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To explore the effects and mechanisms of the Xianhecao-Huanglian drug pair on autophagy-mediated intervention in acute inflammatory bowel disease (IBD) via the JAK2/STAT3 pathway. The study examined the underlying mechanisms of action of Xianhecao (APL) and Huanglian (CR) using a mouse model of dextran sodium sulfate (DSS)-induced acute inflammatory bowel disease (IBD) and in an in vitro model of IBD induced by lipopolysaccharide (LPS). The assessment of the therapeutic efficacy of the Xianhecao-Huanglian drug combination in a mouse model of IBD caused by DSS included the following parameters: Assessment of weight loss or gain. Measurement of the disease activity index (DAI). Assessment of histological damage. Determination of organ index. Measurement of colon length. Ascertain the levels of inflammatory cytokines in the intestinal tissues and serum of mice. Immunohistochemistry (IHC) for the measurement of tight junction protein concentrations in the colon mucosa, including ZO-1, claudin-1, and occludin. Measurement of mucin levels, specifically Mucin 2 (Muc2). Hematoxylin and eosin (HE) staining for the observation of histopathological alterations in colonic tissues. Examining the effect on goblet cells using periodic acid-Schiff (PAS) labeling. Application of Western blot and immunofluorescence techniques for the detection of autophagy-related markers in colonic tissues and proteins associated with the JAK2/STAT3 pathway. A cell inflammation model of IBD was induced through LPS stimulation, and a serum containing the Xianhecao-Huanglian drug pair (referred to as ACHP-DS) was formulated. Cell viability, anti-proinflammatory cytokines, tight junction proteins, mucins, autophagy-related markers, and the JAK2/STAT3 signaling pathway were assessed. The Xianhecao-Huanglian drug pair significantly ameliorated the symptoms and survival quality of acute IBD mice, reducing the disease activity index score, raising MUC2 secretion and tight junction protein expression to improve the integrity of the intestinal barrier, and preserving goblet cell function; thus, protecting the intestines. It effectively restrained triggering the signaling pathway that involves JAK2 and STAT3, leading to the suppression of inflammation and amelioration of colonic inflammation damage. Additionally, it induced autophagy in mouse colonic tissues.The in vitro experiments demonstrated that the Xianhecao-Huanglian drug combination enhanced the viability of LOVO and NCM460 cells when exposed to LPS stimulation. Furthermore, it suppressed the production of inflammatory cytokines such as IL-6, IL-1β, as well as TNF-α, whilst increasing the production of IL-10, ZO-1, along with MUC2. These effects collectively led to the alleviation of inflammation and the restoration of mucosal integrity. The results were consistent with what was shown in the in vivo trial. Moreover, the medication demonstrated effectiveness in reducing JAK2 along with STAT3 phosphorylation levels in the LPS-induced inflammatory model of IBD cells. The intervention with either the Xianhecao-Huanglian drug combination-containing serum or the JAK2/STAT3 pathway inhibitor AG490 reversed the pro-inflammatory effects and increased autophagy levels in the LPS-stimulated cells. The Xianhecao-Huanglian drug combination modulates the JAK2/STAT3 pathway, leading to the induction of autophagy, which serves as an intervention for IBD. [ABSTRACT FROM AUTHOR]

Oncolytic viruses (OVs), a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact, are emerging as promising living anticancer agents. Unlike traditional drugs composed of non-replicating compounds or biomolecules, the replicative nature of viruses confer unique pharmacokinetic properties that require further studies. Despite some pharmacokinetics studies of OVs, mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague. Here, we characterized the pharmacokinetic profile of oncolytic virus M1 (OVM) in immunocompetent mouse tumor models and identified the JAK‒STAT pathway as a key modulator of OVM pharmacokinetics. By suppressing the JAK‒STAT pathway, early OVM pharmacokinetics are ameliorated, leading to enhanced tumor-specific viral accumulation, increased AUC and C max , and improved antitumor efficacy. Rather than compromising antitumor immunity after JAK‒STAT inhibition, the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment, providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade, such as anti-PD-L1. Taken together, this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy. This study reveals the pharmacokinetics of OVM, as a replicable living drug, in various tumor models. Amelioration of early OVM pharmacokinetics results in stronger oncolytic efficacy and antitumor immunity via targeting JAK‒STAT pathway (figure was created with Biorender.com). [Display omitted] [ABSTRACT FROM AUTHOR]

Aging leads to a decrease in muscle function, mass, and strength in skeletal muscle of animals and humans. The transcriptome identified activation of the JAK/STAT pathway, a pathway that is associated with skeletal muscle atrophy, and endurance training has a significant effect on improving sarcopenia; however, the exact mechanism still requires further study. We investigated the effect of endurance training on sarcopenia. Six-month-old male SAMR1 mice were used as a young control group (group C), and the same month-old male SAMP8 mice were divided into an exercise group (group E) and a model group (group M). A 3-month running exercise intervention was performed on group E, and the other two groups were kept normally. Aging caused significant signs of sarcopenia in the SAMP8 mice, and endurance training effectively improved muscle function, muscle mass, and muscle strength in the SAMP8 mice. The expression of JAK2/STAT3 pathway factor was decreased in group E compared with group M, and the expression of SOCS3, the target gene of STAT3, and NR1D1, an atrophy-related factor, was significantly increased. Endurance training significantly improved the phenotypes associated with sarcopenia, and the JAK2/STAT3 pathway is a possible mechanism for the improvement of sarcopenia by endurance training, while NR1D1 may be its potential target. [ABSTRACT FROM AUTHOR]

Normalizing inflamed soils including reactive oxygen species (ROS), nitric oxide (NO), cell-free DNA, and regulating inflammation-related seeds such as macrophages, neutrophils, fibroblasts, represent a promising strategy to maintain synovial tissue homeostasis for rheumatoid arthritis (RA) treatment. Herein, ROS scavenging amphiphilic block copolymer PEGylated bilirubin and NO-scavenging PEGylated o -phenylenediamine were fabricated to self-assemble into a dually responsive nanoparticle loaded with JAK inhibitor notopterol (Not@BR/oPDA-PEG, NBOP NPs). The simultaneous ROS and NO depletion combined with JAK-STAT pathway inhibition could not only promote M2 polarization to reduce further ROS and NO generation, but also decrease cytokines and chemokines to prevent immune cell recruitment. Specifically, NBOP NPs responded to high level ROS and NO, and disintegrated to release notopterol in inflamed joints as the hydrophobic heads BR and oPDA were transformed into hydrophilic ones. The released notopterol could inhibit the JAK-STAT pathway of inflammatory cells to reduce the secretion of pro-inflammatory cytokines and chemokines. This strategy represented an effective way to regulate RA soils and seeds through breaking the positive feedback loop of inflammation aggravation, achieving an excellent anti-RA efficacy in a collagen-induced arthritis rat model. Taken together, our work offered a reference to adjust RA soils and seeds for enhanced RA treatment. A dually responsive nanoparticle loaded with JAK inhibitor notopterol (Not@BR/ o PDA-PEG, NBOP NPs) exhibited anti-arthritis efficacy based on reactive oxygen species (ROS) and nitric oxide (NO) scavenging as well as JAK-STAT inhibition. [Display omitted] [ABSTRACT FROM AUTHOR]

The use of RNA as therapeutic agents is a visionary idea in contemporary medicine. Some forms of RNA can modulate the immune response of the host to enhance tissue regeneration events such as osteogenesis. Herein, RNA molecules commercially available for immunomodulatory applications (imRNA) were used to prepare biomaterials for bone regeneration. The polyanionic imRNA stabilized calcium phosphate ionic clusters to produce imRNA-ACP that had the capacity to mineralize the intrafibrillar compartments of collagen fibrils. For the first time, it was shown that incorporating imRNA-ACP into collagen scaffolds resulted in rapid new bone formation in cranial defects of mice. Both in vivo and in vitro results demonstrated that macrophage polarization was highly-sensitive to the imRNA-ACP containing collagen scaffolds. Macrophages were polarized into the anti-inflammatory M2 phenotype that produced anti-inflammation cytokines and growth factors. The favorable osteoimmunological microenvironment created by the scaffolds prevented their immunorejection and facilitated osteogenesis. The potential of RNA in creating immunomodulatory biomaterials has been underestimated in the past. The overall aim of this study was to explore the potential application of imRNA-based biomaterials in bone tissue engineering, with the competitive edge of facile synthesis and excellent biocompatibility. In this work, commercially available RNA extracted from bovine spleens for immunomodulatory applications (imRNA) were used to stabilize amorphous calcium phosphate (ACP) and induce mineralization within collagen fibrils. Incorporation of imRNA-ACP into collagen scaffolds regenerated new bone in-situ. Because of its immunomodulatory effects, the imRNA-ACP that was incorporated into collagen scaffolds modulated the local immune environment of murine cranial defects by altering the macrophage phenotype through JAK2/STAT3 signaling pathway. The novelty of this work existed in the discovery of RNA's potential in creating immunomodulatory biomaterials. With the competitive edge of facile synthesis and excellent biocompatibility, the imRNA-based biomaterials are potentially useful for future bone tissue engineering applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Mitotic arrest is necessary for the embryonic development of germ cells, and thus, it is important to understand the signaling pathways that regulate mitotic arrest. Here, we investigated the signaling pathway dynamics of male embryonic chicken germ cells during mitotic arrest by single‐cell transcriptome analysis using germ‐cell tracing models. We identified signaling pathways that change at the transcriptional level during chicken male germ‐cell development after sex determination. We found that several components of the BMP, Notch, and JAK–STAT signaling pathways were downregulated at the mitotic‐arrest stage and were reactivated 1 week after hatching when all germ cells are quiescent after entering mitotic arrest. In addition, the transcriptional levels of components of the MAPK, Hedgehog, and thyroid‐hormone signaling pathways were steadily upregulated after mitotic arrest. This suggests the cooperation of multiple signaling pathways during entry into mitotic arrest and subsequent quiescence of chicken male germ cells. [ABSTRACT FROM AUTHOR]

Background: Highly pathogenic avian influenza viruses (HPAIVs) is an extremely contagious and high mortality rates in chickens resulting in substantial economic impact on the poultry sector. Therefore, it is necessary to elucidate the pathogenic mechanism of HPAIV for infection control. Objective: Gene set enrichment analysis (GSEA) can effectively avoid the limitations of subjective screening for differential gene expression. Therefore, we performed GSEA to compare HPAI-infected resistant and susceptible Ri chicken lines. Methods: The Ri chickens Mx(A)/BF2(B21) were chosen as resistant, and the chickens Mx(G)/BF2(B13) were selected as susceptible by genotyping the Mx and BF2 genes. The tracheal tissues of HPAIV H5N1 infected chickens were collected for RNA sequencing followed by GSEA analysis to define gene subsets to elucidate the sequencing results. Results: We identified four differentially expressed pathways, which were immune-related pathways with a total of 78 genes. The expression levels of cytokines (IL-1β, IL-6, IL-12), chemokines (CCL4 and CCL5), type interferons and their receptors (IFN-β, IFNAR1, IFNAR2, and IFNGR1), Jak-STAT signaling pathway genes (STAT1, STAT2, and JAK1), MHC class I and II and their co-stimulatory molecules (CD80, CD86, CD40, DMB2, BLB2, and B2M), and interferon stimulated genes (EIF2AK2 and EIF2AK1) in resistant chickens were higher than those in susceptible chickens. Conclusions: Resistant Ri chickens exhibit a stronger antiviral response to HPAIV H5N1 compared with susceptible chickens. Our findings provide insights into the immune responses of genetically disparate chickens against HPAIV. [ABSTRACT FROM AUTHOR]

• L-arg is significantly elevated in the plasma of TMD patients. • L-arg exerts different functions in distinct tissue microenvironments. • Targeting L-arg-activated signals might benefit for the treatment of TMD. TMJOA as a progressive degenerative disease of the TMJ, is featured as enhanced inflammation, chondrocyte apoptosis, ECM degradation and subchondral bone remodeling, resulting in local pain and functional impairment that further reduces patients' quality of life. However, its etiology is ambiguous, leading to no consensus regarding the most effective treatment for patients with TMJOA. L-arg is a conditionally essential amino acid that participates in regulating inflammation, ECM orchestration, cellular growth and proliferation, but the role and mechanism of L-arg in TMJOA remain unclear. L-arg exerts different functions in contexts- and tissue microenvironments-dependent manner. For example, excess L-arg induces acute pancreatitis via the JAK2/STAT3 pathway, the iNOS/NO pathway and the HMGB1/TLR4/NF-κB pathway; Arg-Ⅱ in advanced atherosclerosis impairs endothelial autophagy through regulation of mTOR signaling. Interestingly, these signaling pathways are tightly involved in the reported pathological process of TMJOA. We here unexpectedly found that L-arg is significantly elevated in the plasma of TMD patients using mass spectrometry. Thus, through literature review and analysis, we proposed that the upregulation of L-arg activated iNOS/NO pathway, Arg-Ⅱ pathway, mTOR pathway and NF-κB pathway to prompt TMJOA development. Related pathway inhibitors could be an alternative treatment strategy for TMJOA. [ABSTRACT FROM AUTHOR]

Abnormal proliferation, migration, and foam cell formation of Vascular smooth muscle cells (VSMCs) each play a role in the development of atherosclerosis (AS). Schisandrin (Sch) is the active lignan ingredient with broad-spectrum pharmacological effects. However, the role of Sch in the AS process is not clear. Therefore, this study was proposed to explore the therapeutic effect and potential mechanism of Sch on VSMCs. Ox-LDL was selected to create an atherosclerosis injury environment for VSMCs and macrophages. The MTT assay, Oil red O staining, wound healing, transwell experiments and ELISA were used to investigate the phenotype effects of Sch. Network pharmacology, molecular docking, flow cytometry, and western blot were used to investigate the underlying mechanisms of Sch on AS progression. Our findings implied that Sch treatment inhibited the proliferation and migration of VSMCs, and suppressed the ROS production and inflammatory cytokines up-regulation of VSMCs and macrophages. Moreover, Sch reduced lipid uptake and foam cell formation through downregulating LOX-1. Mechanistically, we found that Sch can inhibit the activation of JAK2/STAT3 signaling by targeting JAK2, and arrest cell cycle in GO/G1 phase. In summary, Sch can inhibit VSMCs proliferation and migration by arresting cell cycle and targeting JAK2 to regulating the JAK2/STAT3 pathway. Sch may serve as a potential drug for patients with AS. • Sch inhibited ox-LDL-induced VSMCs proliferation and migration by regulating JAK2/STAT3 signaling pathway. • The inhibitory effect of Sch on ox-LDL uptake prevents lipid accumulation and foam cell formation. • Sch alleviated inflammatory response via inhibiting TNF-α, IL-6 and NO production. • Sch down-regulated PCNA, MMP-2, ICAM-1 and CyclinD1 expression. [ABSTRACT FROM AUTHOR]

COVID-19 is a rapidly spreading disease, causing a global pandemic. It is circulating in multiple countries and causing a series of respiratory infections. Due to the uncertain safety and efficacy of the vaccines and lack of specific medicines, it's important to investigate new pharmacological procedures and find out new drugs that help us eradicate this pandemic. We suggest the hypothesis that Notopterol (NOT), the main Secondary metabolite of Notopterygium incisum Ting ex H.T (a common Chinese medicinal herb), may have the potential benefits on SARS-CoV2 infection for this reasons: (a) NOT exhibits anti-inflammatory, anticancer, and anti-angiogenic properties, (b) NOT indicates a significant reduction in cytokines and chemokines releasing including TNFa, IL-6, interferon-γ, which may decrease COVID-19 cytokine storm (c) NOT can suppress the expression of genes which leads to inflammation via Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway. It is exactly acting like tocilizumab, (an approved drug against COVID-19) and (d) Notopterygium incisum has antiviral activity against influenza virus, it can reduce the viral-induced oxidative stress. By these explanations, it is hopeful that NOT may be effective in COVID-19 infections which needs further investigations to examine Notopterol as a beneficial agent against the SARS-CoV2 infection. [ABSTRACT FROM AUTHOR]

In this study, we explored the anti-inflammatory effects of bound polyphenols derived from the insoluble dietary fiber of navel orange peel (BPP) on LPS-induced RAW264.7 macrophages, and investigated the underlying molecular mechanisms. The experimental findings revealed that BPP effectively suppressed COX-2 and iNOS protein expression, and concurrently decreased intracellular ROS production and NO release. RNA sequencing identified 1894 differentially expressed genes between the model and BPP groups, with 1009 genes upregulated and 885 downregulated. Notably, the NF-κB and JAK-STAT pathways were among the 20 most significantly altered signaling pathways, as determined by KEGG analysis. Western blot analysis further showed that BPP significantly inhibited the phosphorylation of key proteins in the MAPKs (ERK, JNK, p38), NF-κB (p65, IκBα), and JAK-STAT (JAK1, STAT3) pathways. Additionally, the use of p65 and STAT3 activators markedly elevated NO and ROS levels, whereas BPP treatment effectively reduced them. These findings suggest that BPP may attenuate LPS-induced inflammatory responses through the NF-κB and JAK-STAT pathways, highlighting its potential as a natural anti-inflammatory agent and its implications for functional food applications. [ABSTRACT FROM AUTHOR]

Polybrominated diphenyl ethers (PBDEs) are widely present in water ecosystems where they pose a significant threat to aquatic life, but our knowledge about how PBDEs affect feeding is limited. Therefore, this study explored the effects of continuous dietary exposure to 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) (40 and 4000 ng/g) on the feeding in common carp (Cyprinus carpio) and the underlying mechanism. BDE-47 significantly decreased the food intake of carp. Transcriptome analysis of brain tissue showed that BDE-47 mainly affected the nervous, immune, and endocrine systems. Further examination of the expression levels of appetite factors in the brain revealed that BDE-47 caused dysregulation of appetite factors expressions such as agrp , pomc , cart , etc. In addition, the JAK-STAT signaling pathway was activated under BDE-47 exposure. It can be concluded from these findings that BDE-47 activated the JAK-STAT signaling pathway, causing imbalanced expression of appetite factors, leading to disordered feeding behavior and decreased food intake in carp. These results provide an important reference for a more comprehensive understanding of the hazards posed by BDE-47 on animal feeding and the associated mechanisms. [Display omitted] • Long term exposure to BDE-47 reduces carp's food intake. • BDE-47 affects the nervous, immune, and endocrine systems of carp. • Long term exposure to BDE-47 leads to imbalanced expression of appetite factors. • BDE-47 activates the JAK-STAT signaling pathway to inhibit feeding. [ABSTRACT FROM AUTHOR]

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) intracellular signaling pathway is utilized by many proinflammatory molecules to mediate downstream effects and activate gene transcription. Activation of the JAK-STAT pathway contributes to a number of inflammatory dermatoses. Clinical trials and smaller studies have demonstrated the efficacy of JAK inhibitors in the treatment of a variety of dermatologic conditions. Here, we review the use of JAK inhibitors for the treatment of a wide range of dermatologic diseases in a two-part review series. [ABSTRACT FROM AUTHOR]

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) intracellular signaling pathway is implicated in the pathogenesis of a number of inflammatory dermatoses. Clinical trials and other studies have demonstrated the efficacy of JAK inhibitors in the treatment of a variety of dermatologic conditions. Here we review JAK inhibitors currently under investigation for the treatment of alopecia areata, vitiligo, sarcoidosis, necrobiosis lipoidica, granuloma annulare, and systemic lupus erythematosus with a special emphasis on safety and the implications of JAK inhibitors during the novel coronavirus 2019 pandemic. [ABSTRACT FROM AUTHOR]

As the incidence of COVID-19 increases with time, more and more efforts are made to pave a way out for the therapeutic strategies to deal with the disease progression. Inflammation being a significant influencer in COVID-19 patients, it drives our focus onto the signaling cascades of the JAK/STAT pathway. JAK phosphorylation mediated by cytokine receptor activation leads to phosphorylation of STATs that translocate into the nucleus to translate for inflammatory mediators. The SARS-CoV-2 structural proteins like spike, nucleocapsid, membrane and envelope proteins along with the non- structural proteins 1-16 including proteases like 3CL pro and PLpro promote its entry and survival in hosts. The SARS-CoV-2 infection triggers inflammation via the JAK/STAT pathway leading to recruitment of pneumocytes, endothelial cells, macrophages, monocytes, lymphocytes, natural killer cells and dendritic cells progressing towards cytokine storm. This produces various inflammatory markers in the host that determine the disease severity. The JAK/STAT signaling also mediates immune responses via B cell and T cell differentiation.With an attempt to reduce excessive inflammation, JAK/STAT inhibitors like Ruxolitinib, Baricitinib, Tofacitinib have been employed that mediate its actions via suppressors of cytokine signaling, cytokine inducible SH2 containing protein, Protein inhibitor of activated STAT and protein tyrosine phosphatases. Even though they are implicated with multiple adverse effects, the regulatory authorities have supported its use, and numerous clinical trials are in progress to prove their safety and efficacy. On the contrary, the exact mechanism of JAK/STAT inhibition at molecular levels remains speculative for which further investigations are required. [ABSTRACT FROM AUTHOR]

Background: Interferon lambda receptor 1 (IFNLR1) is a type II cytokine receptor that clings to interleukins IL-28A, IL29B, and IL-29 referred to as type III IFNs (IFN-γs). IFN-γs act through the JAK-STAT signaling pathway to exert antiviral effects related to preventing and curing an infection. Although the immune function of IFN-γs in virus invasion has been described, the molecular mechanism of IFNLR1 in that process is unclear. Objectives: The purpose of this study was to elucidate the role of IFNLR1 in the pathogenesis and treatment of porcine reproductive and respiratory syndrome virus (PRRSV). Methods: The effects of IFNLR1 on the proliferation of porcine alveolar macrophages (PAMs) during PRRSV infection were investigated using interference and overexpression methods. Results: In this study, the expressions of the IFNLR1 gene in the liver, large intestine, small intestine, kidney, and lung tissues of Dapulian pigs were significantly higher than those in Landrace pigs. It was determined that porcine IFNLR1 overexpression suppresses PRRSV replication. The qRT-PCR results revealed that overexpression of IFNLR1 upregulated antiviral and IFN-stimulated genes. IFNLR1 overexpression inhibits the proliferation of PAMs and upregulation of p-STAT1. By contrast, knockdown of IFNLR1 expression promotes PAMs proliferation. The G0/G1 phase proportion in IFNLR1-overexpressing cells increased, and the opposite change was observed in IFNLR1-underexpressing cells. After inhibition of the JAK/STAT signaling pathway, the G2/M phase proportion in the IFNLR1-overexpressing cells showed a significant increasing trend. In conclusion, overexpression of IFNLR1 induces activation of the JAK/STAT pathway, thereby inhibiting the proliferation of PAMs infected with PRRSV. Conclusion: Expression of the IFNLR1 gene has an important regulatory role in PRRSVinfected PAMs, indicating it has potential as a molecular target in developing a new strategy for the treatment of PRRSV. [ABSTRACT FROM AUTHOR]

This research aimed to evaluate the antihepatic fibrosis effect and explore the mechanism of Qiwei Qinggan Powder (QGS-7) in vivo and in vitro. Carbon tetrachloride (CCl4)-treated rats and hepatic stellate cells (HSCs) were used. QGS-7 treatment significantly improved the liver function of rats as indicated by decreased serum enzymatic activities of alanine aminotransferase, aspartate transaminase, and alkaline phosphatase. Meanwhile, the hydroxyproline of liver was significantly decreased. Histopathological results indicated that QGS-7 alleviated liver damage and reduced the formation of fibrosis septa. Moreover, QGS-7 significantly attenuated expressions of Alpha smooth muscle actin, Collagen I, Janus kinase 2 (JAK2), phosphorylation-JAK2, signal transducer and activator of transcription 3 (STAT3), phosphorylation-STAT3 in the rat hepatic fibrosis model. QGS-7 inhibited HSC proliferation and promoted it apoptosis. QGS-7 may affect hepatic fibrosis through JAK2/STAT3 signaling pathway so as to play an antihepatic fibrosis role. [ABSTRACT FROM AUTHOR]

Enniatin B1 (ENN B1) is a mycotoxin that can be found in various foods. However, whether ENN B1 is hazardous to the reproductive system is still elusive. Leydig cells are testosterone-generating cells that reside in the interstitial compartment between seminiferous tubules. Dysfunction of Leydig cells could result in male infertility. This study aimed to examine the toxicological effects of ENN B1 against TM3 Leydig cells. ENN B1 significantly inhibited cell viability in a dose-dependent manner. ENN B1 treatment also decreased the expression of functional genes in Leydig cells. Moreover, ENN B1 induced Leydig cells apoptosis and oxidative stress. Mechanistically, ENN B1 leads to the upregulation of Bax and downregulation of Bcl-2 in Leydig cells. In addition, ENN B1 inhibited the Nrf2/HO-1 pathway, which is critical for the induction of oxidative stress. Additionally, ENN B1 treatment repressed the JAK/STAT3 signaling pathway in Leydig cells. Rescue experiments showed that activation of STAT3 resulted in alleviation of ENN B1-induced damage in Leydig cells. Collectively, our study demonstrated that ENN B1 induced Leydig cell dysfunction via multiple mechanisms. [Display omitted] • ENN B1 inhibits the cellular viability and expression of functional genes in Leydig cells. • ENN B1 induces apoptosis of Leydig cells in a caspase-dependent manner. • ENN B1 induces oxidative stress via modulation of Keap1/Nrf2/HO-1 signalling pathway. • ENN B1 regulates SHP1 and the JAK/STAT3 signalling pathway in Leydig cells. [ABSTRACT FROM AUTHOR]

Recently, populations of Chinese spiny frogs (Quasipaa spinosa), an important amphibian species in China, have decreased, mainly due to a disease caused by the gram-negative bacteria Proteus mirabilis. To elucidate the immune response of the frogs, this study aimed to identify novel candidate genes functionally associated with P. mirabilis infection-induced "rotting skin" disease. Chinese spiny frogs were infected with P. mirabilis , and the skin transcriptome was sequenced using the MGISEQ-2000 platform. A total of 233,965 unigenes were obtained by sequencing, of which 27.23 % were known genes. Screening of differentially expressed genes (DEGs) indicated 210 unigenes differentially expressed after P. mirabilis infection, of which 132 unigenes were up-regulated, and 78 unigenes were down-regulated. Using Kyoto Encyclopedia of Genes and Genomes enrichment analysis, DEGs were identified as enriched in signal pathways, such as oxidative phosphorylation, apoptosis, and the Janus kinase-signal transducer and activator of transcription pathway. Of the DEGs, there was a significant upregulation of the colony stimulating factor 2 receptor beta common subunit , interleukin 2 receptor subunit gamma , cathelicidin antimicrobial peptide , interleukin-17 receptor E , receptor-interacting serine/threonine-protein kinase 3 , and pulmonary surfactant-associated protein D immune genes following P. mirabilis infection. Conversely, scavenger receptor cysteine-rich domain-containing group B protein , tumor protein p53 inducible nuclear protein 2 , suppressor of cytokine signaling 2 , and metalloreductase STEAP3 were significantly downregulated. In conclusion, the first skin transcriptome database of Chinese spiny frogs was established, and several immune genes were identified to elucidate the pathogenic mechanism of "skin rot" in Chinese spiny frogs and other cultured frogs. [Display omitted] • Skin transcriptomes were obtained from Chinese spiny frogs with Proteus mirabilis. • 210 genes were differentially expressed between the P. mirabilis infected group and the control group. • Among the DEGs, many immune-related genes were closely associated with P. mirabilis infection. [ABSTRACT FROM AUTHOR]

Di-(2-ethylhexyl) phthalate (DEHP), a common endocrine-disrupting chemical (EDC), is widely used in daily articles, early exposure to DEHP is associated with many behavioral changes in pups. This study aimed to investigate the effects and underlying mechanisms of maternal exposure to DEHP on the impaired social interaction in pups. Pregnant rats were administered 0, 30, 300, or 750 mg/kg/d DEHP daily by oral gavage. Highly aggressive proliferating immortalized (HAPI) cells were treated with mono-(2-ethylhexyl) phthalate (MEHP) and tyrosine phosphorylation inhibitor (AG490). Our results showed that DEHP exposure induced the activation of microglias (MGs) via activating the janus kinase 2 / signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway, and increased the level of pro-inflammatory factors, then impaired the social behavior in male pups, but not female pups. Moreover, MEHP exposure could also activate HAPI via activating this signaling pathway, and AG490 could inhibit the activation of this signaling pathway caused by MEHP. Therefore, we indicated that maternal exposure to DEHP could cause the gender-specific impaired social interaction in pups that might be related to the activation of MGs. [Display omitted] • Maternal exposure to DEHP caused the gender-specific impaired social interaction in pups. • DEHP induced the activation of MGs and increased the levels of pro-inflammatory factors. • The activation of MGs following DEHP exposure was associated with the upregulation of JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Cytokines are soluble factors that affect host defense and maintain immune homeostasis. Altered cytokine production leads to a dysfunctional immune responses and immune-related diseases. Cytokines bind to specific receptors and trigger various intracellular signaling cascades and targeting cytokines and/or their receptors has been effective in treating inflammatory diseases. Type I and II cytokine receptors activate four Janus kinases (JAKs), namely JAK1, JAK2, JAK3 and TYK2 and targeting of these enzymes resulted in the development of successful drugs now referred as JAK inhibitors or JAKinibs. JAKinibs can be divided in three "generations." First-generation JAKinibs, molecules acting in an orthosteric manner, inhibit multiple JAKs and interfere with the biologic activity of many factors. With the idea of reducing side effects, second-generation JAKinibs, still orthosteric ATP competitors, have been developed with increased selectivity towards one or two JAKs. Third-generation JAKinibs have exploited our increased understanding of the structure and function of JAK domains and are allosteric inhibitors as they bind to specific residues in the pseudokinase domain. These third generation JAKInb indeed seems to possess a better safety profile. Notably, inhibition of cytokine activity in specific tissues could be more important than selective enzymatic blockade and for this reason, topical, inhaled, or as a non-absorbable JAKinibs are also being developed. While JAKinibs entered the clinical arena about ten years ago, our understanding of these drugs and their selectivity relative to their activity and safety is still incomplete. More research is therefore needed to achieve better usage of these class of drugs. [ABSTRACT FROM AUTHOR]

Nanopolystyrene (NP) and diclofenac (DCF) are common environmental contaminants in the aquatic ecosystem; therefore, the present study aimed to investigate the hepatotoxicity of NP and/or DCF exposure on aquatic organisms and the underlying mechanisms. Juvenile Mylopharyngodon piceus were used as a model organism to study the effects of NP and/or DCF exposure at environmentally relevant concentrations for 21 days. Subchronic exposure to NP and/or DCF resulted in liver histological damage. In the NP group, the presence of large lipid droplets was observed, whereas the DCF group exhibited marked hepatic sinusoidal dilatation accompanied by inflammation. Additionally, this exposure induced liver oxidative stress, as evidenced by the changes in several physiological parameters, including catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), reactive oxygen species (ROS), and malondialdehyde (MDA). Integrated transcriptomic and metabolomic analysis was performed to further investigate the molecular mechanism underlying hepatotoxicity. Multi-omics analysis demonstrated, for the first time to our knowledge, that NP induced hepatic steatosis mainly through activating the glycerol-3-phosphate pathway and inhibiting VLDL assembly by targeting several key enzyme genes including GPAT , DGAT , ACSL , APOB , and MTTP. Furthermore, NP exposure disrupted arachidonic acid metabolism, which induced the release of inflammatory factors and inhibited the release of anti-inflammatory factors, ultimately causing liver inflammation in M. piceus. In contrast, DCF induced interleukin production and downregulated KLF2 , causing hepatic sinusoidal dilatation with inflammation in juvenile M. piceus , which is consistent with the finding of JAK–STAT signaling pathway activation. In addition, the upregulated AMPK signaling pathway in the DCF group suggested perturbation of energy metabolism. Collectively, these findings provide novel insights into the molecular mechanism of the multiple hepatotoxicity endpoints of NP and/or DCF exposure in aquatic organisms. [Display omitted] • NP and/or DCF exposure reduced the survival rate of Mylopharyngodon piceus. • NP and/or DCF exposure induced liver injury and oxidative stress in M. piceus. • NP exposure resulted in hepatic steatosis and liver inflammation. • DCF exposure caused hepatic sinusoidal dilatation and liver inflammation. [ABSTRACT FROM AUTHOR]

To explore the Simiao Pill's mode of action in the treatment of knee osteoarthritis (KOA) by integrating network pharmacology. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was searched for Simiao Pills' active ingredients and pharmacological targets. Microarray data from GSE55457, GSE55235, and GSE12021 were screened, and the common differential genes of KOA were determined by intersecting the three datasets. Simiao Pill's potential targets for treating KOA could be the junction of pharmacological targets and KOA differential genes. Cytoscape software is used for the network visualisation, and network topology analysis is used to identify the essential elements and primary targets. Finally, R language (Version 3.6.0) is used to conduct gene ontology (GO) and Kyoto encyclopaedia of genes and genomes (KEGG) enrichment analysis. Nineteen prospective targets of Simiao Pill for KOA were projected. Four key active components, quercetin, wogonin, kaempferol, and baicalein, and six core targets, vascular endothelial growth factor A (VEGFA), interleukin-6 (IL6), Jun, Myc, estrogen receptor alpha (ESR1), and prostaglandin-endoperoxide synthase 2 (PTGS2) were screened by network topology analysis. PI3K-Akt signalling pathway, JAK/STAT3 signalling pathway, and mitogen-activated protein kinase (MAPK) signalling pathway are considered as key signalling pathways. Simiao Pill may have therapeutic effects through anti-inflammatory, regulating cell proliferation and apoptosis, estrogen function, and anti-angiogenesis, according to the 'Drug-Active component-Target' network, which lays the groundwork for further study. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs), which are RNA molecules that do not code for proteins and have a length exceeding 200 base pairs, have been found to play a crucial role in regulating intestinal immunity. The high mortality of various fish species induced by high temperatures is known to be associated with enteritis. Our investigation demonstrated that acute heat stress was responsible for inducing fish enteritis. However, the specific lncRNAs involved this process remains unknown. In this current study, we utilized intestinal sequencing data from the largemouth bass species Micropterus salmoides under acute heat stress, resulting in a total of 347,351,492 clean reads obtained from six cDNA libraries. A total of 3399 novel lncRNA transcripts originating from 2488 distinct lncRNA genes were successfully identified. Consistent with previous findings in other fish species, these lncRNAs demonstrated comparatively shorter transcript lengths when compared to protein-coding genes. Furthermore, a total of 216 novel lncRNA exhibited differential expression (DE) in the intestine of largemouth bass, meeting the criteria of absolute log 2 fold change exceeding 2 and a p -value below 0.05. Additionally, these DE-lncRNAs were found to regulate 210 neighboring genes in a cis -regulatory manner. An examination of GO/KEGG enrichment revealed a notable enrichment of immune regulation (p < 0.05) among these cis -genes, with lncRNA MSTRG.8573.1 playing a significant role in regulating the jak-stat signaling pathway during this process. This study presents a comprehensive inventory of novel DE-lncRNA implicated in the development of enteritis in largemouth bass under acute heat stress. These findings offer valuable insights for future investigations on the regulation of lncRNAs to mitigate heat stress-induced fish enteritis. [Display omitted] • Acute heat stress induced the occurrence of fish enteritis. • Many lncRNAs were significantly enriched in the intestinal immune regulation of fish under acute heat stress. • lncRNA MSTRG.8573.1 might be involved in the regulation of jak-stat signaling pathway during acute heat stress. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a chronic disease associated with bone and muscle degeneration that causes great disturbances to daily lives. Skipjack tuna elastin peptides (STEP) is a kind of small molecule mixed peptides extracted from skipjack tuna bulbus cordis that have multiple active functions, including anti-inflammatory activity. However, it is ambiguous whether STEP reduce OA inflammation. Zebrafish served as a model in the present research for verifying the anti-inflammatory efficacy of STEP. Then, the composition of STEP was figured out by LC-MS/MS analysis, and the potential anti-inflammatory peptides were screened by molecular docking and microscale thermophoresis (MST). Finally, in vitro experiments were conducted on the potential peptides. According to the in vivo findings, STEP protected the cartilage tissues of zebrafish and regulated the expression of inflammatory factors and the JAK2/STAT3 signaling pathway. The in vitro results showed that the potential peptides (LGVGSPPGK, GFDPSR and PGAPGGGFDI) positively regulated the inflammatory responses and the JAK2/STAT3 signaling pathway and were effective in inhibiting extracellular matrix (ECM) degeneration and chondrocyte apoptosis. As a consequence, STEP possess anti-inflammatory and chondroprotective effects and could be a functional product for the alleviation of OA. [Display omitted] • Skipjack tuna elastin peptides (STEP) exhibited a protective effect on cartilage in vivo. • Composition of STEP obtained by LC‒MS/MS analysis was determined and screening of three dominant peptides with anti-inflammatory potential. • STEP alleviated osteoarthritis (OA) by regulating inflammatory factors and JAK2/STAT3 signaling pathway in vivo and in vitro. • The three dominant peptides improved extracellular matrix degradation in vitro. • STEP could be a potential functional food for OA patients. [ABSTRACT FROM AUTHOR]

Flutolanil has been detected worldwide in aquatic environment and fish, which has become an undeniable stressor on ecosystem and human health. Flutolanil has been reported to be toxic to aquatic organisms. However, the pathophysiological and molecular mechanism behind the detrimental effects remains obscure. Here we reported hepatotoxicity induced by flutolanil in HepG2 cells and zebrafish, as revealed by toxicokinetic, HE staining, miRNAs-mRNAs sequencing, molecular dynamic simulations and dual luciferase reporter assays. Collectively, our results indicated that flutolanil could be absorbed by and accumulated in the liver of zebrafish, causing hepatic vacuolar degeneration, steatosis and nuclear condensation and abnormal liver function, where its exposure at environmental levels disrupted the expressions of miRNA-26a-5p and its target gene socs1a by mediating JAK-STAT signaling pathway, which was partially responsible for hepatotoxicity, correlated with oxidative stress, cell apoptosis, inflammation, cell cycle disorder and mitochondrial dysfunction. These findings suggest that miRNA-26a-5p/socs1a can serve as potential biomarkers of hepatotoxicity in zebrafish following exposure to flutolanil. This uncovered route will provide a new tool for the risk assessment of flutolanil and a guide to proper use of flutolanil and environmental remedy, and open up a new horizon for liver disease assessment. [Display omitted] • Flutolanil could permeate in and out of HepG2 cells and incite hepatic cytotoxicity. • Flutolanil could be absorbed into liver and accumulated in zebrafish. • Flutolanil produced hepatoxicity by causing zebrafish liver damage and dysfunction. • miRNA-26a-5p/socs1a played key roles in flutolanil induced hepatoxicity in zebrafish. [ABSTRACT FROM AUTHOR]

Background: Treatment for metastatic nasopharyngeal carcinoma (NPC) is challenging. Till now, a truly effective chemotherapy regimen for NPC has not yet been identified. These clinical observations prompted us to investigate a potential drug as alternative option for treating.Purpose: This study evaluated the inhibitory effects of Ovatodiolide (Ova), on tumorigenic and cancer stem cell characteristics of NPC cells.Methods: Two NPC cell lines (NPC-BM1 and NPC-BM2) were used to examine the anticancer effects of Ova and the molecular mechanism underlying these activities by using sulforhodamine B cytotoxicity assay, western blot, immunofluorescence, migration, colony and tumorsphere formation assays.Results: Ova significantly inhibited the viability of BM1 and BM2 cells, downregulated Bcl-xL and Puma, and upregulated Bax/Bad expression levels. Ova dose-dependent suppressed migratory/invasive potential of NPC cells, and reduced ability to form colonies. Ova-induced apoptosis correlated with increased Bax/Bcl-xL ratio while NPC motility and colony formation inhibition were associated with reduced expression of p-FAK, p-PXN, F-actin, and Slug proteins and increased E-cadherin. Furthermore, ova inhibited NPC tumorsphere formation, associated with decreased SOX2, OCT4 and JAK-STAT signaling pathway. Ova also attenuated NPC stem cell tumorigenicity, inhibited tumor growth, and enhanced the sensitivity of NPC cells to cisplatin treatment, in vivo.Conclusions: Our results demonstrated the anticancer efficacy of Ova in NPC and its potential as a putative inhibitor of JAK2 and STAT3, which are essential in tumorigenesis of NPC. Further development of Ova is encouraged. [ABSTRACT FROM AUTHOR]

Unknown compounds with (anti-)androgenic activities enter the aquatic environment via municipal wastewater treatment plants (WWTPs). Progestins are well-known environmental contaminants capable of interfering with androgen receptor (AR) signaling pathway. The aim of the present study was to determine if 15 selected progestins have potential to contribute to (anti-)androgenic activities in municipal wastewaters and the respective recipient surface waters. AR-specific Chemically Activated LUciferase gene eXpression bioassay in agonistic (AR-CALUX) and antagonistic (anti-AR-CALUX) modes and liquid chromatography tandem atmospheric pressure chemical ionization/atmospheric photoionization with hybrid quadrupole/orbital trap mass spectrometry operated in high resolution product scan mode (LC-APCI/APPI-HRPS) methods were used to assess (anti-)androgenic activity and to detect the target compounds, respectively. The contribution of progestins to (anti-)androgenic activities was evaluated by means of a biologically and chemically derived toxicity equivalent approach. Androgenic (0.08–59 ng/L dihydrotestosterone equivalents – DHT EQs) and anti-androgenic (2.4–26 μg/L flutamide equivalents – FLU EQs) activities and progestins (0.19–75 ng/L) were detected in selected aquatic environments. Progestins displayed androgenic potencies (0.01–0.22 fold of dihydrotestosterone) and strong anti-androgenic potencies (9–62 fold of flutamide). Although they accounted to some extent for androgenic (0.3–29%) and anti-androgenic (4.6–27%) activities in influents, the progestins’ contribution to (anti-)androgenic activities was negligible (≤2.1%) in effluents and surface waters. We also tested joint effect of equimolar mixtures of target compounds and the results indicate that compounds interact in an additive manner. Even if progestins possess relatively strong (anti-)androgenic activities, when considering their low concentrations (sub-ng/L to ng/L) it seems unlikely that they would be the drivers of (anti-)androgenic effects in Czech aquatic environments. [ABSTRACT FROM AUTHOR]

Abstract Interferons (IFNs) are cytokines with fundamental roles in resistance to infections, cancer and other diseases. Type-I IFNs, interferon α (IFN- α) and interferon β (IFN- β), act through a shared receptor complex (IFNAR) comprised of IFNAR1 and IFNAR2 subunits. Binding of type-I IFN to IFNAR1 will robustly activate Janus activated kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Aberrant activation of the type-I IFN response results in a spectrum of disorders called interferonopathies. The purpose of this research is to develop an assay for high-throughput screening (HTS) of small molecule inhibitors of the type-I IFN signaling pathway. Inhibition of type-I IFN signaling can be beneficial in terms of therapeutic use and understanding the underlying mechanism of action. We report here a HTS campaign with the secreted embryonic alkaline phosphatase (SEAP) reporter gene assay against 32,000 compounds which yielded 25 confirmed hits. These compounds were subsequently characterized for their cytotoxicity, effects on STAT phosphorylation and activities in IFN regulatory factor (IRF) transcription. Graphical abstract A high-throughput screening campaign is described here for small molecule inhibitors of the type-I interferon signaling pathway utilizing the SEAP reporter gene assay. Screening against 32,000 pure compounds yielded 25 confirmed hits. Several of them were tested in SH-SY5Y cells and showed inhibition of STAT1/STAT3 phosphorylation and IRF7 mRNA transcription. fx1 [ABSTRACT FROM AUTHOR]

Ultraviolet (UV) is a common and abundant environmental factor that affects daily life. Although the effects of UV radiation on the skin have been extensively reported, studies on the influence of UV radiation on internal organs are still limited. This study aimed to evaluate the influence of UVB exposure on the kidney of mice and to investigate the possible mechanism. In the present study, histopathology changes, oxidative stress, and inflammatory response were used to evaluate the kidney and colon injury induced by UVB exposure. The results showed that the 14-week chronic skin exposure to UVB triggers a kidney injury response characterized by macrophage infiltration, elevated oxidative stress as well as inflammatory and injury markers. The RNA sequencing demonstrated that chronic UVB exposure could alter the kidney transcriptomic profile distinguished by the regulation of genes involved in the Notch signaling pathway, JAK-STAT signaling pathway, and ECM-receptor interaction. Besides, chronic UVB exposure also resulted in gut dysbiosis, manifested as colon macrophage infiltration, stimulated inflammatory responses, impaired barrier integrity, and microbiota structural and functional disorders. The Spearman analysis results further revealed a strong correlation between gut microbiota and kidney injury. In conclusion, skin chronic exposure to UVB causes nephritis and gut microbiota dysbiosis in mice, and these findings provide new insight into the underlying risks of chronic UVB exposure to human wellness. [Display omitted] • Mice chronic exposure to UVB induced renal inflammation and colonic injury. • More than 1700 DEGs were identified by RNA-seq in kidneys of UVB-irradiated mice. • Chronic UVB exposure upregulated Notch, JAK-STAT, and ECM pathways in the kidneys. • Chronic UVB exposure altered the gut microbiota structure and function in mice. [ABSTRACT FROM AUTHOR]

Mongolian medicine prescriptions are recognized as promising gastroprotective agents. This study is to explore the effects and mechanisms of Liuwei Anxiao San (LAS) in gastric ulcer (GU). GU rat models were established using acetic acid, followed by treatment with LAS at different doses and/or the JAK2 agonist Coumermycin A1 (CA1). The ulcerous area and inhibition rates were calculated. The mucosal damage and cell apoptosis in gastric tissues were assessed by H&E and TUNEL staining. The activities of SOD, GSH-Px, and CAT, and MDA levels were measured. The levels of pro-inflammatory and anti-inflammatory factors were determined by ELISA. The activation of the JAK2/STAT3 pathway was determined by Western blot. As the results suggested, LAS dose-dependently ameliorated gastric mucosal damage and inhibited oxidative stress and inflammatory response, evidenced by increased activities of SOD, GSH-Px, and CAT, decreased MDA level, increment of anti-inflammatory factors and decrement of pro-inflammatory factors, and inhibited the activation of the JAK2/STAT3 pathway in GU rats. CA1 partly abolished the function of LAS on gastric mucosal injury, oxidative stress, and inflammation in GU rats. In conclusion, LAS protects against gastric mucosal injury in GU rats through inhibition of oxidative stress and inflammation by suppressing the JAK2/STAT3 pathway. • LAS alleviates gastric mucosal injury in GU rats. • LAS inhibits oxidative stress and inflammation in gastric tissues of GU rats. • LAS inhibits the activation of the JAK2/STAT3 pathway. • CA1 partially averts LAS-mediated inhibition on oxidative stress and inflammation. • LAS mitigates gastric mucosal injury in GU rats by inhibiting JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Traditional drug chemotherapy reveals numerous unsatisfactory aspects for malignant tumors that is prone to recurrence and metastasis, such as low therapy effect, systemic side effects, and multidrug resistance. Based on the above considerations, we herein propose a non-drug chemotherapy-like in synergy with gas-/immunotherapy strategy based on tumor cell membrane (M) coating Ferulic acid (FA)- L -Arg-ovalbumin (OVA) nanoparticles (F-L-O@M NPs). It is found that the non-drug of FA can efficiently induce cancer cell apoptosis via the Janus kinases/signal transducer and activator of transcription 3 (JAK/STAT3) signal pathway. Moreover, the generation of NO gas ascribed to the oxidation of L -Arg by H 2 O 2 , not only restricts the respiratory metabolism of mitochondria and reduces the generation of ATP, but also downregulates the expression of P-gp protein, exhibiting a superior synergistic with FA-mediated antineoplastic. More importantly, NO gas augments FA-induced tumor cell apoptosis and efficiently release tumor-associated antigens, which in synergy with OVA enables significant activation and recruits cytotoxic T lymphocytes to infiltrate in tumor tissues, further combining with immune checkpoint blockade antibody to trigger a long-term immune memory response, as well as anti-metastasis/recurrence. It is highly expected that such a non-drug chemotherapy-like strategy that combines with gas-/immunotherapy showing great promising in the clinical translational potential of nanomedicine. [Display omitted] • A non-drug chemotherapy-like strategy is based on a tumor cell membrane coating Ferulic acid-L-Arg-ovalbumin nanoparticles. • The FA can efficiently induce cancer cell apoptosis via the JAK/STAT3 signal pathway. • F-L-O@M NPs combine with aPD-L1 can trigger a long-term immune memory response, as well as for anti-metastasis/recurrence. [ABSTRACT FROM AUTHOR]

The function of prolactin in mammary gland development and lactation has been demonstrated in previous studies. However, the potential action of prolactin on mammary duct morphogenesis at mammary anlagen stage (E13.5~15.5) has not been elucidated. Transplantation of mammary cells or tissue is an effective approach for the regeneration of damaged mammary gland. Defining the actions of prolactin stimulation on embryonic mammary anlagen has important implications for defining the role of prolactin in the poorly understood processes of mammary duct morphogenesis and regeneration. Here, we have employed the GFP-transgenic mouse model to examine the effects of prolactin on stem cell activity. Using in vitro prolactin stimulation and transplantation of E14.5 mouse mammary anlagen, we identified the influence of prolactin on their mammary repopulating ability. Furthermore, using immunofluorescence staining and microarray analysis, the influence of prolactin on cell characteristics and gene expression in mammary anlagen were also profiled. We also demonstrate that E14.5 mouse mammary anlagen possess mammary stem cells (MaSCs) which achieve mammary repopulation. Furthermore, we found that in vitro prolactin stimulation elevates MaSC activity and promotes the mammary repopulating ability of mammary anlagen. Finally, microarray and pathway analysis showed that MAPK, Akt and JAK-STAT signaling was activated by prolactin stimulation, and drove the mammary repopulation of mammary anlagen. We conclude that prolactin stimulation elevates the stem cell-dependent mammary repopulating ability of embryonic mammary anlagen. [ABSTRACT FROM AUTHOR]

Objective: The role of CD40/CD40 ligand (CD40L) in microvascular thrombosis is now widely accepted. However, the exact mechanisms linking the CD40/CD40L system and the soluble form of CD40L (sCD40L) with microvascular thrombosis are currently a topic of intensive research. The objective of this study was to assess the potential mechanisms in CD40/CD40L system-regulated microvascular thrombosis after focal ischemia/reperfusion (I/R). Methods: Rats were subjected to 60-min transient middle cerebral artery occlusion (MCAO). The experiments were divided into three groups: sham operation, MCAO, and MCAO + CD40 antagonist. Dynamic changes of serum-free sCD40L levels for 0, 1, 3, 5, 6, and 12 h by ELISA detecting kit after focal I/R were observed, and the CD40 expression levels in both platelet surface and vascular endothelial cell surface were measured by flow cytometry and immunofluorescence, respectively. Cerebral infarct volume was analyzed 12 h after reperfusion. mTOR/S6K signaling was determined by Western blot. Results: A comparison of thrombus formation between MCAO and CD40 antagonist treatment rats revealed a role for CD40 and/or CD40L in the inflammation-enhanced thrombosis responses in both of the platelet and vascular endothelial cell. MCAO rats yielded an acceleration of thrombus formation that was accompanied by increased CD40 levels in serum. The brain infarction was significantly decreased in CD40 antagonist treatment group compared to MCAO model group. The mTOR/S6K signaling was activated in MACO model than that of CD40 antagonist treatment group. Conclusions: Our findings indicate that CD40/CD40L system contributes to microvascular thrombosis and brain infarction induced by MCAO and reperfusion. The mTOR/S6K signaling pathway is involved in the regulation of cerebral microvasculature after focal I/R by CD40/ CD40L. Abbreviations: AKT: protein kinase B; CD40L: CD40 ligand; CSF: cerebrospinal fluid; FITC: fluorescein isothiocyanate; I/R: ischemia/reperfusion; MCAO: middle cerebral artery occlusion; mTOR: mechanistic target of rapamycin; PE: P-phycoerythrin; sCD40L: soluble form of CD40L; TNF-a: tumor necrosis factor-alpha; WT: wild type. [ABSTRACT FROM AUTHOR]

HER3 belongs to the human epidermal growth factor receptor (HER) family which also includes HER1/EGFR/erbB1, HER2/erbB2, and HER4/erbB4. As a unique member of the HER family, HER3 lacks or has little intrinsic tyrosine kinase activity. It frequently co-expresses and forms heterodimers with other receptor tyrosine kinases (RTKs) in cancer cells to activate oncogenic signaling, especially the PI-3K/Akt pathway and Src kinase. Elevated expression of HER3 has been observed in a wide variety of human cancers and associates with a worse survival in cancer patients with solid tumors. Studies on the underlying mechanism implicate HER3 expression as a major cause of treatment failure in cancer therapy. Activation of HER3 signaling has also been shown to promote cancer metastasis. These data strongly support the notion that therapeutic inactivation of HER3 and/or its downstream signaling is required to overcome treatment resistance and improve the outcomes of cancer patients. [ABSTRACT FROM AUTHOR]

This review summarizes recent advances in leg regeneration research, focusing on the cricket Gryllus bimaculatus. Recent studies have revealed molecular mechanisms on blastema formation, establishment of positional information, and epigenetic regulation during leg regeneration. Especially, these studies have provided molecular bases in classical conceptual models such as the polar coordinate model, the intercalation model, the boundary model, the steepness model, etc., which were proposed to interpret regeneration processes of the cockroach legs. When a leg is amputated, a blastema is formed through the activation of the Janus-kinase (Jak)/Signal-Transduction-and-Activator-of-Transcription (STAT) pathway. Subsequently, the Hedgehog/Wingless/Decapentaplegic/Epidermal-growth-factor pathways instruct distalization in the blastema, designated as the molecular boundary model. Downstream targets of this pathway are transcription factors Distal-less (Dll) and dachshund (dac), functioning as key regulators of proximodistal pattern formation. Dll and dac specify the distal and proximal regions in the blastema, respectively, through the regulation of tarsal patterning genes. The expression of leg patterning genes during regeneration may be epigenetically controlled by histone H3K27 methylation via Enhancer-of-zeste and Ubiquitously-transcribed-tetratricopeptide-repeat-gene-X-chromosome. For the molecular mechanism of intercalation of the missing structures between the amputated position and the most distal one, Dachsous/Fat (Ds/Ft) steepness model has been proposed, in which the Ds/Ft pathway maintains positional information and determines leg size through dac expression. This model was theoretically verified to interpret the experimental results obtained with cricket legs. Availability of whole-genome sequence information, regeneration-dependent RNA interference, and genome editing technique will have the cricket be an ideal model system to reveal gene functions in leg regeneration. [ABSTRACT FROM AUTHOR]

Elevated levels of eukaryotic initiation factor 4E (eIF4E) are implicated in neoplasia, with cumulative evidence pointing to its role in the etiopathogenesis of hematological diseases. As a node of convergence for several oncogenic signaling pathways, eIF4E has attracted a great deal of interest from biologists and clinicians whose efforts have been targeting this translation factor and its biological circuits in the battle against leukemia. The role of eIF4E in myeloid leukemia has been ascertained and drugs targeting its functions have found their place in clinical trials. Little is known, however, about the pertinence of eIF4E to the biology of lymphocytic leukemia and a paucity of literature is available in this regard that prospectively evaluates the topic to guide practice in hematological cancer. A comprehensive analysis on the significance of eIF4E translation factor in the clinical picture of leukemia arises, therefore, as a compelling need. This review presents aspects of eIF4E involvement in the realm of the lymphoblastic leukemia status; translational control of immunological function via eIF4E and the state-of-the-art in drugs will also be outlined. [ABSTRACT FROM AUTHOR]

It is reported that growth factor (GF) is able to enhance the repair of articular cartilage (AC) defect, however underlying mechanisms of which are not fully elucidated yet. Moreover, the strategy for delivering GF needs to be optimized. The crosstalk between AC and subchondral bone (SB) play important role in the homeostasis and integrity of AC, therefore SB targeted delivery of GF represents one promising way to facilitate the repair of AC defect. In this study, we firstly investigated the effects and mechanism of FGF2 on surrounding SB and cartilage of detect defects in rabbits by using a homogenous collagen-based membranes. It was found that FGF2 had a modulating effect on the defect-surrounding SB via upregulation of bone morphogenetic protein (BMP)-2, BMP4 and SOX9 at the early stage. Low dose FGF2 improved the repair upon directly injected to SB. Inhibition of BMP signaling pathway compromised the beneficial effects of FGF2, which indicated the pivotal roles of BMP in the process. To facilitate SB targeted FGF2 delivery, a double-layered inhomogeneous collagen membrane was prepared and it induced increase of BMP2 and BMP4 in the synovial fluid, and subsequent successful repair of AC defect. Taken together, this targeted delivery of FGF2 to SB provides a promising strategy for AC repair owing to the relatively clear mechanism, less amount of it, and short duration of delivery. Statement of Significance Articular cartilage (AC) and subchondral bone (SB) form an integral functional unit. The homeostasis and integrity of AC depend on its crosstalk with the SB. However, the function of the SB in AC defect repair is not completely understood. The application of growth factors to promote the repair articular cartilage defect is a promising strategy, but still under the optimization. Our study demonstrate that SB plays important roles in the repair of AC defect. Particularly, SB is the effective target of fibroblast growth factor 2 (FGF2), and targeted delivery of FGF2 can modulate SB and thus significantly enhances the repair of AC defect. Therefore, targeted delivery of growth factor to SB is a novel promising strategy to improve the repair of AC defect. [ABSTRACT FROM AUTHOR]

Background The cellular and molecular mechanisms implicated in age-associated changes in myocardial structure are of paramount importance since they cause profound alterations in the functional response and represent targets for alleviating age-related pathologies. One of these mechanisms is the JAK/STAT/SOCS signaling pathway. Aim of the study The present study is designed to elucidate age-dependent changes of the myocardium to provide morphological basis displaying the pathogenesis of myocardial hypertrophy, fibrosis and inflammation with aging. Material and methods Thirty male Sprague Dawley rats aged; 6, 30 and 36 months were used in this study. The animals were divided into three age groups, young adult, senile and very senile rats, respectively. The heart weight/body weight ratio was determined. The heart was subjected to gross morphologic examination, microscopic examination using H&E and Masson’s trichrome stains and immunohistochemical examination for detection of JAK, pSTAT3, α-SMA, β-MHC and CD45. Western blotting was also carried out to detect SOCS genes. Real-time PCR was used to detect the inflammatory markers TNFα and IL1β and the hypertrophy marker α-SKA. Biochemical analysis of cardiac troponin I and creatine kinase-MB was done. Quantitative histomorphometric estimations included estimation of cardiac myocyte cross sectional area, estimation of the area percent of collagen fibers in Masson's trichrome stained sections and determination of optical density in immunostained sections. Electron microscopic examination was done to determine capillary density. Results Jak and pSTAT3 were predominantly localized to the nuclei and exhibited progressive decline with aging, while SOCS3 activity displayed an age-related increase. The aged myocardium displayed profound age associated structural changes as well as myocardial hypertrophy, fibrosis and inflammation in senile and very senile rats. Conclusion The age-related modifications in the JAK/STAT/SOCS signaling as well as the age-associated pathological changes in myocardial structure are of particular interest as they provide further insight in age-associated heart pathologies and represent potential targets for cardioprotective and therapeutic approaches. [ABSTRACT FROM AUTHOR]

The inflammatory reaction initiates fracture healing and could play a role in the osteoinductive effect of calcium phosphate (CaP) ceramics, which has been widely confirmed; however, the underlying mechanism has not been fully elucidated. In this study, various signaling molecules from macrophages under the stimulation of osteoinductive biphasic calcium phosphate (BCP) ceramic and its degradation products were examined and evaluated for their influence on the migration and osteoblastic differentiation of mesenchymal stem cells (MSCs). The results of cellular experiments confirmed that the gene expression of most inflammatory factors (IL-1, IL-6 and MCP-1) and growth factors (VEGF, PDGF and EGF) by macrophages were up-regulated to varying degrees by BCP ceramic and its degradation products. Cell migration tests demonstrated that the conditioned media (CMs), which contained abundant signaling molecules secreted by macrophages cultured on BCP ceramic and its degradation products, promoted the migration of MSCs. qRT-PCR analysis indicated that CMs promoted the gene expression of osteogenic markers (ALP, COL-I, OSX, BSP and OPN) in MSCs. ALP activity and mineralization staining further confirmed that CMs promoted the osteoblastic differentiation of MSCs. The present study confirmed the correlation between the inflammatory reaction and osteoinductive capacity of BCP ceramic. The ceramic itself and its degradation products can induce macrophages to express and secrete various signaling molecules, which then recruit and promote the MSCs to differentiate into osteoblasts. Compared with BCP conditioned media, degradation particles played a more substantial role in this process. Thus, inflammation initiated by BCP ceramic and its degradation products could be necessary for osteoinduction by the ceramic. Statement of Significance It is known that the inflammatory reaction initiates fracture healing. The aim of this study was to examine whether osteoinductive BCP ceramics could cause macrophages to change their secretion patterns and whether the secreted cytokines could affect migration and osteoblastic differentiation of MSCs. Moreover, the duration of inflammation could be influenced by the local ionic environment and the degradation products of the implant. Our experimental results revealed the correlation between the inflammatory reaction and osteoinductive capacity of BCP ceramic. The ceramic itself and its degradation products can induce macrophages to express and secrete various signaling molecules, which then recruit and promote the MSCs to differentiate into osteoblasts. Compared with ionic microenvironment, degradation particles played a more substantial role in this process. Therefore, the appropriate inflammation initiated by BCP ceramic and its degradation products could be essential for osteoinduction by the ceramic. We believe that the present study improves the understanding of the effect of biomaterial-mediated inflammation on MSC migration and differentiation and established a preliminary correlation between the immune system and osteoinduction by biomaterials. [ABSTRACT FROM AUTHOR]

Wear debris-induced inhibition of bone regeneration and extensive bone resorption were common features in peri-prosthetic osteolysis (PPO). Here, we investigated the effect of melatonin on titanium particle-stimulated osteolysis in a murine calvariae model and mouse-mesenchymal-stem cells (mMSCs) culture system. Melatonin inhibited titanium particle-induced osteolysis and increased bone formation at osteolytic sites, confirmed by radiological and histomorphometric data. Furthermore, osteoclast numbers decreased dramatically in the low- and high-melatonin administration mice, as respectively, compared with the untreated animals. Melatonin alleviated titanium particle-induced depression of osteoblastic differentiation and mineralization in mMSCs. Mechanistically, melatonin was found to reduce the degradation of β-catenin, levels of which were decreased in presence of titanium particles both in vivo and in vitro . To further ensure whether the protective effect of melatonin was mediated by the Wnt/β-catenin signaling pathway, ICG-001, a selective β-catenin inhibitor, was added to the melatonin-treated groups and was found to attenuate the effect of melatonin on mMSC mineralization. We also demonstrated that melatonin modulated the balance between receptor activator of nuclear factor kappa-B ligand and osteoprotegerin via activation of Wnt/β-catenin signaling pathway. These findings strongly suggest that melatonin represents a promising candidate in the treatment of PPO. Statement of Significance Peri-prosthetic osteolysis, initiated by wear debris-induced inhibition of bone regeneration and extensive bone resorption, is the leading cause for implant failure and reason for revision surgery. In the current study, we demonstrated for the first time that melatonin can induce bone regeneration and reduce bone resorption at osteolytic sites caused by titanium-particle stimulation. These effects might be mediated by activating Wnt/β-catenin signaling pathway and enhancing osteogenic differentiation. Meanwhile, the ability of melatonin to modulate the balance between receptor activator of nuclear factor kappa-B ligand and osteoprotegerin mediated by Wnt/β-catenin signaling pathway, thereby suppressing osteoclastogenesis, may be implicated in the protective effects of melatonin on titanium-particle-induced bone resorption. These results suggested that melatonin can be considered as a promising therapeutic agent for the prevention and treatment of peri-prosthetic osteolysis. [ABSTRACT FROM AUTHOR]

Arsenic is a common environmental pollutant, typically affecting the skin most severely. Recent studies have shown that arsenic's toxicity may be linked to N6-methyladenosine (m6A), an abundant and dynamic epigenetic RNA modification. However, it is not completely understood how m6A contributes to arsenite-induced skin lesions. Herein, it is shown that methyltransferase-like 3 (METTL3) plays a crucial role in the involvement of arsenite-induced skin lesions in an m6A-dependent manner. Using bioinformatic analysis and experimental approaches, we demonstrate that arsenite induces METTL3 upregulation, represses suppressors of cytokine signaling 3 (SOCS3) expression in an m6A- YTH m6A RNA binding protein 2 (YTHDF2)-dependent manner, and leads to the aberrant activation of the Janus kinase (JAK)2/signal transducer and activator of transcription 3(STAT3) signaling pathway. We further found that the activated transcription factor STAT3 binds to the promoter regions of Krt1 and Krt10, promoting their transcription, which ultimately leads to arsenite-induced skin lesions. In conclusion, our study reveals the role of m6A in arsenite-induced skin lesions through the activation of the JAK2/STAT3/Krt signaling axis. The findings provide new insight into the potential molecular mechanisms underlying arsenic toxicity regulation through m6A modification. [Display omitted] • METTL3-mediated m6A methylation is involved in arsenite-induced HaCaT cell damage. • METTL3 may be involved in arsenicosis by regulating the JAK-STAT signaling pathway. • Arsenite induces METTL3 inhibition of JAK2/STAT3 signaling pathway activation by SOCS3. • Arsenite disrupts SOCS3 protein levels in a METTL3-YTHDF2-dependent manner. • Arsenite participates in skin lesions by inducing METTL3 activation STAT3 with Krt. [ABSTRACT FROM AUTHOR]

In the last few decades, short-chain chlorinated paraffins (SCCPs) have become the most heavily produced monomeric organohalogen compounds, and have been reported to induce multiple organ toxicity. However, the effects of SCCPs on the central nervous system are unknown. In the present study, we show that SCCP exposure induced astrocyte proliferation and increased the expression of two critical markers of astrocyte activation, glial fibrillary acidic protein and inducible nitric oxide synthase, in vivo and in vitro. SCCP exposure also increased inflammatory factory gene expression. Moreover, SCCP treatment triggered Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signalling, as shown by increased phosphorylation and STAT3 translocation to the nucleus. Both JAK2 and STAT3 inhibition effectively attenuated SCCP-induced astrocyte activation. Finally, JAK2 inhibition significantly rescued STAT3 phosphorylation and nuclear translocation. Taken together, JAK2/STAT3 pathway activation contributed to SCCP-induced astrocyte activation. These data will help elucidate the molecular mechanism underlying SCCP-induced neurotoxicity. • SCCP exposure triggered astrocyte activation in vivo and in vitro. • SCCP exposure activated JAK2/STAT3 signaling pathway and increased STAT3 phosphorylation and translocation to the nucleus. • Both JAK2 and STAT3 inhibition effectively attenuated SCCP-induced astrocyte activation. [ABSTRACT FROM AUTHOR]

Intermuscular bones (IBs), which are little, bony spicules in muscle, are embedded in lower teleosts' myosepta. Despite the importance of studying IB development in freshwater aquaculture species, the genes associated with IB development need to be further explored. In the present study, we identified four stages of IB development in barbel steed (Hemibarbus labeo), namely stage 1: IBs have not emerged, stage 2: a few small IBs have emerged in the tail, stage 3: longer IBs gradually emerged in the tail and stage 4: all of the IBs in the tail are mature and long, via Alizarin red staining. Subsequently, we used the HiseqXTen platform to sequence and de novo assemble the transcriptome of epaxial muscle (between 35th and 40th myomere) of barbel steed at 29 days (stage 1) and 42 days (stage 3) after hatching. A total of 190,814 unigenes were obtained with an average length and N 50 of 648 bp and 1027 bp, respectively. We found 2174 differentially expressed genes (DEGs) between stages 1 and 3, of which 378 and 1796 were up- and down-regulated, respectively. Functional enrichment analysis showed that several DEGs functioned in ossification, positive regulation of osteoblast differentiation, osteoblast differentiation, and BMP signaling pathway, and were further enriched in signal pathway, including osteoclast differentiation, TGF-β signaling pathway, cytokine-cytokine receptor interaction, Jak-STAT signaling pathway, and other KEEG pathways. In conclusion, we identified genes that may be related to IB development, such as kazal type serine peptidase inhibitor domain 1 (KAZALD1), extracellular matrix protein 1 (ECM1), tetranectin , bone morphogenetic protein 1 (bmp1), acid phosphatase 5 (ACP5), collagen type XI alpha 1 chain (COL11A1), matrix metallopeptidase 9 (MMP9), pannexin-3 (PANX3), sp7 transcription factor (Sp7), and c-x-c motif chemokine ligand 8 (CXCL8), by comparing the transcriptomes of epaxial muscle before and after IB ossification. This study provided a theoretical basis for identifying the molecular mechanisms underlying IB development in fish. [Display omitted] • We performed RNA-seq on epaxial muscle (with intermuscular bones) of barbel steed before and after IB ossification. • We identified 2174 DEGs, some of which matched the enrichment and signaling pathway components associated with bone formation. • We have identified several genes that may be related to IB ossification, such as bmp1 , COL11A1 , Sp7 , and KAZALD1. [ABSTRACT FROM AUTHOR]

To explore the regulation of SOCS3 in the JAK2/STAT3 pathway during vocal fold fibroblast activation after vocal fold injury. Normal vocal fold fibroblasts (VFFs), injured VFFs, and simulated injured VFFs (normal VFFs supplemented with transforming growth factor beta [TGF-β]) were treated with a JAK2 inhibitor (AG490), and SOCS3 was overexpressed in each group. Type I collagen (COL1), α-smooth muscle actin (α-SMA), SOCS3, JAK2, and STAT3 were detected using immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting. Compared with normal VFFs, expression of SOCS3 was lower, but p-JAK/p-STAT3 and JAK2/STAT3 were higher in injured and simulated injured VFFs. After the addition of AG490, COL1 and α-SMA expressions did not change significantly in normal VFFs but was significantly decreased in the other two groups. The protein and mRNA expression levels of SOCS3 were significantly increased, while those of p-JAK/p-STAT3 and JAK2/STAT3 were significantly decreased. When SOCS3 was overexpressed, the COL1 and α-SMA expression levels in normal VFFs were not altered significantly, whereas they were significantly decreased in injured and simulated injured VFFs. The expression of p-JAK2/p-STAT3 significantly decreased when SOCS3 was overexpressed in injured and simulated injured VFFs. SOCS3 may regulate the activation of JAK2/STATA3 pathway after vocal fold injury. In addition, SOCS3 may inhibit excessive activation of vocal fold fibroblasts by downregulating JAK2/STAT3 in the early stages of vocal fold injury. • SOCS3 significantly decreased after vocal fold injury • SOCS3 can inhibit the activation of the JAK2/STAT3 signalling pathway • JAK2 inhibition can partially reverse the fibrotic phenotype of injured VFFs [ABSTRACT FROM AUTHOR]

Macrophages play an important role in causing silicosis eventually becoming an irreversible fibrotic disease, and there are no specific drugs for silicosis in the clinic so far. Pirfenidone has consistently been shown to have anti-inflammatory and anti-fibrotic effects, but the specific mechanism by which it ameliorates fibrosis in silicosis is unclear. A rat silicosis model was established in this study, and lung tissues and serum were collected by batch execution at 14, 28, and 56 days. Also, the effects of Pirfenidone on macrophage polarization and pulmonary fibrosis were evaluated in silicosis with early intervention and late treatment by histological examination, Enzyme-linked immunosorbent assay, Hydroxyproline assay, Western blot and Quantitative reverse transcription polymerase chain reaction. The results showed that Pirfenidone significantly reduced pulmonary fibrosis in rats with silicosis, and both early intervention and late treatment effectively inhibited the expression of α-SMA, Col-I, Vimentin, Hydroxyproline, IL-1β, IL-18, and the M2 macrophage marker CD206 and Arg-1, while only early intervention effectively inhibited E-cad, TGF-β1, TNF-α, and the M1 macrophage marker iNOS, CD86. Furthermore, Pirfenidone dramatically reduced the mRNA expression of the JAK2/STAT3. These findings imply that Pirfenidone may reduce pulmonary fibrosis in silicosis rats by inhibiting macrophage polarization via the JAK2/STAT3 signaling pathway. [Display omitted] • Pirfenidone inhibits macrophage polarization and pulmonary fibrosis in silicosis rats. • JAK2 and STAT3 are involved in silicosis fibrosis process and can be inhibited by pirfenidone. • Pirfenidone may improve silicosis fibrosis by inhibiting macrophage polarization through the JAK2/STAT3 pathway. • The early intervention effect of pirfenidone in rats with silicosis is better than the later treatment effect. [ABSTRACT FROM AUTHOR]

Brucella spp. avoid host immune recognition and thus, weaken the immune response to infection. The Toll/interleukin-1 receptor (TIR) domain-containing protein (TcpB/Btp1) of Brucella spp. is thought to be involved in blocking host innate immune responses by binding to adaptors downstream of Toll-like receptors. In this study, based on the observation that TcpB binds to the host target proteins, MAL, through the TIR domain, we examined decoy peptides from TcpB TIR domains and found that TB-8 and TB-9 substantially inhibit lipopolysaccharide (LPS)-induced signaling in vitro and in vivo . Both these peptides share a common loop, the DD loop, indicating a novel structural region mediating TIR interactions. The inhibition of LPS signaling by TB-8 and TB-9 shows no preference to MyD88-dependent cytokines, such as TNF-α and IL-1β or TRIF-dependent cytokines including IFN-β and IL-6. Furthermore, these two peptides rescue the virulence of Brucella Δ tcpB mutants at the cellular level, indicating key roles of the DD loop in Brucella pathogenesis. In conclusion, identification of inhibitors from the bacterial TIR domains is helpful not only for illustrating interacting mechanisms between TIR domains and bacterial pathogenesis, but also for developing novel signaling inhibitors and therapeutics for human inflammatory diseases. [ABSTRACT FROM AUTHOR]

4-Nitrophenol (PNP) is a persistent organic pollutant that was proven to be an environmental endocrine disruptor. The aim of this study was to evaluate the role of the estrogen receptor-α (ER-α) and aryl hydrocarbon receptor (AhR) signaling pathway in regulating the damage response to PNP in the small intestine of rats. Wistar-Imamichi male rats (21 d) were randomly divided into two groups: the control group and PNP group. Each group had three processes that were gavaged with PNP or vehicle daily: single dose (1 d), repeated dose (3 consecutive days) (3 d), and repeated dose with recovery (3 consecutive days and 3 recovery days) (6 d). The weight of the body, the related viscera, and small intestine were examined. Histological parameters of the small intestine and the quantity of mucus proteins secreted by small goblet cells were determined using HE staining and PAS staining. The mRNA expression of AhR , ER-α , CYP1A1 , and GST was measured by real-time qPCR. In addition, we also analyzed the AhR, ER-α, and CYP1A1 expression in the small intestine by immunohistochemical staining. The small intestines histologically changed in the PNP-treated rat and the expression of AhR, CYP1A1, and GST was increased. While ER-α was significantly decreased in the small intestine, simultaneously, when rats were exposed to a longer PNP treatment, the damages disappeared. Our results demonstrate that PNP has an effect on the expression of AhR signaling pathway genes, AhR, CYP1A1, and GST, and ER-α in the rat small intestine. [ABSTRACT FROM AUTHOR]

Cosic discovered that spectral analyses of a protein sequence after each constituent amino acid had been transformed into an appropriate pseudopotential predicted a resonant energy between interacting molecules. Several experimental studies have verified the predicted peak wavelength of photons within the visible or near-visible light band for specific molecules. Here, this concept has been applied to a classic signaling pathway, JAK–STAT, traditionally composed of nine sequential protein interactions. The weighted linear average of the spectral power density (SPD) profiles of each of the eight “precursor” proteins displayed remarkable congruence with the SPD profile of the terminal molecule (CASP-9) in the pathway. These results suggest that classic and complex signaling pathways in cells can also be expressed as combinations of resonance energies. [ABSTRACT FROM AUTHOR]