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Simple Summary: Targeted therapy for malignant esophageal squamous cell carcinoma (ESCC) remains a big challenge for our clinicians. In an effort to search for the vulnerability of ESCC, we applied a high-throughput drug-screening strategy and found that CuET, a copper chelation product of disulfiram, had a strong synergy effect with the JMJD3/UTX inhibitor GSK J4 in treating ESCC in vitro and in vivo. Interestingly, JMJD3/UTX's diagnostic and prognostic value, as well as the underlying mechanisms associated with endoplasmic reticulum stress were revealed. Targeting JMJD3 and UTX in combination with disulfiram has the potential to provide a new safe, effective, and available therapy for ESCC. The alcohol-averse drug disulfiram has been reported to have anti-tumor effects and is well suited for drug combinations. In order to identify potential drug combinations in esophageal squamous cell carcinoma (ESCC), we screened a bioactive compound library with the disulfiram copper chelation product CuET. The Jumonji domain-containing protein 3 (JMJD3) and the ubiquitously transcribed tetratricopeptide repeat protein X-linked (UTX) inhibitor GSK J4 were identified. To further understand the molecular mechanism underlying the efficient drug combination, we applied quantitative mass spectrometry to analyze the signaling pathway perturbation after drug treatment. The data revealed that the synergistic effect of GSK J4 and CuET was due to the interaction among JMJD3 and UTX, which may play important roles in maintaining endoplasmic reticulum (ER) homeostasis in tumor cells. Interestingly, our clinical data analysis showed that high expression of JMJD3 and UTX was associated with T stage and worse prognosis of ESCC patients, further supporting the importance of the above findings. In conclusion, our findings suggest that the combination of CuET and targeting JMJD3/UTX may be a safe, effective, and available treatment for ESCC. [ABSTRACT FROM AUTHOR]

Objective. Angiogenesis is one of the therapeutic targets of cerebral infarction. Long noncoding RNAs (lncRNAs) can regulate the pathological process of angiogenesis following ischemic stroke. Taurine-upregulated gene 1 (TUG1), an lncRNA, is correlated to ischemic stroke. We intended to determine the effect of TUG1 on angiogenesis following an ischemic stroke. Materials and Methods. Middle cerebral artery occlusion (MCAO) was adopted to build a focal ischemic model of the rat brain, and pcDNA-TUG1 and miR-26a mimics were injected into rats. Neurological function was estimated through modified neurological severity scores. The volume of focal brain infarction was calculated through 2,3,5-triphenyltetrazolium chloride staining. The level of TUG1 and miR-26a was measured by PCR. The expression of vascular endothelial growth factor (VEGF) and CD31 was checked using immunohistochemistry and western blot. The correlation between miR-26a and TUG1 was verified through a luciferase reporter assay. Results. TUG1 increased noticeably while miR-26a was markedly reduced in MCAO rats. Overexpression of miR-26a improved neurological function recovery and enhanced cerebral angiogenesis in MCAO rats. TUG1 overexpression aggravated neurological deficits and suppressed cerebral angiogenesis in MCAO rats. Bioinformatics analysis revealed that miR-26a was one of the predicted targets of TUG1. Furthermore, TUG1 combined with miR-26a to regulate angiogenesis. TUG1 overexpression antagonized the role of miR-26a in neurological recovery and angiogenesis in MCAO rats. Conclusions. TUG1/miR-26a, which may act as a regulatory axis in angiogenesis following ischemic stroke, can be considered a potential target for cerebral infarction therapy. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the antidiarrheal effect of Berberis heteropoda Schrenk roots (BHS), which are used by Chinese minorities to treat diarrhea, through regulation of intestinal flora and related signaling pathways. Wistar rats were randomly divided into 6 groups: Control group (Con), Model group (Mod), three BHS groups (BHS-L (0.65 g/kg), BHS-M (1.955 g/kg), BHS-H (5.86 g/kg) and Bifidobacterium group (Bif). The model of diarrhea-based irritable bowel syndrome (D-IBS) was induced by intragastric administration combined with restraint stress. The CRD method was used to determine the AWR score and the Bristol fecal score. Quantification of the intestinal bacteria groups in feces was performed using colony counting on plates. The mRNA expression levels of Gpr41, Gpr43, TLR2, TLR4, and nuclear protein κB were determined by qRT-PCR, and the relative abundances of intestinal flora in the intestinal contents were determined by high-throughput gene sequencing ratios. Oral administration of BHS (L, M and H) significantly reduced the AWR score and the Bristol fecal score, significantly relieved diarrhea in D-IBS rats, reduced the number of Enterococci and Enterobacteria in feces, increased the number of Bifidobacteria and Lactobacilli , and upregulated the expression of SCFA in plasma. qRT-PCR analysis showed that the expression of TLR2, TLR4, Gpr41, Gpr43 and NF-κB in the BHS groups was downregulated. D-IBS rats reduced the abundance and diversity of intestinal flora and BHS (L, M and H) regulated the abundance and diversity of their intestinal flora. The above data suggest that BHS potentially alleviates diarrhea, intestinal flora disorder and intestinal inflammation in D-IBS rats by regulating the immunological pathways. BHS is a promising agent in the treatment of D-IBS. Image 1 [ABSTRACT FROM AUTHOR]

Myocardial fibrosis (MF) can cause heart remodeling and it is an independent risk factor for malignant arrhythmias, sudden cardiac death, and other malignant cardiovascular events. It is often characterized by myocardial interstitial collagen deposition and hyperproliferation of cardiac fibroblasts (CFs). The transforming growth factor-β1 (TGF-β1) is the most influential profibrogenic factor. Resveratrol (RSV) is an active polyphenol substance that inhibits myocardial fibrosis. The mechanism of RSV-mediated inhibition of the proliferation of CFs at the microRNA level is not fully understood. We used TGF-β1 to induce CFs proliferation to simulate the pathogenesis of myocardial fibrosis. Neonatal rat CFs were treated with TGF-β1 in the presence or absence of resveratrol. Cell proliferation was measured using the CCK-8 and EdU assay. Collagen secretion was measured using hydroxyproline kit. Further, qPCR analysis was performed to determine microRNA levels after TGF-β1 or resveratrol treatment. To identify the target gene for miR-17, miR-17 was overexpressed or silenced, and the mRNA and protein levels of Smad7 were assessed. The effects of miR-17 silencing or Smad7 overexpression on cell proliferation and collagen secretion were also examined. Resveratrol treatment significantly decreased the TGF-β1-induced CF proliferation and collagen secretion. Resveratrol also decreased the levels of miR-17, miR-34a, and miR-181a in TGF-β1-treated CFs. Overexpression of miR-17 decreased the Smad7 mRNA and protein levels while silencing miR-17 increased them. Additionally, silencing miR-17 or overexpressing Smad7 decreased the TGF-β1-induced CFs proliferation and collagen secretion. In conclusion, resveratrol inhibits TGF-β1-induced CFs proliferation and collagen secretion. This inhibitory effect of resveratrol is orchestrated by the downregulation of miR-17 and the regulation of Smad7. [ABSTRACT FROM AUTHOR]

Panax japonicus C. A. Meye (PJ) has unique effects on diseases by "qi" stagnation and blood stasis in ancient. Modern studies have shown that PJ can treat diabetic kidney disease (DKD) caused by deficiency and blood stasis. This study evaluated the potential effects of PJ on DKD, a microvascular complication, and investigated its possible mechanisms. In this study, the chemical constituents of PJ were analyzed by HPLC. In vivo studies, we constructed a diabetic mice model by HDF combined with STZ, then administered PJ to diabetic mice for 6 weeks. Blood lipid, BUN, 24h urine protein, and renal tissue HE staining were detected to comprehensively evaluate the protective effect of PJ on DKD. Metabolomics investigated the metabolic pathways influenced by PJ in the treatment of DKD. Moreover, the potential targets and signal pathways were investigated using network pharmacology. Finally, molecular docking predicts affinity of active compounds and core targets, and western blotting was used to detect core target expression levels. In vivo study, PJ can reduce hyperlipidemia, serum BUN, and 24-h urinary protein in diabetic mice, and protect the pathological changes in renal tissue. Metabolomics results showed that PJ had significant regulatory effect on unsaturated fatty acids, glycerophospholipid metabolism, and purine metabolism. Network pharmacology showed that MAPK1, MAPK8, Bcl-2, and Caspase 3 were the core targets in PJ against DKD. Molecular docking revealed that Bcl-2 and Caspase 3 have a strong affinity for Chikusetsusaponin Iva, Ginsenoside Rb1, and Ginsenoside Rg1. Moreover, when compared to the model group, the PJ group had higher levels of anti-apoptosis protein Bcl-2 and lower levels of pro-apoptosis protein Caspase 3. PJ can reduce blood lipids, regulate the biosynthesis of unsaturated fatty acids and purine metabolism, thereby alleviating the renal injury of diabetic mice. Moreover, it can regulate the Bcl-2/caspase 3 apoptosis signaling pathway to prevent the apoptosis of renal cells and protect the renal function of diabetic mice. [Display omitted] • Panax japonicus can alleviate renal ectopic fat deposition to protect renal function in diabetic mice. • Panax japonicus involved glycerophospholipid metabolism and biosynthesis of unsaturated fatty acids in diabetic mice to protect renal function. • Panax japonicus can prevent the progression of diabetic kidney disease via anti-apoptosis in HDF combined with STZ-induced diabetic mice. [ABSTRACT FROM AUTHOR]

Clematidis Radix et Rhizoma, a kind of traditional Chinese medicine, is derived from Clematis chinensis Osbeck, Clematis hexapetala Pall. and Clematis manshurica Rupr. This herb shows great effects on expelling wind and dispelling dampness in ancient and it has anti-inflammatory and analgesic activity in modern clinical application. This experiment aimed to research anti-rheumatoid arthritis effect of crude and wine processed RC based on glycolysis metabolism to provide new ideas treating RA. Network pharmacology was applied to preliminarily forecast the potential pathways of common targets of RC and RA. RAW264.7 macrophages were induced by LPS, NO production, glucose uptake, lactate production, ROS and MMP were detected as instructions in vitro. ELISA was used to measure the content of HK2, PKM2 and LDHA involving in glycolysis process. Gut microbiota was analyzed by 16S rRNA gene amplicon sequencing in CIA rats. Crude and wine processed RC had good anti-inflammatory effect by reducing NO in RAW264.7 macrophages and ameliorating inflammatory infiltration and cartilage surface erosion in CIA rats. Whether in LPS-induced macrophages or CIA rats, crude and wine processed RC could inhibit glycolysis by down-regulating the expression of PKM2, causing less glucose uptake and lactic acid, which lead to less ROS and higher MMP to normal. PI3K-AKT and HIF-1α pathways were deduced to possibly play a crucial part in controlling glycolysis metabolism by network pharmacology analysis. Besides, it was displayed that Firmicutes and Bacteroidetes were prominent gut microbiota in CIA rats feces. CC-H and PZ-H groups could both increase the relative abundance of Firmicutes and decrease Bacteroidetes. These microbiota also played a role in RA pathological process via involving in energy metabolism, carbohydrate metabolism and immune system. Crude and wine processed RC have a good influence in ameliorating rheumatoid arthritis by inhibiting glycolysis and modulating gut microbiota together. [Display omitted] • Thermal and wine processed RC had good anti-inflammatory effects to ameliorate RA in vitro and vivo. • Thermal and wine processed RC inhibited glycolysis via mainly decreasing PKM2 in vitro and vivo. • The gut microbiota Roseburia and Prevotella were related with glycolytic enzyme PKM2 and LDHA. • PI3K-AKT pathway and HIF-1α pathway were deduced to be closed with glycolysis metabolism by network pharmacology analysis. • Thermal and wine processed RC may treat RA through inhibiting glycolysis combined with modulating gut microbiota. [ABSTRACT FROM AUTHOR]

Lewy bodies are characteristic spherical inclusions in Parkinson's disease (PD) that are formed by α-synuclein fibrils. Ferruginol (Fer) is an amonomeric compound isolated from a traditional Chinese herb. Here, we show that Fer exerted potent neuroprotective effects in both in vitro and in vivo PD models. Neuronal cells transfected with A53T mutant (A53T) α-synuclein plasmids and treated with Fer exhibited attenuated the cytotoxicity induced by pathogenic A53T α-synuclein overexpression. Further, when we transfected neuronal cells with siRNA-SNCA (alpha-synuclein) plasmids and incubated them with Fer, the protective role of Fer decreased. We also found that Fer was a potent α-synuclein inhibitor in neuronal cells, which promotes the clearance of αsynuclein in dopaminergic neurons exposed to 1-Methyl-4-phenylpyridinium (MPP +). Fer could inhibit abnormal α-synuclein aggregation and dopaminergic neuron depletion in A53T-Tg mice, suggesting that a role for Fer in α-synuclein accumulation and nigrostriatal pathway injury. Our study revealed that Fer strongly alleviated neurodegeneration by promoting α-synuclein clearance, indicating a neuroprotective role against α-synuclein oligomer-induced neurodegeneration, which makes it a promising candidate for the treatment of PD and other neurodegenerative diseases. [Display omitted] • Ferruginol is a compound isolated from a traditional Chinese herb. • We examined the neuroprotective effects of Fer in Parkinson's Disease models. • Fer attenuated α-synuclein cytotoxicity in neuronal cells in vitro. • Fer protected transgenic mice against α-synuclein-induced neurodegeneration. • Fer is a promising therapeutic candidate for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background and Purpose: The C-C chemokine receptor CCR5, and the C-X-C chemokine receptor CXCR3 are involved in the regulation of T cell-mediated immune responses, and in the migration and activation of these cells. To determine whether blockade of these chemokine receptors modulated inflammatory responses in the central nervous sytem (CNS), we investigated the effect of a non-peptide chemokine receptor antagonist, TAK-779, in mice with experimental autoimmune encephalomyelitis (EAE).Experimental Approach: EAE was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG) 35-55. TAK-779 was injected s.c. once a day after immunization. Disease incidence and severity (over 3 weeks) were monitored by histopathological evaluation and FACS assay of inflammatory cells infiltrating into the spinal cord, polymerase chain reaction quantification of mRNA expression, assay of T cell proliferation, by [3H]-thymidine incorporation and cytokine production by enzyme-linked immunosorbent assay.Key Results: Treatment with TAK-779 reduced incidence and severity of EAE. It strongly inhibited migration of CXCR3/CCR5 bearing CD4+, CD8+ and CD11b+ leukocytes to the CNS. TAK-779 did not reduce proliferation of anti-MOG T cells, the production of IFN-gamma by T cells or CXCR3 expression on T cells. In addition, TAK-779 did not affect production of IL-12 by antigen-presenting cells, CCR5 induction on T cells and the potential of MOG-specific T cells to transfer EAE.Conclusions and Implications: TAK-779 restricted the development of MOG-induced EAE. This effect involved reduced migration of inflammatory cells into the CNS without affecting responses of anti-MOG T cells or the ability of MOG-specific T cells to transfer EAE. [ABSTRACT FROM AUTHOR]