability. Diverse prescriptions of traditional Chinese medicine (TCM) containing Epimedii Herba (EH) achieve greatly curative effects against RA. The present review aims to systemically summarize the therapeutic effect, pharmacological mechanism, bioavailability and safety assessment of EH to provide a novel insight for subsequent studies. The search terms included were "Epimedii Herba", "yinyanghuo", "arthritis, rheumatoid" and "Rheumatoid Arthritis", and relevant literatures were collected on the database such as Google Scholar, Pubmed, Web of Science and CNKI. In this review, 15 compounds from EH for the treatment of RA were summarized from the aspects of anti-inflammatory, immunoregulatory, cartilage and bone protective, antiangiogenic and antioxidant activities. Although EH has been frequently used to treat RA in clinical practice, studies on mechanisms of these activities are still scarce. Various compounds of EH have the multifunctional traits in the treatment of RA, so EH may be a great complementary medicine option and it is necessary to pay more attention to further research and development.

Low SOX12 Expression Is Correlated With Poor Prognosis in Patients With Gastric Cancer.

BACKGROUND: SRY-related HMG box-12, which is associated with the prognosis of cancer, has been frequently described. However, both SRY-related HMG box-12 expression and its relationship with clinicopathological variables and patient survival have not been defined in gastric cancer. The aim of our study was to examine the prognostic value of SRY-related HMG box-12 expression in patients with gastric cancer. METHODS: In this study, we determined SRY-related HMG box-12 expression in 79 primary gastric cancer tissues and 79 matched adjacent nontumor tissues by immunohistochemistry and then calculated the survival rate using the Kaplan-Meier method. Cox proportional hazard regression model was used to analyze predictors of gastric cancer. Western blot and quantitative real-time polymerase chain reaction were used to investigate the difference in SRY-related HMG box-12 expression between normal gastric epithelial cells and gastric cancer cells at the protein level and RNA level, respectively. RESULTS: SRY-related HMG box-12 was downregulated in gastric cancer tissues. Low SRY-related HMG box-12 expression was significantly associated not only with lymph node metastasis (P = .027) and TNM stage (P = .021) but also with disease-specific survival in patients with gastric cancer. Multivariate analysis demonstrated TNM stage was an independent factor predicting poor survival (P = .034). CONCLUSIONS: Low SRY-related HMG box-12 expression is associated with poor clinical outcomes in gastric cancer.