Pyroptosis, which is characterized by gasdermin family protein‐mediated pore formation, cellular lysis and the release of pro‐inflammatory cytokines, is a form of programmed cell death associated ...with intracellular pathogens‐induced infection. However, emerging evidence indicates that pyroptosis also contributes to sterile inflammation. In this review, we will first illustrate the biological process of pyroptosis. Then, we will focus on the pathogenic effects of pyroptosis on multiple noninfectious disorders. At last, we will characterize several specific pyroptotic inhibitors targeting the pyroptotic signalling pathway. These data demonstrate that pyroptosis plays a prominent role in sterile diseases, thereby providing a promising approach to the treatment of noninfective inflammatory disorders.
Pyroptosis contributes to multiple noninfectious disorders including neuronal diseases, sterile inflammatory diseases, cancer, atherosclerosis, acute injury, adverse pregnancy complications and autoimmune diseases via lytic cell death, cytokines releases, dysfunction of organelles and auto‐antigens release. Meanwhile, pyroptosis can also inhibit the development of some specific tumor via pyroptotic cell death and anti‐tumor immunity. Red line and text mean promotion. Green line and text indicate suppression. AT1‐AA, angiotensin II type 1 receptor autoantibody.
Metabolic syndrome, characterized by central obesity, hypertension, and hyperlipidemia, increases the morbidity and mortality of cardiovascular disease, type 2 diabetes, nonalcoholic fatty liver ...disease, and other metabolic diseases. It is well known that insulin resistance, especially hepatic insulin resistance, is a risk factor for metabolic syndrome. Current research has shown that hepatic fatty acid accumulation can cause hepatic insulin resistance through increased gluconeogenesis, lipogenesis, chronic inflammation, oxidative stress and endoplasmic reticulum stress, and impaired insulin signal pathway. Mitochondria are the major sites of fatty acid β-oxidation, which is the major degradation mechanism of fatty acids. Mitochondrial dysfunction has been shown to be involved in the development of hepatic fatty acid–induced hepatic insulin resistance. Mitochondrial autophagy (mitophagy), a catabolic process, selectively degrades damaged mitochondria to reverse mitochondrial dysfunction and preserve mitochondrial dynamics and function. Therefore, mitophagy can promote mitochondrial fatty acid oxidation to inhibit hepatic fatty acid accumulation and improve hepatic insulin resistance. Here, we review advances in our understanding of the relationship between mitophagy and hepatic insulin resistance. Additionally, we also highlight the potential value of mitophagy in the treatment of hepatic insulin resistance and metabolic syndrome.
Heat stress can have an impact on parental gamete maturation and reproduction functions. According to current research, the microbial composition of the vaginal cavity is species specific. Pregnancy, ...menstruation, and genital diseases have been linked to the dynamics of vaginal ecology. In this study, we characterized the vaginal microbiota and metabolites after heat stress. At the phylum level, the rabbit's vaginal microbial composition of rabbit showed high similarity with that of humans. In the Heat group, the relative abundance of the dominant microbiota
,
, and
increased, while the relative abundance of
decreased. Furthermore, heat stress significantly increased the relative abundance of
,
,
,
,
, and
, whereas the relative abundance of 12 genera significantly decreased, including
,
,
,
,
,
,
,
,
,
,
, and
Besides, the relative concentrations of 158 metabolites differed significantly between the Heat and Control groups. Among them, the endocrine hormone estradiol (E
) increased in the Heat group and was positively associated with a number of metabolites such as linolelaidic acid (C18:2N6T), N-acetylsphingosine, N-oleoyl glycine, trans-petroselinic acid, syringic acid, 2-(1-adamantyl)-1-morpholinoethan-1-one, 5-OxoETE, and 16-heptadecyne-1,2,4-triol. Further, the majority of the differential metabolites were enriched in steroid biosynthesis and endocrine and other factor-regulated calcium reabsorption pathways, reflecting that heat stress may affect calcium metabolism, hormone-induced signaling, and endocrine balance of vaginal ecology. These findings provide a comprehensive depiction of rabbit vaginal ecology and reveal the effects of heat stress on the vagina
the analysis of vaginal microbiome and metabolome, which may provide a new thought for low female fertility under heat stress.
Psoriasis, which is a common chronic inflammatory skin disease, endangers human health and brings about a major economic burden worldwide. To date, treatments for psoriasis remain unsatisfied because ...of their clinical limitations and various side effects. Thus, developing a safer and more effective therapy for psoriasis is compelling. Previous studies have explicitly shown that psoriasis is an autoimmune disease that is predominantly mediated by T helper 17 (Th17) cells, which express high levels of interleukin-17 (IL-17) in response to interleukin-23 (IL-23). The discovery of the IL-23-Th17-IL-17 axis in the development of psoriasis has led to the paradigm shift of understanding pathogenesis of psoriasis. Although anti-IL-17 antibodies show marked clinical efficacy in treating psoriasis, compared with antibodies targeting IL-17A or IL-17R alone, targeting Th17 cells themselves may have a maximal benefit by affecting multiple proinflammatory cytokines, including IL-17A, IL-17F, IL-22, and granulocyte-macrophage colony-stimulating factor, which likely act synergistically to drive skin inflammation in psoriasis. In this review, we mainly focus on the critical role of Th17 cells in the pathogenesis of psoriasis. Especially, we explore the small molecules that target retinoid-related orphan receptor γt (RORγt), a vital transcription factor for Th17 cells. Given that RORγt is the lineage-defining transcription factor for Th17 cell differentiation, targeting RORγt
small molecular inverse agonists may be a promising strategy for the treatment of Th17-mediated psoriasis.
Significance Although oncolytic virotherapy is showing great promise in clinical trials, not all patients are benefiting. Identifying predictors of therapeutic effectiveness for each oncolytic virus ...would provide a good chance to increase response rate. Here, we describe an alphavirus (M1) that possesses selective and potent antitumor activity through intravenous infusion, whereas its replication is controlled by the zinc-finger antiviral protein (ZAP) gene. A survey of cancer tissue banks reveals that ZAP is commonly deficient in human cancers, suggesting extensive application prospects of M1. Our work provides an example of a potentially personalized cancer therapy using a targeted oncolytic virus that can be selectively administered to patients with ZAP-deficient tumors. We predict that such agents will form the armamentarium of cancer therapy in the future.
Oncolytic virotherapy is a growing treatment modality that uses replicating viruses as selective antineoplastic agents. Safety and efficacy considerations dictate that an ideal oncolytic agent would discriminate between normal and cancer cells on the basis of common genetic abnormalities in human cancers. Here, we identify a naturally occurring alphavirus (M1) as a novel selective killer targeting zinc-finger antiviral protein (ZAP)-deficient cancer cells. In vitro, in vivo, and ex vivo studies showed potent oncolytic efficacy and high tumor tropism of M1. We showed that the selectivity depends on ZAP deficiency by systematic identification. A large-scale multicenter pathology study using tissue microarrays reveals that ZAP is commonly deficient in human cancers, suggesting extensive application prospects for M1. Additionally, M1 killed cancer cells by inducing endoplasmic reticulum stress-mediated apoptosis. Our report provides novel insights into potentially personalized cancer therapy using oncolytic viruses.
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related deaths worldwide. Despite new technologies in diagnosis and treatment, the incidence and ...mortality of HCC continue rising. And its pathogenesis is still unclear. As a highly conserved protein of the Golgi apparatus, Golgi phosphoprotein 3 (GOLPH3) has been shown to be involved in tumorigenesis of HCC. This study aimed to explore the exact oncogenic mechanism of GOLPH3 and provide a novel diagnose biomarker and therapeutic strategy for patients with HCC.
Firstly, the expression of GOLPH3 was detected in the HCC tissue specimens and HCC cell lines. Secondly, RNA interference was used for GOLPH3 gene inhibition. Thirdly, cell proliferation was analyzed by MTT; cell apoptosis was analyzed by Annexin-V/PI staining, Hoechst 33,342 staining and caspase 3/7 activity assay. Fourthly, xenograft tumor model was used to study the function of GOLPH3 in tumor growth in vivo. Finally, western blotting and immunohistochemistry were used to investigate the role of GOLHP3 in the mTOR signaling pathway.
Data showed that the mRNA and protein expression of GOLPH3 were up-regulated in HCC tumor tissue and cell lines compared with those of control (P < 0.05). Correlation analyses showed that GOLPH3 expression was positively correlated with serum alpha-fetoprotein level (AFP, P = 0.006). Knockdown GOLPH3 expression inhibited proliferation and promoted apoptosis in HCC cell lines. What's more, knockdown GOLPH3 expression led to tumor growth restriction in xenograft tumor model. The expression of phosphorylated mTOR, AKT and S6 K1 were significantly higher in HCC tumor tissue and cell lines compared with those in normal liver tissues (p < 0.05). While the phosphorylated mTOR, AKT and S6 K1 were much lower when diminished GOLPH3 expression in HCC cell lines both in vitro and in vivo.
The current study suggests that GOLPH3 contributes to the tumorigenesis of HCC by activating mTOR signaling pathway. GOLPH3 is a promising diagnose biomarker and therapeutic target for HCC. Our study may provide a scientific basis for developing effective approaches to treat the HCC patients with GOLPH3 overexpression.
Psoriasis is a chronic inflammatory skin disorder characterized by abnormal keratinocytes proliferation and multiple immune cells infiltration in the dermis and epidermis. Although most ...psoriasis-related researches have been concentrated on the interleukin-23 (IL-23)/interleukin-17 (IL-17) axis, new data suggest that keratinocytes also play a pivotal role in psoriasis. Previously, we found that punicalagin (PUN), a bioactive ellagitannin extracted from
Pericarpium Granati
(the pericarpium of
Punica granatum
L.), exerts a therapeutic effect on psoriasis. However, the underlying mechanism, especially its potential modulatory effect on keratinocytes, remains obscure. Our study aims to reveal the potential regulatory effect and its underlying cellular mechanism of PUN on the hyperproliferation of keratinocytes. We used tumor necrosis factor α (TNF-α), IL-17A and interleukin-6 (IL-6) to induce abnormal proliferation of HaCaT cells (Human Keratinocytes Cells) in vitro. Then, we evaluated the effects of PUN through MTT assay, EdU staining and cell cycle detection. Finally, we explored the underlying cellular mechanisms of PUN via RNA-sequencing, WB in vitro and in vivo. Here, we found that PUN can directly and dose-dependently decrease TNF-α, IL-17A and IL-6-induced abnormal proliferation of HaCaT cells in vitro. Mechanically, PUN suppresses the hyperproliferation of keratinocytes through repressing S-phase kinase-associated protein 2 (SKP2) expression in vitro and in vivo. Moreover, overexpression of SKP2 can partly abolish PUN-mediated inhibition of aberrantly proliferative keratinocytes. These results illustrate that PUN can reduce the severity of psoriasis through directly repressing SKP2-mediated abnormal proliferation of keratinocytes, which gives new insight into the therapeutic mechanism of PUN on psoriasis. Moreover, these findings imply that PUN might be a promising drug candidate for the treatment of psoriasis.
Graphical Abstract
Heat stress can impair the rabbit immune system, induce oxidative stress, and cause many complications. These diseases are characterized by metabolic disorders, but the underlying mechanism is ...unknown. As a result, the current research determines the effects of HS on intestinal microorganisms in rabbits and the metabolic pathway disorders caused by HS. Twelve rabbits were randomly assigned to one of two groups: CON (22-24°C) and HS (30°C-32°C). Both the groups were treated for 15 days. Blood and fecal samples were collected on day 15. Serum immune oxidation indices were determined using a commercial ELISA kit, and the microbiome of rabbit feces was studied using 16S rRNA gene sequencing. Non-targeted metabolomics was analyzed using ultra-high-performance liquid chromatography-mass spectrometry (UHPC MS/MS). The findings revealed that HS significantly increased IgG and T-AOC levels in serum, whereas it decreased TNF-α and IL-10. NMDS analysis revealed a substantial difference in bacterial community composition between HS and CON groups. At the phylum level, the abundance of
,
, and
was significantly higher in the HS group, whereas the abundance of
was reduced in the CON group.
,
,
,
,
,
, at the genus level
,
,
,
,
,
,
,
,
, and
were significantly upregulated in the HS group. The metabolism of the HS group was considerably upregulated compared with the metabolism of the CON group, according to principal component analysis (PCA) and least-squares discriminant analysis (PLS-DA). HS increased the concentrations of 4-pyridoxic acid, kynurenine, 20-OH-leukotriene B4, and dopamine and decreased the concentration of pyridoxal. In the rabbit gut, these compounds primarily impact the metabolic pathways of vitamin B6, tryptophan, neutrophil activation, and prolactin. 4-Pyridoxic acid, pyridoxal, kynurenine, 20-OH-leukotriene B4, and dopamine are essential inflammatory response markers and oxidative stress.
In this work, we study the trans influence of boryl ligands and other commonly used non-boryl ligands in order to search for a more active catalyst than the ruthenium dihydride complex Ru(PNP)(CO)H2 ...for the hydrogenation of CO2. The theoretical calculation results show that only the B ligands exhibit a stronger trans influence than the hydride ligand and are along increasing order of trans influence as follows: –H < –BBr2 < –BCl2 ≈ –B(OCH)2 < –Bcat < –B(OCH2)2 ≈ –B(OH)2 < –Bpin < –B(NHCH2)2 < –B(OCH3)2 < –B(CH3)2 < –BH2. The computed activation free energy for the direct hydride addition to CO2 and the NBO analysis of the property of the Ru–H bond indicate that the activity of the hydride can be enhanced by the strong trans influence of the B ligands through the change in the Ru–H bond property. The function of the strong trans influence of B ligands is to decrease the d orbital component of Ru in the Ru–H bond. The design of a more active catalyst than the Ru(PNP)(CO)H2 complex is possible.
N
6
-methyladenosine (m
6
A) modification, the addition of a methylation decoration at the position of N6 of adenosine, is one of the most prevalent modifications among the over 100 known chemical ...modifications of RNA. Numerous studies have recently characterized that RNA m
6
A modification functions as a critical post-transcriptional regulator of gene expression through modulating various aspects of RNA metabolism. In this review, we will illustrate the current perspectives on the biological process of m
6
A methylation. Then we will further summarize the vital modulatory effects of m
6
A modification on immunity, viral infection, and autoinflammatory disorders. Recent studies suggest that m
6
A decoration plays an important role in immunity, viral infection, and autoimmune diseases, thereby providing promising biomarkers and therapeutic targets for viral infection and autoimmune disorders.
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