Signal Transducer And Activator Of Transcription 3 Research Articles

Humanin-G Ameliorates Hemorrhage-Induced Acute Lung Injury in Mice Through AMPKα1-Dependent and -Independent Mechanisms

Background/Objectives: The severity of acute lung injury is significantly impacted by age and sex in patients with hemorrhagic shock. AMP-activated protein kinase (AMPK) is a crucial regulator of energy metabolism but its activity declines with aging. Humanin is a mitochondrial peptide that exerts cytoprotective effects in response to oxidative stressors and is associated with longevity. Using a mouse model of hemorrhagic shock that mimics the clinical condition of adult patients, we investigated whether treatment with a humanin analog, humanin-G, mitigates lung injury and whether its mechanisms of action are dependent on the catalytic AMPKα1 subunit activation. Methods: Male and female AMPKα1 wild-type (WT) and knock-out (KO) mice (8–13 months old) were subjected to hemorrhagic shock by blood withdrawal, followed by resuscitation with shed blood and lactated Ringer’s solution. The mice were treated with PEGylated humanin-G or vehicle and euthanized 3 h post-resuscitation. Results: Sex- and genotype-related differences were observed after hemorrhagic shock as lung neutrophil infiltration was more pronounced in the male AMPKα1 WT mice than the female WT mice; also, the male AMPKα1 KO mice experienced a significant decline in mean arterial blood pressure when compared to the male WT mice after resuscitation. The scores of histological lung injury were similarly elevated in all the male and female AMPKα1 WT and KO mice when compared to the control mice. At molecular analysis, acute lung injury was associated with the downregulation of AMPKα1/α2 catalytic subunits in the WT mice, whereas an increased activation of the signal transducer and activator of transcription-3 (STAT3) was observed in all the vehicle-treated groups. The in vivo administration of humanin-G ameliorated histological lung damage in all the groups of animals and ameliorated mean arterial blood pressure in the male AMPKα1 KO mice. The in vivo administration of humanin-G lowered lung neutrophil infiltration in the male and female AMPKα1 WT mice only but not in the KO mice. The beneficial results of humanin-G correlated with the lung cytosolic and nuclear activation of AMPKα in the male and female AMPKα1 WT groups, whereas STAT3 activation was not modified. Conclusions: In adult age, hemorrhage-induced acute lung injury manifests with sex-dependent characteristics. Humanin-G has therapeutic potential and the AMPKα1subunit is an important requisite for its inhibitory effects on lung leucosequestration, but not for the amelioration of lung alveolar structure or the hemodynamic effects of the peptide.

Gallein, G protein βγ subunits inhibitor, suppresses the TGF-α-induced migration of hepatocellular carcinoma cells via inhibition of the c-Jun N-terminal kinase.

G protein-coupled receptor (GPCR) signaling regulates a wide range of pathophysiological cell functions via G protein α and βγ subunits. Small molecules targeting the subunits of Gα and Gβγ have been developed as cancer therapeutics. We have previously reported that transforming growth factor-α (TGF-α) induces the migration of human hepatocellular carcinoma (HCC) HuH7 cells through the activation of AKT, p38 mitogen-activated protein kinase (MAPK), Rho-kinase and c-Jun N-terminal kinase (JNK). This study aims to determine whether Gβγ subunits regulate the TGF-α-induced migration of HCC HuH7 cells using gallein, a Gβγ subunits inhibitor. The Janus family of tyrosine kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway was also involved in the regulation of the migration. Gallein significantly reduced the TGF-α-induced cell migration. In contrast, fluorescein, a gallein-related compound that has no effect on Gβγ subunits, failed to affect the cell migration. Gallein suppressed the TGF-α-stimulated phosphorylation of JNK without affecting the phosphorylation of epidermal growth factor receptor, AKT, p38 MAPK, target protein of Rho-kinase and STAT3. Conversely, fluorescein did not attenuate the phosphorylation of JNK. These results strongly suggest that Gβγ subunits act as positive regulators in TGF-α-induced migration of HCC cells via the JNK signalling pathway.

TMET-03. ONCOGENIC STAT3 PROMOTES TUMOR GROWTH VIA STIMULATION THE SCAP- AND SREBP-1-REGULATED LIPOGENIC PATHWAY

Abstract Augmented lipogenesis is a hallmark of cancer. In addition, signal transducer and activator of transcription 3 (STAT3) is aberrantly activated and associated with poor prognosis in multiple cancers. Whether oncogenic STAT3 has an intrinsic and causal link to lipogenesis in cancer remains unclear. Here, we show that inhibition of STAT3 significantly alters the lipid profile of tumor cells, including free fatty acids and derived membrane structural phospholipids (phosphatidic acid, phosphatidylinositol, phosphatidylserine and sphingomyelin), this change results in cell death which could be rescued by lipids (oleic acid and palmitoleic acid) supplementation, while suppressing the gene and protein expression of major mediators of the lipogenic pathway including sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), SREBP-1, fatty acid synthase and stearoyl-CoA desaturase 1. Furthermore, we show that STAT3 binds the promoter of SCAP, SREBP-1a and SREBP-1c, to promote their transcription in tumor cells. Finally, targeting STAT3 in a xenograft mouse model blocked glioblastoma growth and lipogenic enzyme expression. Our study reveals a novel regulatory pathway of STAT3-SCAP/SREBP-1 involved in tumor growth in vitro and in vivo, connecting STAT3 signaling with SCAP- and SREBP-1-mediated lipogenesis.

EXTH-43. ANTI-GLIOMA ACTIVITY OF BIMODAL CGAS-AGONISTIC AND STAT3-INHIBITORY SPHERICAL NUCLEIC ACIDS

Abstract Activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of Interferon Genes) pathway enhances T cell activation and infiltration into tumors, reversing the immunosuppressive phenotype of myeloid cells. Targeting the STING receptor with synthetic cyclic dinucleotide (CDN) ligands offers a promising immunotherapeutic strategy for lymphocyte-depleted, myeloid cell-enriched tumors like Glioblastoma (GBM). However, this approach is constrained by the structural instability of CDNs and the presence of immune-evasive, STING-inhibitory mechanisms in the tumor microenvironment (TME), particularly those driven by the master transcriptional regulator STAT3 (Signal Transducer and Activator of Transcription 3). To activate cGAS anti-tumor responses and simultaneously inhibit STAT3-driven immunosuppression in the GBM TME, we developed Spherical Nucleic Acids (SNAs) consisting of a nanoparticle core densely functionalized with radially oriented stem-loop dsDNA oligonucleotides containing a guanine repeat element flanked by palindromic STAT3 decoy sequences. In vitro studies demonstrated that these SNAs effectively activate cGAS and inhibit STAT3 in reporter cell lines, exhibit high-affinity binding to both the cGAS enzyme and STAT3 proteins, and downregulate IL-6-induced STAT3 transcriptional targets. Furthermore, intratumoral injection of these bimodal SNA architectures induced type I interferon (IFN) and proinflammatory cytokines, activated T cells and B cells, and natural killer cells; and reprogrammed immunosuppressive tumor-associated macrophages (TAMs). Importantly, bimodal SNAs showed profound sex-based differential pharmacological action with therapeutic benefits seen in females but not in male mice in aggressive immune checkpoint-resistant murine glioma models. In the absence of cGAS transcriptional changes, western blot and flow cytometry analysis revealed that cGAS protein levels were approximately twice as high in female BMDMs (bone marrow-derived macrophages) and TAMs than males. In summary, our study establishes bimodal SNAs as a first-in-class, single-entity nucleic acid therapeutic capable of targeting multiple pathways for the immunological reprogramming of the GBM TME.

PSTAT3 Expression is Increased in Advanced Prostate Cancer in Post-Initiation of Androgen Deprivation Therapy.

The transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) plays a role in carcinogenesis and is involved in processes, such as proliferation, differentiation, drug resistance and immunosuppression. STAT3 can be activated by phosphorylation of tyrosine at position 705 (pSTAT3Tyr705) or serine at 727 (pSTAT3Ser727). High expression levels of pSTAT3 are implicated in advanced stages of prostate cancer (PCa) and are known to interact with the androgen receptor signaling pathway. However, not much is known about how androgen deprivation therapy (ADT) in advanced disease affects pSTAT3 expression. The aim of this study was to determine the influence of ADT on pSTAT3 expression in PCa tissue. The study cohort came from a PCa tissue microarray resource containing prostate specimens from patients before and post-initiation of ADT. Tissue samples from 111 patients were immunostained for pSTAT3Tyr705 and pSTAT3Ser727. H-score was used to evaluate the intensity and the percentage of pSTAT3 expression in malignant epithelial and stromal compartments. Univariate and multivariable Cox regression analyses were used to assess pSTAT3Tyr705 and pSTAT3Ser727 as biomarkers of oncological outcome in patients undergoing ADT. Post-ADT PCa samples demonstrated increased nuclear and cytoplasmic levels of pSTAT3Ser727 in the stroma compared to pre-ADT samples, whereas pSTAT3Tyr705 expression was increased significantly in both stromal and malignant epithelial compartments except for stromal cytoplasm. High cytoplasmic pSTAT3Ser727 in stromal compartments correlated with reduced overall survival, shorter time to castration-resistant PCa development, and decreased metastasis-free survival. An increase in nuclear and cytoplasmic pSTAT3Ser727 expression within the stromal compartment of post-ADT samples corresponded to a shorter time to CRPC development, which was not observed for pSTAT3Tyr705. Multivariable survival analysis using Cox's regression identified that high cytoplasmic pSTAT3Ser727 expression in the stroma of post-ADT samples and pT3 or pT4-stage were associated with worse overall survival and 5-year metastasis-free survival (MFS). This study presents novel insights into the impact of ADT on the expression levels of pSTAT3Tyr705 and pSTAT3Ser727 in PCa. Cytoplasmic pSTAT3Ser727 status of cancer-associated stromal cells in post-ADT samples may serve as an independent prognostic marker for OS and 5-year MFS, identifying prostate cancer patients prone to developing resistance to ADT.

Matrine regulates autophagy in ileal epithelial cells in a porcine circovirus type 2-infected murine model

IntroductionPorcine circovirus type 2 (PCV2) is an important pathogen that causes diarrhea in nursery and fattening pigs, resulting in huge economic losses for commercial pig farms. Protective efficacy of vaccines is compromised by mutations in pathogens. There is an urgent need to articulate the mechanism by which PCV2 destroys the host’s intestinal mucosal barrier and to find effective therapeutic drugs. Increasing attention has been paid to the natural antiviral compounds extracted from traditional Chinese medicines. In the present study, we investigated the role of Matrine in mitigating PCV2-induced intestinal damage and enhancing autophagy as a potential therapeutic strategy in mice.MethodsA total of 40 female, specific-pathogen-free-grade Kunming mice were randomly divided into four groups with 10 mice in each group: control, PCV2 infection, Matrine treatment (40 mg/kg Matrine), and Ribavirin treatment (40 mg/kg Ribavirin). Except for the control group, all mice were injected intraperitoneally with 0.5 mL 105.4 50% tissue culture infectious dose (TCID50)/mL PCV2.ResultsWhile attenuating PCV2-induced downregulation of ZO-1 and occludin and restoring intestinal barrier function in a PCV2 Kunming mouse model, treatment with Matrine (40 mg/kg) attenuated ultrastructural damage and improved intestinal morphology. Mechanistically, Matrine reversed PCV2-induced autophagosome accumulation by inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation and upregulating Beclin1 protein expression, thus resisting viral hijacking of enterocyte autophagy.DiscussionOur findings demonstrate that Matrine may be a novel, potential antiviral agent against PCV2 by activating intestine cellular autophagy, which provides a new strategy for host-directed drug discovery.

HUCMSCs Regulate Bile Acid Metabolism to Prevent Heart Failure–Induced Intestinal Injury by Inhibiting the Activation of the STAT3/NF‐κB/MAPK Signaling Pathway via TGR5

ABSTRACTThe protective effects of human umbilical cord mesenchymal stem cells (hUCMSCs) on heart failure (HF)‐induced intestinal injury have not been fully understood. Flow cytometry and immunofluorescence analysis revealed that hUCMSCs renewed themselves, grew, and transformed into various cell types. Meanwhile, hUCMSCs safeguarded against intestinal damage, regulated imbalances in the intestinal flora and bile acid metabolism, and enhanced the levels of hyodeoxycholic acid (HDCA) in pigs with HF. HDCA protected against HF‐induced intestinal injury in mice through Takeda G protein–coupled receptor 5 (TGR5). Protein analysis showed that HDCA exerted protective effects on the intestines via the signal transducer and activator of transcription 3 (STAT3)/nuclear factor kappa B (NF‐κB)/mitogen‐activated protein kinase (MAPK) signaling pathway. Mouse experiments revealed that HDCA bound to TGR5 to inhibit MAPK and NF‐κB signaling pathway activation, which relies on the STAT3 signaling pathway. Moreover, hUCMSCs protected against intestinal injury in the pig model of HF by suppressing the activation of the STAT3/NF‐κB/MAPK signaling pathway via TGR5.

Empagliflozin Attenuates Neointima Formation After Arterial Injury and Inhibits Smooth Muscle Cell Proliferation and Migration by Suppressing Platelet-Derived Growth Factor-Related Signaling.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events. However, the precise mechanisms beyond glycemic control are not fully understood. The objective of this study was to determine the role of PDGF (platelet-derived growth factor)-related signaling in empagliflozin-mediated inhibition of neointima formation. Adult male nondiabetic Wistar rats were subjected to carotid artery balloon injury. Empagliflozin (30 mg/kg per day) was administered by oral gavage for 18 days beginning 4 days before surgery. The invitro effects of empagliflozin on rat aortic vascular smooth muscle cell (VSMC) proliferation and migration were also determined. Empagliflozin attenuated balloon injury-induced neointima formation in carotid arteries. In VSMCs, empagliflozin attenuated PDGF-BB-induced proliferation and migration. Moreover, empagliflozin-treated VSMCs did not undergo apoptosis or cytotoxic death. Empagliflozin suppressed PDGF-related signaling, including phosphorylation of PDGF receptor β, Akt, and STAT3 (signal transducer and activator of transcription 3). Overactivation of PDGF signaling attenuated empagliflozin-mediated inhibition of VSMC function. SGLT2 mRNA levels in rat VSMCs were undetectable, and SGLT2 silencing did not alter the empagliflozin-mediated effects, supporting the SGLT2-independent effects of empagliflozin on VSMC. This study highlights the crucial role of suppressing PDGF-related signaling in mediating the beneficial effects of empagliflozin on neointima formation and VSMC function, which are independent of SGLT2 and glycemic control. Our study provides a novel mechanistic aspect of empagliflozin for the prevention of vascular stenosis disorders.

Curcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function

Lytic induction therapy was devised to selectively combat malignancies associated with Epstein–Barr virus (EBV) by triggering viral reactivation from latency. At present, the major challenges of lytic induction therapy are to maximize reactivating efficiencies and meanwhile minimize infectious virion production. C210, a novel curcumin derivative with potent Hsp90 inhibitory activity, was explored for EBV-reactivating and virion-producing effects in EBV-positive nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) cell lines. And the molecular mechanisms underlying these effects were determined. Follow C210 treatment, EBV lytic RNAs and proteins were upregulated, but infectious virions were not produced. Knockdown of heat shock protein 90 (Hsp90) induced expression of lytic RNAs and proteins, and diminished C210-driven EBV lytic induction. Pretreatment with an X box binding protein 1 (XBP1) inhibitor reduced C210-induced EBV lytic RNA. Furthermore, we demonstrated that C210 inhibited the binding of Hsp90 with its clients, signal transducer and activator of transcription 3 (STAT3) and xeroderma pigmentosum group B-complementing protein (XPB), which subsequently promoted their proteasomal degradation. Degradation of STAT3 by C210 enhanced the EBV-reactivating and anticancer capacity of suberoylanilide hydroxamic acid (SAHA). Depletion of XPB blocked SAHA-induced expression of late viral genes and production of infectious virions. These results elucidate a novel Hsp90 inhibitor targeting EBV lytic phase and extend the research on lytic induction strategy, which may offer reference value in the treatment of EBV-positive malignancies.

Sevoflurane Postconditioning Mitigates Neuronal Hypoxic-Ischemic Injury via Regulating Reactive Astrocytic STAT3 Protein Modification

Astrocyte activation plays a pivotal role in accelerating the cascade of neuroinflammation associated with the development of hypoxic-ischemic brain injury. This study aimed to investigate the mechanism by which sevoflurane postconditioning mitigates neuronal damage through astrocytes by regulating reactive astrocytic Signal Transducer and Activator of Transcription 3 (STAT3) modifications. A modified Rice‒Vannucci model in rats and a conditioned culture system established by subjecting primary astrocytes to oxygen glucose deprivation, followed by using the conditioned medium to culture the neuron cell line SH-SY5Y were used to simulate HI insult in vivo and in vitro, respectively. These models were followed by 30 minutes of 2.5% sevoflurane treatment. Stattic was used to inhibit STAT3 phosphorylation, and (Z)-PUGNAc or OSMI-1 was added to regulate O-linked-β-N-acetylglucosamine modification (O-GlcNAcylation) in primary astrocytes in vitro. Neurobehavioral tests, Nissl staining, CCK8 assay, and flow cytometry for apoptosis were used to assess neuronal function. Immunofluorescence staining was used to detect astrocyte reactivity and the intracellular distribution of STAT3. Immunoprecipitation combined with Western blotting was used to evaluate the O-GlcNAcylation of STAT3. Protein expression and phosphorylation levels were detected by Western blotting. ELISA was conducted to detect the detrimental cytokines IL-6 and IL-1β in astrocyte-conditioned medium. Sevoflurane postconditioning enhanced the O-GlcNAcylation of astrocytic STAT3 following HI insult via the manner of OGT. Crosstalk between O-GlcNAcylation and phosphorylation of STAT3 showed that O-GlcNAcylation inhibited STAT3 phosphorylation. The inhibitory effect on astrocytes suppressed STAT3 nuclear translocation, reduced astrocyte reactivity, decreased the release of the inflammatory cytokines IL6 and IL-1β, attenuated neuronal apoptosis following HI insult, and improved neuron viability. Sevoflurane postconditioning increased astrocytic STAT3 O-GlcNAcylation level to competitively inhibit STAT3 phosphorylation. This deactivated downstream inflammation pathways and reduced astrocyte reactivity, thereby mitigating HI insult in neurons both in vivo and in vitro.

Gypenosides alleviates HaCaT keratinocyte hyperproliferation and ameliorates imiquimod-induced psoriasis in mice.

Psoriasis is an autoimmune skin condition characterized by hyperproliferation of keratinocytes and chronic immune responses. Gypenosides (Gyp) exhibits anti-proliferative and anti-inflammatory effects on different diseases. However, its functioning and mechanism of Gyp on psoriasis remains unknown. To explore the effect and mechanism of Gyp on psoriasis. The impact and mechanism of Gyp on psoriasis in vitro and in vivo were probed through cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, reverse transcription quantitative polymerase chain reaction, hematoxylin and eosin staining, enzyme-linked immunosorbent serologic assay, immunofluorescence, and Western Blotting assays. Gyp inhibited cell proliferation and the release of inflammatory cytokinesin interleukin (IL-22)-induced spontaneously transformed human aneuploid immortal keratinocyte cell line (HaCaT). In addition, Gyp demonstrated enhancement in erythema and scaling as well as reductions in the thickness of epidermal layers, release of inflammatory factors, and Ki-67 (a nuclear protein) level in imiquimod (IMQ)-induced mice. Mechanistically, Gyp upregulated nuclear factor erythroid 2-related factor 2 (Nrf-2) expression and diminished the level of p-p65/p65 and p-STAT3/STAT3 in skin tissues from IMQ-induced mice and IL-22-induced HaCaT cells, which were reversed with the application of ML385, an inhibitor of Nrf2. In addition, the administration of ML385 reversed decrease in cell viability and reduced the expressions of IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) in IL-22-induced HaCaT cells caused by Gyp. In summary, Gyp reduced excessive cell growth and inflammation in psoriasis by suppressing nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) through activation of Nrf2.

Euphorbia helioscopia L. inhibits lung tumorigenesis through alleviating exhausted T cell induced by chronic inflammation

Ethnopharmacological RelevanceEuphorbia helioscopia L. (ZQ) is a very effective traditional Chinese medicine for treating pneumonia and lung cancer. However, the effects and mechanisms by which ZQ prevents lung tumorigenesis in the presence of chronic inflammation remain unexplored. AimTo examine the effects and mechanisms of ZQ in alleviating chronic inflammation-induced T cell exhaustion and inhibiting lung tumorigenesis. MethodsA mice model of lung tumorigenesis under chronic inflammation conditions was established by repeated administration of lipopolysaccharide (LPS) and exposure to the tobacco carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Mice were treated with ZQ ( 0.9, 1.8, and 3.6 g/kg/day) for 25 weeks. Lung pathology and tumor incidence were assessed, and inflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) and serum were measured. Additionally, the proportions of CD3+ T, CD4+ T, and CD8+ T cells and their inhibitory receptors expression were evaluated. In vitro, T cell exhaustion models were induced using inflammatory-conditioned media, followed by treatment with ZQ (0.5, 2, 8 μg/mL). T cell exhaustion markers and characteristics were analyzed, and molecular mechanisms were explored using RNA sequencing and Immunoblotting analysis. ResultsIn vivo, ZQ significantly reduced inflammatory infiltration and lung damage, tumor incidence, number, size, and lung and spleen indices in mice. It also markedly lowered the levels of pro-inflammatory cytokines and immunosuppressive cytokines in BALF and serum. Additionally, ZQ improved the proportions of CD3+ T, CD4+ T, and CD8+ T cells and significantly decreased the expression of inhibitory receptors on CD4+ T and CD8+ T cells in the lung tissues and spleen. In vitro, ZQ effectively alleviated T cell exhaustion induced by the inflammatory environment, marked by reduced expression of inhibitory receptors, increased cytokine secretion, improved proliferation, and enhanced tumoricidal activity. RNA sequencing revealed that ZQ significantly downregulated the JAK-STAT signaling and upregulated stemness-associated pathways. Immunoblotting results indicated that treatment with ZQ markedly reduced the phosphorylation of Signal transducer and activator of transcription 3 (STAT3) and increased the expression of T cell factor -1/7 (TCF1/7). ConclusionZQ inhibits lung tumorigenesis in LPS/NNK-treated mice through alleviating exhausted T cells induced by chronic inflammation, which is attributed to the suppression of STAT3 activation and the maintenance of stemness characteristics in T cells. These findings provide experimental evidence for the potential use of ZQ in preventing and treating lung tumourigenesis in patients with chronic inflammation and the clinical management of lung cancer patients with concomitant chronic inflammation.

Avelumab reduces STAT3 expression with effects on IL-17RA and CD15.

Avelumab is a human antibody that targets the programmed cell death ligand-1 (PD-L1) protein in cancer cells. Novel anticancer therapies for renal cell carcinoma (RCC) consider cluster of differentiation 15 (CD15) and interleukin 17 receptor A (IL-17RA) as potential targets. Notably, the expression of PD-L1, CD15 and IL-17RA is dependent on signal transducer and activator of transcription 3 (STAT3). The aim of the study was to investigate whether targeting PD-L1 with avelumab alters the expression levels of CD15 and IL-17RA, and to assess the STAT3-mediated regulation of CD15 and IL-17RA. We applied immunocytochemistry (ICC) and confocal laser scanning (CLS) microscopy to assess the expression and localization of the immunotherapy targets in 3 renal cancer cell lines and 1 healthy renal cell line. After treatment with 20 ng/mL avelumab, renal cancer cells showed a reduction in STAT3 expression. The expression of CD15 increased in cancer cells that exhibited a high level of IL-17RA, and the membrane signal of CD15 was reduced. In other renal cancer cell lines, the expression of CD15 decreased. Conversely, the level of IL-17RA changed only in healthy renal cells after treatment with avelumab, with no impact on renal cancer cells. Our study suggests that the targeting of PD-L1 with avelumab alters the expression of CD15 and IL-17RA, which play an important prognostic and therapeutic role in novel anticancer therapy.

ACY1215 Exerts Anti-inflammatory Effects by Inhibition of NF-κB and STAT3 Signaling Pathway to Repair Spinal Cord Injury.

Spinal cord injury (SCI), a public health problem caused by mechanical injury, leads to secondary excessive inflammatory reactions and long-term damage to neurological function. ACY1215 is a highly selective histone deacetylase 6 (HDAC6) inhibitor and reportedly has anti-inflammatory effects; however, its regulatory role in SCI has not been studied. The purpose of this study was to explore the role of ACY1215 in preventing inflammation, inhibiting astrogliosis, enhancing remyelination and preserving axons after spinal cord injury and further exploring the possible cellular signaling pathways involved. First, lipopolysaccharide (LPS) was utilized to stimulate rat astrocytes in vitro. Quantitative RT (qRT)-PCR and Western blotting showed that ACY1215 inhibited the expression of glial fibrillary acidic protein (GFAP), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα) in LPS-activated astrocytes. In addition, Western blotting results showed that ACY1215 could inhibit the signal transduction pathway of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3). In vivo, ACY1215 could exert anti-inflammatory effects by inhibiting the expression of inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Moreover, ACY1215 repaired spinal cord injury by reducing the formation of glial scars and promoting remyelination and nerve recovery. In summary, ACY1215 can inhibit the NF-κB and STAT3 signaling pathways in astrocytes, reduce inflammation and ameliorate SCI. Our results provide a novel strategy for the treatment of SCI.

HOXB8 mediates resistance to cetuximab in colorectal cancer cells through activation of the STAT3 pathway

Homeobox B8 (HOXB8) belongs to the HOX family and was essential to the development of colorectal carcinoma. Among the prevalent monoclonal antibodies for treating RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients, cetuximab stands out, but resistance to cetuximab frequently arises in targeted treatments. Currently, the role of HOXB8 in cetuximab-resistant mCRC remains unclear. By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.

Magnesium Lithospermate B Inhibits Colorectal Cancer Cell Progression Through JAK2-STAT3 Signaling.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide. The discovery of new effective therapeutic drugs is always a priority. Magnesium lithospermate B (MLB), a native polyphenol acid, is the major component of the aqueous extracts from Danshen, a traditional Chinese medicine derived from the dry root and rhizome of Salvia miltiorrhiza. MLB has been reported to have antioxidant, anti-inflammatory, and ion channel-regulating activities in several diseases, including cardiovascular, renal, and neuronal diseases. However, the effect of MLB on cancer progression has not been reported. In this study, a series of cellular and molecular experiments were conducted on two CRC cell lines (HCT116 and SW480) to investigate the effects of. The results demonstrated that MLB exerted inhibitory effects on cell proliferation, migration, and invasion. The administration of 50 mg/kg MLB inhibited tumor growth in HCT116 cells in xenografted models. Importantly, we found that MLB treatment inhibited the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway, and activation of JAK2-STAT3 signaling with interleukin 6 or overexpression STAT3 significantly suppressed the inhibitory effect of MLB. These findings provide evidence that MLB could inhibit CRC cell progression in vitro and might serve as a potential therapeutic drug for the treatment of CRC.

Probing the Depths of Molecular Complexity: STAT3 as a Key Architect in Colorectal Cancer Pathogenesis.

Colorectal cancer (CRC) has become a significant threat in recent decades, and its incidence is predicted to continue rising. Despite notable advancements in therapeutic strategies, managing CRC poses complex challenges, primarily due to the lack of clinically feasible therapeutic targets. Among the myriad molecules implicated in CRC, the signal transducer and activator of transcription 3 (STAT3) stands out as a promising target tightly regulated by various genes. This intracellular transcription factor, spanning 750-795 amino acids and weighing approximately 92 kDa, is crucial in key cellular activities such as growth, migration, invasion, inflammation, and angiogenesis. Aberrant activation of STAT3 signaling has been linked to various cancers, including CRC. Therefore, targeting this signaling pathway holds significance for potential CRC treatment strategies.STAT3, as a central intracellular transcription factor, is implicated in colorectal cancer development by activating aberrant signaling pathways. Numerous studies have demonstrated that the abnormal hyperactivation of STAT3 in CRC tissues enhances cell proliferation, suppresses apoptosis, promotes angiogenesis, and facilitates tumor invasion and metastasis. As a focal point in colorectal cancer research, STAT3 emerges as a promising candidate for detecting and treating CRC. This review aims to present recent data on STAT3, emphasizing the activation and functions of STAT3 inhibitors in CRC. Indeed, STAT3 inhibitors have been identified to have therapeutic potential in CRC, especially inhibitors targeting the DNA-binding domain (DBD). Indeed, STAT3 inhibitors have been identified to have a therapeutic potential in CRC, especially the inhibitors targeting the DNA binding domain (DBD). For example, imatinib acts by targeting cell surface receptors, and these inhibitors have shown potential for the control and treatment of tumor growth, angiogenesis, and metastasis. Imatinib, for example acts by targeting cell surface receptors, and these inhibitors have shown the future direction toward the control and treatment of tumor growth, angiogenesis, and metastasis.

Deciphering STAT3’s negative regulation of LHPP in ESCC progression through single-cell transcriptomics analysis

BackgroundEsophageal Squamous Cell Carcinoma (ESCC) remains a predominant health concern in the world, characterized by high prevalence and mortality rates. Advances in single-cell transcriptomics have revolutionized cancer research by enabling a precise dissection of cellular and molecular diversity within tumors.ObjectiveThis study aims to elucidate the cellular dynamics and molecular mechanisms in ESCC, focusing on the transcriptional influence of STAT3 (Signal Transducer and Activator of Transcription 3) and its interaction with LHPP, thereby uncovering potential therapeutic targets.MethodsSingle-cell RNA sequencing was employed to analyze 44,206 cells from tumor and adjacent normal tissues of ESCC patients, identifying distinct cell types and their transcriptional shifts. We conducted differential gene expression analysis to assess changes within the tumor microenvironment (TME). Validation of key regulatory interactions was performed using qPCR in a cohort of 21 ESCC patients and further substantiated through experimental assays in ESCC cell lines.ResultsThe study revealed critical alterations in cell composition and gene expression across identified cell populations, with a notable shift towards pro-tumorigenic states. A significant regulatory influence of STAT3 on LHPP was discovered, establishing a novel aspect of ESCC pathogenesis. Elevated levels of STAT3 and suppressed LHPP expression were validated in clinical samples. Functional assays confirmed that STAT3 directly represses LHPP at the promoter level, and disruption of this interaction by promoter mutations diminished STAT3's repressive effect.ConclusionThis investigation underscores the central role of STAT3 as a regulator in ESCC, directly impacting LHPP expression and suggesting a regulatory loop crucial for tumor behavior. The insights gained from our comprehensive cellular and molecular analysis offer a deeper understanding of the dynamics within the ESCC microenvironment. These findings pave the way for targeted therapeutic interventions focusing on the STAT3-LHPP axis, providing a strategic approach to improve ESCC management and prognosis.

Allicin Ameliorated High-glucose Peritoneal Dialysis Solution-induced Peritoneal Fibrosis in Rats via the JAK2/STAT3 Signaling Pathway.

Peritoneal fibrosis (PF) is one of the most serious complications of peritoneal dialysis (PD) and is the greatest obstacle to the clinical application of PD. Chinese herbal monomers have been effective in the prevention and treatment of PF. The aim of this study was to observe the effect of allicin on PF in rats induced by high glucose and to investigate its molecular mechanism of action. A rat model of PF was established by using a 4.25% glucose-based standard peritoneal dialysis solution. The degree of peritoneal pathological damage was assessed by Hematoxylin and eosin (H&E) staining. Peritoneal collagen deposition was detected by Masson's trichrome staining. The levels of Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1) in the serum were measured by Enzyme Linked Immunosorbent Assay (ELISA). The expression levels of TGF-β, α-smooth muscle actin (α-SMA) and collagen I were examined by western blotting and immunohistochemistry. The protein expression levels and mRNA levels of E-cadherin, N-cadherin, vimentin, janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) in peritoneal tissue were determined by western blotting and qRT-PCR. TGF-β1 stimulated human peritoneal mesothelial cells (HPMCs), and the cells were treated with allicin and the JAK2/STAT3 pathway activator colivelin alone or in combination. A cell counting kit-8 (CCK-8) assay was used to measure cell viability. The role of JAK2/STAT3 in the effects of allicin was confirmed via in vitro mechanistic research by western blotting, wound healing assays and Transwell assays. Allicin relieves the inflammatory response by downregulating the levels of IL-1β, IL-6, MCP-1 and TNF-α. Furthermore, allicin decreased the expression of TGF-β, α-SMA and collagen I. Allicin also alleviated epithelial-to-mesenchymal transition (EMT), as specifically manifested by increased E-cadherin and reduced N-cadherin and vimentin. Further studies revealed that allicin reduced the protein levels of JAK2, STAT3, p-JAK2, and p-STAT3. The results of the cellular experiments verified the above results. The ability of allicin to inhibit fibrosis and the EMT process was significantly attenuated after HPMCs were treated with colivelin. Taken together, these findings suggest that allicin inhibits inflammation and EMT, thereby improving PF, and this protective effect may be achieved by inhibiting the JAK2/STAT3 signaling pathway.

Neuronal cathepsin S increases neuroinflammation and causes cognitive decline via CX3CL1-CX3CR1 axis and JAK2-STAT3 pathway in aging and Alzheimer's disease.

Aging is an intricate process involving interactions among multiple factors, which is one of the main risks for chronic diseases, including Alzheimer's disease (AD). As a member of cysteine protease, cathepsin S (CTSS) has been implicated in inflammation across various diseases. Here, we investigated the role of neuronal CTSS in aging and AD started by examining CTSS expression in hippocampus neurons of aging mice and identified a significant increase, which was negatively correlated with recognition abilities. Concurrently, we observed an elevation of CTSS concentration in the serum of elderly people. Transcriptome and fluorescence-activated cell sorting (FACS) results revealed that CTSS overexpression in neurons aggravated brain inflammatory milieu with microglia activation to M1 pro-inflammatory phenotype, activation of chemokine C-X3-C-motif ligand 1 (CX3CL1)-chemokine C-X3-C-motif receptor 1 (CX3CR1) axis and janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway. As CX3CL1 is secreted by neurons and acts on the CX3CR1 in microglia, our results revealed for the first time the role of neuron CTSS in neuron-microglia "crosstalk." Besides, we observed elevated CTSS expression in multiple brain regions of AD patients, including the hippocampus. Utilizing CTSS selective inhibitor, LY3000328, rescued AD-related pathological features in APP/PS1 mice. We further noticed that neuronal CTSS overexpression increased cathepsin B (CTSB) activity, but decreased cathepsin L (CTSL) activity in microglia. Overall, we provide evidence that CTSS can be used as an aging biomarker and plays regulatory roles through modulating neuroinflammation and recognition in aging and AD process.