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Lymphoma is the sixth most prevalent cancer globally. Non‐Hodgkin's lymphomas are the majority group of lymphomas, with B cells accounting for approximately 95% of these lymphomas. A key feature of B‐cell lymphoma is the functional perturbations of essential biological pathways caused by genetic aberrations. These lead to atypical gene expression, providing cells with a selective growth advantage. Molecular analysis reveals that each lymphoma subtype has unique molecular mutations, which pose challenges in disease management and treatment. Substantial efforts over the last decade have led to the integration of this information into clinical applications, resulting in crucial insights into clinical diagnosis and targeted therapies. However, with the growing need for more effective medication development, we anticipate a deeper understanding of signaling pathways and their interactions to emerge. This review aims to demonstrate how the BCR, specific signaling pathways like PI3K/AKT/mTOR, NF‐kB, and JAK/STAT are diverse in common types of B‐cell lymphoma. Furthermore, it offers a detailed examination of each pathway and a synopsis of the approved or in‐development targeted therapies. In conclusion, finding the activated signaling pathways is crucial for developing effective treatment plans to improve the prognosis of patients with relapsed or refractory lymphoma. Trial Registration: ClinicalTrials.gov identifier: NCT02180724, NCT02029443, NCT02477696, NCT03836261, NCT02343120, NCT04440059, NCT01882803, NCT01258998, NCT01742988, NCT02055820, NCT02285062, NCT01855750, NCT03422679, NCT01897571 [ABSTRACT FROM AUTHOR]

AbstractNeuropathic pain is the crucial dose-limiting side effect of paclitaxel in chemotherapy patients that negatively impacts the quality of life and survival. Currently, no effective treatment option is available. Aprepitant, a well-established chemotherapy antiemetic performing neurokinin-1 receptor antagonism, shows analgesic effects in some pain models. We studied aprepitant analgesic effects on the paclitaxel-induced neuropathic pain model in rats besides inflammatory markers assessment. Rats intraperitoneally received paclitaxel, reaching the cumulative paclitaxel dose of 8 mg/kg. Aprepitant was orally administered every alternate day between days 2 and 14, with a prescribed dosage of 10 or 20 mg/kg. The evaluation of mechanical allodynia and cold hyperalgesia involved the measurement of paw withdrawal threshold and acetone test score on days 0, 7, and 14. On day 14, paw licking latency was measured using a hot plate test before scarification and tissue collection for interleukin 1β, tumor necrosis factor α, and nuclear factor kappa B (NF-kB) evaluation. Paclitaxel induced neuropathy as indicated by a lowered hind paw withdrawal threshold in the Von Frey test, a higher score in the acetone test, and shortened hot plate latency. Aprepitant effectively alleviated cold and thermal hyperalgesia as well as mechanical allodynia. Moreover, aprepitant administration significantly reversed paclitaxel-mediated elevation of proinflammatory cytokines levels in dorsal root ganglia. In addition, aprepitant application suppressed the protein expression of NF-kB in the dorsal root ganglia of paclitaxel-treated rats, as revealed by western blot analysis. Aprepitant treatment ameliorates neuropathy induced by paclitaxel, which is associated with decreasing proinflammatory cytokines and NF-kB expression. [ABSTRACT FROM AUTHOR]

Ferroptosis is an iron-dependent form of cell death, which finally culminates in lipid peroxidation and membrane damage. During the past decade, the interest in ferroptosis increased substantially and various regulatory components were discovered. The role of ferroptosis during inflammation and its impact on different immune cell populations is still under debate. Activation of inflammatory pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and hypoxia inducible factors (HIFs) are known to alter the ability of cells to undergo ferroptosis and are closely connected to iron metabolism. During inflammation, iron regulatory systems fundamentally change and cells such as macrophages and neutrophils adapt their metabolism towards iron sequestering phenotypes. In this review, we discuss how ferroptosis alters inflammatory pathways and how iron metabolism under inflammatory conditions affects immune cell ferroptosis. [ABSTRACT FROM AUTHOR]

Summary: The iron chelator deferasirox (DFX) is effective in the treatment of iron overload. In certain patients with myelodysplastic syndrome, DFX can also provide a dramatic therapeutic benefit, improving red blood cell production and decreasing transfusion requirements. Nuclear Factor‐kappa B (NF‐kB) signalling has been implicated as a potential mechanism behind this phenomenon, with studies focusing on the effect of DFX on haematopoietic progenitors. Here, we examine the phenotypic and transcriptional effects of DFX throughout myeloid cell maturation in both murine and human model systems. The effect of DFX depends on the stage of differentiation, with effects on mitochondrial reactive oxygen species (ROS) production and NF‐kB pathway regulation that vary between progenitors and neutrophils. DFX triggers a greater increase in mitochondrial ROS production in neutrophils and this phenomenon is mitigated when cells are cultured in hypoxic conditions. Single‐cell transcriptomic profiling revealed that DFX decreases the expression of NF‐kB and MYC (c‐Myc) targets in progenitors and decreases the expression of PU.1 (SPI1) gene targets in neutrophils. Together, these data suggest a role of DFX in impairing terminal maturation of band neutrophils. [ABSTRACT FROM AUTHOR]

Rationale: Early-life maternal separation can lead to anxiety-like and depression-like behaviors in mice reared under maternal separation conditions. Scopoletin, a compound with anti-inflammatory and antidepressant properties, may offer therapeutic benefits, but its effectiveness against behaviors induced by maternal separation during adulthood remains unexplored. Objectives: This study investigates scopoletin's efficacy in alleviating anxiety-like and depression-like phenotypes in male mice subjected to early-life maternal separation. Methods: Male C57BL/6J mice experienced daily maternal separation for 4 h from postnatal day (PND) 2 to 21. From postnatal day 61(PND 61), scopoletin was administered intraperitoneally at 20 mg/kg/day for four weeks. Behavioral and biochemical assessments were conducted at postnatal day 95 (PND 95). Results: Maternally separated mice displayed marked anxiety-like and depression-like behaviors, evident in behavioral tests like the open field and elevated plus maze. These mice also showed increased immobility in the forced swimming and tail suspension tests. Biochemically, there were elevated levels of IL-1β, IL-6, and TNF-α in the hippocampus, with a decrease in Sirt1 and upregulation in NF-κB p65 expression. Scopoletin treatment significantly mitigated these behavioral abnormalities, normalizing both anxiety-like and depression-like behaviors. Correspondingly, it reduced the levels of pro-inflammatory cytokines and reinstated the expression of Sirt1 and NF-κB p65. Conclusions: Scopoletin effectively reverses the adverse behavioral and biochemical effects induced by early-life maternal separation in male mice, suggesting its potential as a therapeutic agent for treating anxiety-like and depression-like behaviors. Modulation of neuroinflammatory pathways and the Sirt1/NF-κB signaling axis is one possible mechanism. [ABSTRACT FROM AUTHOR]

The NF‐κB family consists of the key transcription factors of the NF‐κB signaling pathway, well known for its role in innate immune response, organogenesis, and a variety of cellular processes. The five NF‐κB subunits—RelA, RelB, c‐Rel, p50, and p52—are functional dimers, each of which share a conserved DNA binding domain which contains the dimerization domain (DD) as well. The NF‐κB subunits can form 15 potential dimers among themselves of which, RelA‐p50 is extensively studied and has largely become synonymous with NF‐κB for transcription activation. While various reports have highlighted the importance of NF‐κB subunit specificity in the transcription regulation of certain target genes, the dynamic nature of the NF‐κB dimer composition is not well understood. In this study, we biophysically characterized six combinatorial dimers from three NF‐κB subunits: RelA, p50, and p52, using NMR spectroscopy and differential scanning calorimetry. We show that the dimer composition is dynamic and can readily undergo exchange although at varied rates. Among the six dimers formed, RelA–p52 is found to be the most stable dimer with RelA–RelA being the least. Our results provide a plausible explanation as to why the RelA–p52 heterodimer is active during the later stages of the NF‐κB activation and serve as a link between the canonical and non‐canonical NF‐κB pathway. [ABSTRACT FROM AUTHOR]

Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths worldwide with limited treatment options due to extensive radiation and chemotherapy resistance. Monotherapy with immune checkpoint blockade showed no survival benefit. A combination of immunomodulation and radiotherapy may offer new treatment strategies, as demonstrated for non-small cell lung cancer. Radiation-induced anti-tumour immunity is mediated through cytosolic nucleic acid sensing pathways that drive the expression of interferon beta-1 (IFNB1) and proinflammatory cytokines. Methods: Human PDAC cell lines (PANC-1, MIA PaCa-2, BxPC-3) were treated with X-rays and protons. Immunogenic cell death was measured based on HMGB1 release. Cytosolic dsDNA and dsRNA were analysed by immunofluorescence microscopy. Cell cycle progression, MHC-I and PD-L1 expression were determined by flow cytometry. Galectin-1 and IFNB1 were measured by ELISA. The expression levels and the phosphorylation status of the cGAS/STING and RIGI/MAVS signalling pathways were analysed by western blotting, the expression of IFNB1 and proinflammatory cytokines was determined by RT-qPCR and genomewide by RNA-seq. CRISPR-Cas9 knock-outs and inhibitors were used to elucidate the relevance of STING, MAVS and NF-kB for radiation-induced IFNB1 activation. Results: We demonstrate that a clinically relevant X-ray hypofractionation regimen (3x8 Gy) induces immunogenic cell death and activates IFNB1 and proinflammatory cytokines. Fractionated radiation induces G2/M arrest and accumulation of cytosolic DNA in PDAC cells, which partly originates from mitochondria. RNA-seq analysis shows a global upregulation of type I interferon response and NF-kB signalling in PDAC cells following 3x8 Gy. Radiation-induced immunogenic response is regulated by STING, MAVS and NF-kB. In addition to immunostimulation, radiation also induces immunosuppressive galectin-1. No significant changes in MHC-I or PD-L1 expression were observed. Moreover, PDAC cell lines show similar radiationinduced immune effects when exposed to single-dose protons or photons. Conclusion: Our findings provide a rationale for combinatorial radiationimmunomodulatory treatment approaches in PDAC using conventional photon-based or proton beam radiotherapy. [ABSTRACT FROM AUTHOR]

Endometriosis is a significant reproductive health issue with pain being the primaru symptom. The complex pain in endometriosis involves the activation of macrophages, inflammatory activators such as NF-kB, neural growth factors (NGF), cytokines, adhesive molecules (ICAM-1), and mediators (PGE2) which they are stimulate sensory nerve fibers and produce nociceptive signals. This study is aim for investigate the effect of Mesenchymal Stem Cell (MSC) administration on the expression of NF-kB, NGF, and PGE2 concentration in a mouse model of endometriosis. Thirty-three mices were randomly divided into 3 groups consist non-endometriosis (P0), endometriosis without treatment (P1), and endometriosis with MSC administration (P2). The results showed MSC administration significantly reduced the expression of NF-kB by found scoring 2 groups (P1: 6.96 ± 0.13 and P2: 4.446 ± 0.228) and NGF (P1: 7.118 ± 0.629 and P2: 4.927 ± 1.187) also PGE2 (P1:1005.862 ± 176.656 and P2: 891.218 ± 54.031. In onclusion, this study demonstrates that MSC administration can able reduce the expression of NF-kB and NGF, but not to PGE2. The suggestion we can said is the MSC have potential therapeutic value in managing endometriosis-asssosciated pain by modulating inflammatory and neurotrophic factors. [ABSTRACT FROM AUTHOR]

Bufadienolides, specifically bufalin, have garnered attention for their potential therapeutic application in modulating inflammatory pathways. Bufalin is derived from toad venom and exhibits promising anti-inflammatory properties. Its anti-inflammatory effects have been demonstrated by influencing crucial signaling pathways like NF-B, MAPK, and JAK-STAT, resulting in the inhibition of pro-inflammatory substances like cytokines, chemokines, and adhesion molecules. Bufalin blocks inflammasome activation and reduces oxidative stress, hence increasing its anti-inflammatory properties. Bufalin has shown effectiveness in reducing inflammation-related diseases such as cancer, cardiovascular problems, and autoimmune ailments in preclinical investigations. Furthermore, producing new approaches of medication delivery and combining therapies with bufalin shows potential for improving its effectiveness and reducing adverse effects. This review explores the pharmacological effects and mechanistic approaches of bufalin as an anti-inflammatory agent, which further highlights its potential for therapy and offers the basis for further study on its therapeutic application in inflammation-related disorders. [ABSTRACT FROM AUTHOR]

Drug resistance used in chemotherapy is a common challenge in cancer treatment. The present review of resistance-modulating molecules in cancer recapitulates in vitro, in vivo, and in silico studies of flavonoids, lactones, taxanes, curcuminoids, catechins, and chalcones stand out among others. The main mechanisms of action involve inhibiting the overexpression and function of efflux proteins and altering signaling pathways related to resistance. For their part, the discussed in silico studies identified key interactions between modulating molecules and multidrug resistance (MDR) transporters. This information supports research on synthetic modifications to create new scaffolds for reversing MDR and minimizing toxicity. [ABSTRACT FROM AUTHOR]

Aging is a risk factor for various human disorders, including cancer. Current literature advocates that the primary principles of aging depend on the endogenous stress‐induced DNA damage caused by reactive oxygen species 50 Hz low‐frequency magnetic field was suggested to induce DNA damage and chromosomal instability. NF‐kB, activated by DNA damage, is upregulated in age‐related cancers and inhibition of NF‐kB results in aging‐related delayed pathologies. Metformin (Met), an NF‐kB inhibitor, significantly reduces both NF‐kB activation and expression in aging and cancer. This in vitro study, therefore, was set out to assess the effects of 5mT MF in 50 Hz frequency and Met treatment on the viability and proliferation of aged mouse NIH/3T3 fibroblasts and expression of RELA/p65, matrix metalloproteinases MMP2 and MMP9, and E‐cadherin (CDH1) genes. The trypan blue exclusion assay was used to determine cell viability and the BrdU incorporation assay to determine cell proliferation. The MMP‐2/9 protein analysis was carried out by immunocytochemistry, NF‐kB activity by ELISA and the expressions of targeted genes by qRT–PCR methods. Four doses of Met (500 uM, 1 mM, 2 mM and 10 mM) suppressed both the proliferation and viability of fibroblasts exposed to the MF in a dose‐dependent pattern, and the peak inhibition was recorded at the 10 mM dose. Met reduced the expression of NF‐kB, and MMP2/9, elevated CDH1 expression and suppressed NF‐kB activity. These findings suggest that Met treatment suppresses the carcinogenic potential of 50 Hz MFs in aged mouse fibroblasts, possibly through modulation of NF‐kB activation and epithelial‐mesenchymal transition modulation. [ABSTRACT FROM AUTHOR]

The defect in the hepatobiliary transport system results in an impairment of bile flow, leading to accumulation of toxic compounds with subsequent liver disorders. Vincamine, a plant indole alkaloid that is utilized as a dietary supplement, has been known for its promising pharmacological activities. For the first time, the present study was planned to estimate, at the molecular level, the potentiality of vincamine against alfa-naphthyl isothiocyanate (ANIT)-induced hepatic cholestasis. Liver function tests were analyzed. Hepatic activity of SOD and levels of GSH and MDA were assessed. Hepatic contents of bax, bcl2, NF-kB, PPARγ, catalase, heme-oxygenase-1, NTCP, and BSEP were evaluated using ELISA. mRNA levels of NF-kB, IL-1β, IL-6, TNFα, PDGF, klf6, PPARγ, and P53 were examined using qRT-PCR. PI3K, Akt and cleaved caspase-3 proteins were assessed using western blotting. Histopathological analyses were performed using hematoxylin & eosin staining. ANIT-induced hepatic cholestasis elevated liver function tests, including AST, ALT, GGT, ALP, and total bilirubin. ANIT reduced the protein expression of NTCP and BSEP hepatic transporters. It induced the expression of the inflammatory genes, TNFα, IL-6, IL-1β, and PDGF, and the expression of NF-kB at the genetic and protein level and suppressed the anti-inflammatory genes, klf6 and PPARγ. Also, antioxidant markers were reduced during ANIT induction such as GSH, SOD, catalase, heme-oxygenase-1 and PI3K/Akt pathway, while MDA levels were elevated. Furthermore, the expression of P53 gene, bax and cleaved caspase 3 proteins were activated, while bcl2 was inhibited. Also, the histopathological analysis showed degeneration of hepatocytes and inflammatory cellular infiltrates. However, vincamine treatment modulated all these markers. It improved liver function tests. It inhibited the expression of NF-kB, TNFα, IL-6, IL-1β and PDGF and activated the expression of klf6 and PPARγ. Furthermore, vincamine reduced MDA levels and induced GSH, SOD, catalase, heme-oxygenase-1 and PI3K/Akt pathway. Additionally, it inhibited expression of P53 gene, bax and cleaved caspase 3 proteins. More interestingly, vincamine showed better outcomes on the hepatic histopathological analysis and improved the alterations induced by ANIT. Vincamine alleviated hepatic dysfunction during ANIT-induced intrahepatic cholestasis through its anti-inflammatory and antioxidant efficacies by the modulation of NF-kB/PDGF/klf6/PPARγ and PI3K/Akt pathways. [ABSTRACT FROM AUTHOR]

Mice with cardiac-specific overexpression of adenylyl cyclase (AC) type 8 (TGAC8) are under a constant state of severe myocardial stress. They have a remarkable ability to adapt to this stress, but they eventually develop accelerated cardiac aging and experience reduced longevity. We have previously demonstrated through bioinformatics that constitutive adenylyl cyclase activation in TGAC8 mice is associated with the activation of inflammation-related signaling pathways. However, the immune response associated with chronic myocardial stress in the TGAC8 mouse remains unexplored. Here we demonstrate that chronic activation of adenylyl cyclase in cardiomyocytes of TGAC8 mice results in activation of cell-autonomous RelA-mediated NF-κB signaling. This is associated with non-cell-autonomous activation of proinflammatory and age-associated signaling in myocardial endothelial cells and myocardial smooth muscle cells, expansion of myocardial immune cells, increase in serum levels of inflammatory cytokines, and changes in the size or composition of lymphoid organs. All these changes precede the appearance of cardiac fibrosis. We provide evidence indicating that RelA activation in cardiomyocytes with chronic activation of adenylyl cyclase is mediated by calcium-protein Kinase A (PKA) signaling. Using a model of chronic cardiomyocyte stress and accelerated aging, we highlight a novel, calcium/PKA/RelA-dependent connection between cardiomyocyte stress, myocardial inflammation, and systemic inflammation. These findings suggest that RelA-mediated signaling in cardiomyocytes might be an adaptive response to stress that, when chronically activated, ultimately contributes to both cardiac and systemic aging. [ABSTRACT FROM AUTHOR]

The anti-tumoral activity of somatostatin has been demonstrated in both animal experiments and human tumors. Clinical trials have reported conflicting results. We therefore hypothesized that somatostatin might have different effects in various hepatocellular carcinoma cells. Their clarification would possibly allow for the better selection of patients suitable for the optimal treatment results. We studied the mRNA and protein expression of TNF receptors and the TNFa-induced apoptosis using the HepG2 and the Hep3B human hepatocellular carcinoma cells after incubation with the somatostatin analog octreotide. RT-PCR, Western blot, and parameters associated with apoptosis (NF-kB nuclear translocation, P65 Ser536 and P65 Ser468 phosphorylation, DNA fragmentation) were assessed. Only TNFR1 was constitutively present in the two cell lines. Octreotide incubation led to an earlier reduction in TNFR1 mRNA and protein in HepG2 compared to Hep3B cells (1 h and 6–12 h, respectively). NF-kB translocation to the nucleus was induced by TNFa and was more prominent in Hep3B. Translocation was unaffected by octreotide. Serine phosphorylation was significantly induced by TNFa and was more evident in the Hep3B cells. TNFa-induced Ser536 phosphorylation was inhibited by octreotide only in the HepG2 cells. DNA fragmentation was not influenced by either octreotide or TNFa in the HepG2 cells, but TNFa induced fragmentation in the Hep3B cells (1.8-fold increase) verified by the TUNEL index (43 compared to 19 for the HepG2 cells). Octreotide and TNFa co-incubation induced apoptosis in the HepG2 cells (1.7-fold increase compared to controls) but inhibited apoptosis in the Hep3B cells. We conclude that: (1) octreotide reduced TNFR1 receptor expression in both cell lines, (2) parameters of apoptosis were differentially affected by octreotide in the two cell lines, and (3) this might be a partial explanation for the conflicting results of somatostatin analog treatment in human hepatocellular carcinoma trials. [ABSTRACT FROM AUTHOR]

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NF-kappaB is a family of inducible transcription factors playing an important role in immune response in vertebrates. All the five members of the family function as dimers in various combinations. Though all the family members recognize and bind to similar DNA elements to regulate the transcription of its target genes, the dimer composition can lead to differential transcriptional outcomes. Here we report the backbone resonance assignment of the 24.2 kDa homodimer of p52 subunit of the NF-kB family. The p52 subunit of NF-kB is a crucial player in the non-canonical NF-kB pathway and its dysregulation has shown detrimental effects in immune response leading to various inflammatory diseases and cancers. While the β-strands predicted using the backbone chemical shifts in this study largely conform with the available crystal structure, the helical turns present in the crystal structure are not observed in our results. [ABSTRACT FROM AUTHOR]

The thymus, a central lymphoid organ in animals, serves as the site for T cell development, differentiation and maturation, vital to adaptive immunity. The thymus is critical for maintaining tissue homeostasis to protect against tumors and tissue damage. An overactive or prolonged immune response can lead to oxidative stress from increased production of reactive oxygen species. Heat stress induces oxidative stress and overwhelms the natural antioxidant defense mechanisms. This study’s objectives were to investigate the protective properties of astaxanthin against heat-induced oxidative stress and apoptosis in the chicken thymus, by comparing the growth performance and gene signaling pathways among three groups: thermal neutral, heat stress, and heat stress with astaxanthin. The thermal neutral temperature was 21–22 °C, and the heat stress temperature was 32–35 °C. Both heat stress groups experienced reduced growth performance, while the astaxanthin-treated group showed a slightly lesser decline. The inflammatory response and antioxidant defense system were activated by the upregulation of the NF-kB, NFE2L2, PPARα, cytoprotective capacity, and apoptotic gene pathways during heat stress compared to the thermal neutral group. However, expression levels showed no significant differences between the thermal neutral and heat stress with antioxidant groups, suggesting that astaxanthin may mitigate inflammation and oxidative stress damage.

The anti-tumoral activity of somatostatin has been demonstrated in both animal experiments and human tumors. Clinical trials have reported conflicting results. We therefore hypothesized that somatostatin might have different effects in various hepatocellular carcinoma cells. Their clarification would possibly allow for the better selection of patients suitable for the optimal treatment results. We studied the mRNA and protein expression of TNF receptors and the TNFa-induced apoptosis using the HepG2 and the Hep3B human hepatocellular carcinoma cells after incubation with the somatostatin analog octreotide. RT-PCR, Western blot, and parameters associated with apoptosis (NF-kB nuclear translocation, P65 Ser536 and P65 Ser468 phosphorylation, DNA fragmentation) were assessed. Only TNFR1 was constitutively present in the two cell lines. Octreotide incubation led to an earlier reduction in TNFR1 mRNA and protein in HepG2 compared to Hep3B cells (1 h and 6–12 h, respectively). NF-kB translocation to the nucleus was induced by TNFa and was more prominent in Hep3B. Translocation was unaffected by octreotide. Serine phosphorylation was significantly induced by TNFa and was more evident in the Hep3B cells. TNFa-induced Ser536 phosphorylation was inhibited by octreotide only in the HepG2 cells. DNA fragmentation was not influenced by either octreotide or TNFa in the HepG2 cells, but TNFa induced fragmentation in the Hep3B cells (1.8-fold increase) verified by the TUNEL index (43 compared to 19 for the HepG2 cells). Octreotide and TNFa co-incubation induced apoptosis in the HepG2 cells (1.7-fold increase compared to controls) but inhibited apoptosis in the Hep3B cells. We conclude that: (1) octreotide reduced TNFR1 receptor expression in both cell lines, (2) parameters of apoptosis were differentially affected by octreotide in the two cell lines, and (3) this might be a partial explanation for the conflicting results of somatostatin analog treatment in human hepatocellular carcinoma trials.

Abstract Sepsis is a potential fetal organ destruction brought on through an overzealous immunologic reaction to infection, causing severe inflammation, septic shock, and damage to different organs. Although there has been progress in the identification and controlling of clinical sepsis, the fatality rates are still significant. This study, for the first time, intended to examine the possible ameliorative impact of Nebivolol, a β1-adrenergic antagonist antihypertensive drug, against nephrotoxicity resulted from cecal ligation and puncture (CLP)-induced sepsis in rats, on molecular basis. Sixty male Wistar albino rats were chosen. Oxidative stress indicators and biochemical markers of kidney activity were evaluated. Inflammatory mediators, fibrosis- and apoptosis-related proteins and gene expressions were investigated. Moreover, renal histopathological investigation was performed. CLP-induced nephrotoxicity characterized by markedly elevated serum levels of creatinine, blood urea nitrogen, uric acid, and renal malondialdhyde. On the other hand, it decreased serum total protein level, renal superoxide dismutase activity and reduced glutathione level. Additionally, it significantly elevated the renal inflammatory mediators (tumor necrosis factor-alpha, ilnerlukin (IL)-6, and IL-1β) and Caspase-3 protein, reduced IL-10 level, amplified the expression of transforming growth factor-beta 1 (TGF-β1), p-Smad2/3 and alpha-smooth-muscle actin proteins, downregulated the B cell lymphoma-2 (Bcl-2) gene and elevated the transcription of Bcl-2-associated X-protein (Bax), p53 and Nuclear factor-kappa B (NF-κB) genes. Furtheremor, kidney tissues exhibited significant histopathological changes with CLP. On the contrary, Nebivolol significantly improved all these biochemical changes and enhanced the histopathological alterations obtained by CLP. This research showed, for the first time, that Nebivolol effectively mitigated the CLP-induced kidney dysfunction via its antioxidant, antifibrotic and anti-apoptotic activity through modulation of oxidative stress, TGF-β/NF-κB and TGF-β/Smad/p53 signaling pathways.

In the current study, two Salmonella Typhimurium strains, JOL 912 and JOL 1800, were engineered from the wild-type JOL 401 strain through in-frame deletions of the lon and cpxR genes, with JOL 1800 also lacking rfaL. These deletions significantly attenuated the strains, impairing their intracellular survival and creating unique immunological profiles. This study investigates the response of these strains to various abiotic stress conditions commonly experienced in vivo, including temperature, acidity, osmotic, and oxidative stress. Notably, cold stress induced a non-significant trend towards increased invasion by Salmonella compared to other stressors. Despite the observed attenuation, no significant alterations in entry mechanisms (trigger vs. zipper) were noted between these strains, although variations were evident depending on the host cell type. Both strains effectively localized within the cytoplasm, demonstrating their ability to invade and interact with the intracellular environment. Immunologically, JOL 912 elicited a robust response, marked by substantial activation of nuclear factor kappa B (NF-kB), and chemokines, interleukin 8 (CXCL 8) and interleukin 10 (CXCL 10), comparable to the wild-type JOL 401 (over a fourfold increase compared to JOL 1800). In contrast, JOL 1800 exhibited a minimal immune response. Additionally, these attenuations influenced the expression of cyclins D1 and B1 and caspases 3 and 7, indicating cell cycle arrest at the G2/M phase and promotion of the G0/G1 to S phase transition, alongside apoptosis in infected cells. These findings provide valuable insights into the mechanisms governing the association, internalization, and survival of Salmonella mutants, enhancing our understanding of their regulatory effects on host cell physiology. [ABSTRACT FROM AUTHOR]

The majority of people with autoimmune disorders, including those with rheumatoid arthritis, osteoarthritis, and tendonitis report pain, stiffness, and inflammation as major contributors to their worse quality of life in terms of overall health. Of all the available treatment options, COX inhibitors are the ones that are utilized most frequently to ease the symptoms. Various signaling cascades have been reported to be involved in the pathogenesis of rheumatoid arthritis which includes JAK/STAT, MAPK, and NF-kB signaling pathways, and several allopathic inhibitors (tofacitinib and baricitinib) have been reported to target the components of these cascades and have received approval for RA treatment. However, the prolonged use of these COX inhibitors and other allopathic drugs can pose serious health challenges due to their significant side effects. Therefore, searching for a more effective and side effect–free treatment for rheumatoid arthritis has unveiled phytochemicals as both productive and promising. Their therapeutic ability helps develop potent and safe drugs targeting immune-inflammatory diseases including RA. Various scientific databases were used for searching articles such as NCBI, SpringerLink, BioMed Central, ResearchGate, Google Scholar, Scopus, Nature, Wiley Online Library, and ScienceDirect. This review lists various phytochemicals and discusses their potential molecular targets in RA treatment, as demonstrated by various in vitro, in vivo (pre-clinical), and clinical studies. Several pre-clinical and clinical studies suggest that various phytochemicals can be an alternative promising intervention for attenuating and managing inflammation-associated pathogenesis of rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Introduction: Mulberry leaf (ML) is known for its antibacterial and anti-inflammatory properties, historically documented in "Shen Nong's Materia Medica". This study aimed to investigate the effects of ML on enterovirus 71 (EV71) using network pharmacology, molecular docking, and in vitro experiments. Methods: We successfully pinpointed shared targets between mulberry leaves (ML) and the EV71 virus by leveraging online databases. Our investigation delved into the interaction among these identified targets, leading to the identification of pivotal components within ML that possess potent anti-EV71 properties. The ability of these components to bind to the targets was verified by molecular docking. Moreover, bioinformatics predictions were used to identify the signaling pathways involved. Finally, the mechanism behind its anti-EV71 action was confirmed through in vitro experiments. Results: Our investigation uncovered 25 active components in ML that targeted 231 specific genes. Of these genes, 29 correlated with the targets of EV71. Quercetin, a major ingredient in ML, was associated with 25 of these genes. According to the molecular docking results, Quercetin has a high binding affinity to the targets of ML and EV71. According to the KEGG pathway analysis, the antiviral effect of Quercetin against EV71 was found to be closely related to the NF-κB signaling pathway. The results of immunofluorescence and Western blotting showed that Quercetin significantly reduced the expression levels of VP1, TNF-α, and IL-1β in EV71-infected human rhabdomyosarcoma cells. The phosphorylation level of NF-κB p65 was reduced, and the activation of NF-κB signaling pathway was suppressed by Quercetin. Furthermore, our results showed that Quercetin downregulated the expression of JNK, ERK, and p38 and their phosphorylation levels dueto EV71 infection. Conclusion: With these findings in mind, we can conclude that inhibiting the NF-κB signaling pathway is a critical mechanism through which Quercetin exerts its anti-EV71 effectiveness. [ABSTRACT FROM AUTHOR]

Introduction: Improper glycemic control is associated with diabetic cognitive dysfunction. Several studies have confirmed the neuroprotective effects of metformin and insulin. This study aimed to investigate the effects of metformin and/or insulin therapy on neurocognitive functions in a type 2 diabetes mellitus (T2DM) rat model. Methods: Fifty adult male Wistar rats were used in this study and had free access to water and a normal chow diet. After an acclimatization period, 10 rats were kept on a normal chow diet and considered as the control group. T2DM was induced in the other 40 rats by a high-fat diet and low-dose streptozotocin method. Then, diabetic rats were randomly allocated into 4 equal groups: Non-treated diabetic group; Metformin-treated diabetic group (treated with metformin 250 mg/kg/day for 6 weeks); Insulin-treated diabetic group (treated with NPH insulin 40 U/kg for 6 weeks); and Metformin and insulin-treated diabetic group. Neurocognitive functions were assessed by footprint assay, Y-maze, open field test, and Morris water maze. Glycaemic profile, serum levels of amyloid A, interleukin-18, and nuclear factor-kappa B were analyzed. Brain malondialdehyde and total antioxidant capacity were measured. A histopathological examination of the frontal lobe was performed. Results: Treatment with metformin and/or insulin significantly improved the impaired neurocognitive dysfunction, brain oxidative stress, changes in biochemical parameters, and the associated histopathological changes in the frontal cortex of diabetic rats. The combined therapy showed a better effect than either monotherapy alone. Conclusion: Metformin and insulin therapy may be valuable for the prevention of neurocognitive dysfunction in T2DM. [ABSTRACT FROM AUTHOR]

Cytokine-induced β-cell apoptosis is a major pathogenic mechanism in type 1 diabetes (T1D). Despite significant advances in understanding its underlying mechanisms, few drugs have been translated to protect β-cells in T1D. Epigenetic modulators such as bromodomain-containing BET (bromo- and extra-terminal) proteins are important regulators of immune responses. Pre-clinical studies have demonstrated a protective effect of BET inhibitors in an NOD (non-obese diabetes) mouse model of T1D. However, the effect of BET protein inhibition on β-cell function in response to cytokines is unknown. Here, we demonstrate that I-BET, a BET protein inhibitor, protected β-cells from cytokine-induced dysfunction and death. In vivo administration of I-BET to mice exposed to low-dose STZ (streptozotocin), a model of T1D, significantly reduced β-cell apoptosis, suggesting a cytoprotective function. Mechanistically, I-BET treatment inhibited cytokine-induced NF-kB signaling and enhanced FOXO1-mediated anti-oxidant response in β-cells. RNA-Seq analysis revealed that I-BET treatment also suppressed pathways involved in apoptosis while maintaining the expression of genes critical for β-cell function, such as Pdx1 and Ins1. Taken together, this study demonstrates that I-BET is effective in protecting β-cells from cytokine-induced dysfunction and apoptosis, and targeting BET proteins could have potential therapeutic value in preserving β-cell functional mass in T1D. [ABSTRACT FROM AUTHOR]

Obesity is associated with chronic inflammation that affects various organs in the body, including the reproductive system, which is a key factor in male infertility. 1-Deoxynojirimycin (1-DNJ) is a natural alkaloid in mulberry leaves, which has anti-inflammatory capabilities, yet, it's effects on obesity-induced inflammation-related male infertility remain unclear. Therefore, this research investigates the underlying mechanism by which 1-DNJ may mitigate fertility impairment in male mice caused by obesity-related inflammation. Male mice with high-fat diet (HFD)-induced obesity were treated with 1-DNJ or metformin for 8 weeks. Metabolic profiles were evaluated by enzyme method. Reproductive capacity was assessed by sperm viability, motility and counts, immunohistochemistry was performed to evaluate the testicular damage caused by obesity and inflammation. The inflammation was assessed by measuring the levels of tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), and interleukin 6 (IL-6). The activation of IκB kinase β (IKKβ) and nuclear factor κB (NF-κB) was examined using western blot and immunohistochemistry. HFD induced obesity in mice with obvious lipid metabolism disorder. The obese male mice had a decreased testosterone level, impaired sperm motility, and increased inflammatory factors. 1-DNJ treatment improved the testosterone level in the obese mice, ameliorated the testicular structure damage and improve sperm viability. In addition, 1-DNJ treatment inhibited IKKβ/NF-kB signaling pathway and reduced inflammation in obese mice. 1-DNJ can improve the fertility of obese men by reducing obesity as well as obesity-induced inflammation. These findings provide new insights for 1-DNJ to alleviate inflammation caused by obesity and provide future possibilities for treating male infertility. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). Mutational analysis has demonstrated that the tumor suppressor, F-box and WD repeat domain containing 7 (FBXW7/FBW7/CDC4), is mutated in primary ATL patients. However, even in the absence of genetic mutations, FBXW7 substrates are stabilized in ATL cells, suggesting additional mechanisms can prevent FBXW7 functions. Here, we report that the viral oncoprotein Tax represses FBXW7 activity, resulting in the stabilization of activated Notch intracellular domain, c-MYC, Cyclin E, and myeloid cell leukemia sequence 1 (BCL2-related) (Mcl-1). Mechanistically, we demonstrate that Tax directly binds to FBXW7 in the nucleus, effectively outcompeting other targets for binding to FBXW7, resulting in decreased ubiquitination and degradation of FBXW7 substrates. In support of the nuclear role of Tax, a non-degradable form of the nuclear factor kappa B subunit 2 (NFκB2/p100) was found to delocalize Tax to the cytoplasm, thereby preventing Tax interactions with FBXW7 and Tax-mediated inhibition of FBXW7. Finally, we characterize a Tax mutant that is unable to interact with FBXW7, unable to block FBXW7 tumor suppressor functions, and unable to effectively transform fibroblasts. These results demonstrate that HTLV-I Tax can inhibit FBXW7 functions without genetic mutations to promote an oncogenic state. These results suggest that Tax-mediated inhibition of FBXW7 is likely critical during the early stages of the cellular transformation process. IMPORTANCE F-box and WD repeat domain containing 7 (FBXW7), a critical tumor suppressor of human cancers, is frequently mutated or epigenetically suppressed. Loss of FBXW7 functions is associated with stabilization and increased expression of oncogenic factors such as Cyclin E, c-Myc, Mcl-1, mTOR, Jun, and Notch. In this study, we demonstrate that the human retrovirus human T-cell leukemia virus type 1 oncoprotein Tax directly interacts with FBXW7, effectively outcompeting other targets for binding to FBXW7, resulting in decreased ubiquitination and degradation of FBXW7 cellular substrates. We further demonstrate that a Tax mutant unable to interact with and inactivate FBXW7 loses its ability to transform primary fibroblasts. Collectively, our results describe a novel mechanism used by a human tumor virus to promote cellular transformation. [ABSTRACT FROM AUTHOR]

Gastric ulceration is a common gastrointestinal ailment with serious consequences that can lead to serious illness or even death. This study aimed to examine the efficacy of tadalafil (TAD) and dexlansoprazole (DLP) in treating stomach ulcers caused by dexamethasone (DEX) in male albino Wister rats. Thirty male albino Wister rats were divided into 5 groups (6 rats each): control group received normal saline, positive control group received DEX 5 mg/kg/day intraperitoneal (i.p.) for 7 days, the third group received DLP 30 mg/kg/day orally after DEX, the fourth group received TAD 5 mg/kg/day orally after DEX, and the fifth group received DLP and TAD orally after DEX. Persistence and prevention of ulcers, pepsin activity, mucin content, and histopathological changes were evaluated after each trial. Reduced glutathione (GSH), nitric oxide (NO), and malondialdehyde (MDA) levels were measured in gastric homogenates. Serum levels of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) were also measured. Treatment with either TAD or DLP alone significantly reduced ulcer index (U.I.), pepsin activity, TNF-α, IL-10 and MDA with significant rise in mucin content, PGE2, NO, GSH, and improved the histological alteration compared to DEX group. When TAD and DLP were administered together, there was a more notable decrease in U.I., pepsin activity, gastric MDA, TNF-α, and IL-10 with concomitant more significant increase in mucin content, NO content, and PGE2 production compared to the TAD or DLP groups alone. Compared to each medicine alone, TAD and DLP together have promising therapeutic potential in preventing stomach ulcers caused by DEX. [ABSTRACT FROM AUTHOR]

Introduction: Chronic obstructive pulmonary disease (COPD) is a major global cause of mortality with limited effective treatments. Sirtuins (SIRT) are histone deacetylases that are involved in the regulation of redox and inflammatory homeostasis. Hence, the present study aims to investigate the role of SIRT-2 in modulating inflammation in a murine model of COPD. Methods: COPD in mice was established by cigarette smoke (CS) exposure for 60 days, and AK-7 was used as the specific SIRT-2 inhibitor. AK-7 (100 µg/kg and 200 µg/kg body weight) was administered intranasally 1 h before CS exposure. Molecular docking was performed to analyze the binding affinity of different inflammatory proteins with AK-7. Results: Immune cell analysis showed a significantly increased number of macrophages (F4/80), neutrophils (Gr-1), and lymphocytes (CD4+, CD8+, and CD19+) in the COPD, group and their population was declined by AK-7 administration. Total reactive oxygen species, total inducible nitric oxide synthase, inflammatory mediators such as neutrophil elastase, C-reactive protein, histamine, and cytokines as IL4, IL-6, IL-17, and TNF-a were elevated in COPD and declined in the AK-7 group. However, IL-10 showed reverse results representing anti-inflammatory potency. AK-7 administration by inhibiting SIRT-2 decreased the expression of p-NF-kB, p-P38, p-Erk, and p-JNK and increased the expression of Nrf-2. Furthermore, AK-7 also declined the lung injury by inhibiting inflammation, parenchymal destruction, emphysema, collagen, club cells, and Kohn pores. AK-7 also showed good binding affinity with inflammatory proteins. Discussion: The current study reveals that SIRT-2 inhibition mitigates COPD severity and enhances pulmonary therapeutic interventions, suggesting AK-7 as a potential therapeutic molecule for COPD medication development. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) cells are a highly formidable cancer to treat. Nonetheless, by continued investigation into the molecular biology underlying the complex regulation of TNBC cell activity, vulnerabilities can be exposed as potential therapeutic targets at the molecular level. We previously revealed that lysyl oxidase-like 4 (LOXL4) promotes the invasiveness of TNBC cells via cell surface annexin A2 as a novel binding substrate of LOXL4, which promotes the abundant localization of integrin-b1 at the cancer plasma membrane. However, it has yet to be uncovered how the LOXL4-mediated abundance of integrin-b1 hastens the invasive outgrowth of TNBC cells at the molecular level. Methods: LOXL4-overexpressing stable clones were established from MDA-MB231 cells and subjected to molecular analyses, real-time qPCR and zymography to clarify their invasiveness, signal transduction, and matrix metalloprotease (MMP) activity, respectively. Results: Our results show that LOXL4 potently promotes the induction of matrix metalloprotease 9 (MMP9) via activation of nuclear factor-kB (NF-kB). Our molecular analysis revealed that TNF receptor-associated factor 4 (TRAF4) and TGF-b activated kinase 1 (TAK1) were required for the activation of NF-kB through Ikb kinase kinase (IKKa/b) phosphorylation. Conclusion: Our results demonstrate that the newly identified LOXL4-mediated axis, integrin-b1-TRAF4-TAK1-IKKa/b-Ikba-NF-kB-MMP9, is crucial for TNBC cell invasiveness. [ABSTRACT FROM AUTHOR]

Background: CD2v, a critical outer envelope glycoprotein of the African swine fever virus (ASFV), plays a central role in the hemadsorption phenomenon during ASFV infection and is recognized as an essential immunoprotective protein. Monoclonal antibodies (mAbs) targeting CD2v have demonstrated promise in both diagnosing and combating African swine fever (ASF). The objective of this study was to develop specific monoclonal antibodies against CD2v. Methods: In this investigation, Recombinant CD2v was expressed in eukaryotic cells, and murine mAbs were generated through meticulous screening and hybridoma cloning. Various techniques, including indirect enzyme-linked immunosorbent assay (ELISA), western blotting, immunofluorescence assay (IFA), and bio-layer interferometry (BLI), were employed to characterize the mAbs. Epitope mapping was conducted using truncation mutants and epitope peptide mapping. Results: An optimal antibody pair for a highly sensitive sandwich ELISA was identified, and the antigenic structures recognized by the mAbs were elucidated. Two linear epitopes highly conserved in ASFV genotype II strains, particularly in Chinese endemic strains, were identified, along with a unique glycosylated epitope. Three mAbs, 2B25, 3G25, and 8G1, effectively blocked CD2v-induced NF-κB activation. Conclusions: This study provides valuable insights into the antigenic structure of ASFV CD2v. The mAbs obtained in this study hold great potential for use in the development of ASF diagnostic strategies, and the identified epitopes may contribute to vaccine development against ASFV. [ABSTRACT FROM AUTHOR]

Background: Altered T‐cell repertoire with an aberrant T‐cell activation and imbalance of the Th17/Treg cells has been reported in acquired aplastic anemia (aAA). miRNAs are well known to orchestrate T‐cell activation and differentiation, however, their role in aAA is poorly characterized. The study aimed at identifying the profile of miRNAs likely to be involved in T‐cell activation and the Th17/Treg‐cell imbalance in aAA, to explore newer therapeutic targets. Methods: Five milliliters peripheral blood samples from 30 patients of aAA and 15 healthy controls were subjected to flow cytometry for evaluating Th17‐ and Treg‐cell subsets. The differential expression of 7 selected miRNAs viz; hsa‐miR‐126‐3p, miR‐146b‐5p, miR‐155‐5p, miR‐16, miR‐17, miR‐326, and miR‐181c was evaluated in the PB‐MNCs. Expression analysis of the miRNAs was performed using qRT‐PCR and fold change was calculated by 2−ΔΔCt method. The alterations in the target genes of deregulated miRNAs were assessed by qRT‐PCR. The targets studied included various transcription factors, cytokines, and downstream proteins. Results: The absolute CD3+ lymphocytes were significantly elevated in the PB of aAA patients when compared with healthy controls (p < 0.0035), however, the CD4:CD8 ratio was unperturbed. Th17: Treg‐cell ratio was altered in aAA patients (9.1 vs. 3.7%, p value <0.05), which correlated positively with disease severity and the PNH positive aAA. Across all severities of aAA, altered expression of the 07 miRNAs was noted in comparison to controls; upregulation of miR‐155 (FC—2.174, p‐value‐0.0001), miR‐146 (FC—2.006, p‐value‐0.0001), and miR‐17 (FC—3.1, p‐value‐0.0001), and downregulation of miR‐126 (FC—0.329, p‐value‐0.0001), miR‐181c (FC—0.317, p‐value‐0.0001), miR‐16 (FC—0.348, p‐value‐0.0001), and miR‐326 (FC—0.334, p‐value‐0.0001). Target study for these miRNAs revealed an increased expression of transcription factors responsible for Th1 and Th17 differentiation (T‐bet, RORϒt, IL‐17, IL‐6, and IFN‐ϒ), T‐cell activation (NFκB, MYC, and PIK3R2), downregulation of FOX‐P3, and other regulatory downstream molecules like SHIP‐1, ETS‐1, IRAK‐1, TRAF‐6, and PTEN. Conclusion: The study for the first time highlights the plausible role of different miRNAs in deregulating the Th17/Treg‐cell imbalance in aAA, and comprehensively suggest the role of altered NF‐kB and mTOR pathways in aAA. The axis may be actively explored for development of newer therapeutic targets in aAA. [ABSTRACT FROM AUTHOR]

Objective To explore the mechanism of Canopy homolog 2 (CNPY2) and aerobic exercise through nuclear factor kappa-B (NF-kB) signal pathway in non-alcoholic fatty liver disease (NAFLD) induced by high fat diet. Methods Male CNPY2 knockout (CNPY2 KO) mice and wild (WT) mice aged (12±1) weeks were randomly divided into control group (CON), hyperlipidemic model group (MOD), and hyperlipidemic model exercise group (MOD+EX) after one week of adaptive feeding, CON group was fed with normal diet, and MOD group and MOD+EX group were fed with high fat diet until the end of 18 weeks. From the 10th week, the mice in the MOD+EX group received adaptive treadmill training for a week, followed by continuous exercise intervention until the end of the 18-week experiment The serum levels of TC, TG, LDL-C, HDL-C, ALT, and AST were detected by automatic biochemical analyzer, the pathological morphology of liver was analyzed by HE staining and oil red 0 staining, the protein expressions of CNPY2, IkB a, p-lKBot, NF-kB, and NF-kB in liver were detected by Western Blot, the levels of TNF-ot and IL6 in liver were detected by ELISA, and the expressions of NF-kB mRNA, TNF-a mRNA, and IL-6 mRNA in liver were detected by q RT-PCR. The data were analyzed by single factor analysis of variance and independent sample t -test. Results The expression of CNPY2 in MOD group was higher than that in CON group Q 二 一5.730, P=0.001) while the expression of CNPY2 in MOD+EX group was lower than that in MOD group(£=3.714, P=0.010). Compared with CON group, the serum levels of TC, TG, LDL-c, ALT, and AST in MOD group of WT mice and CNPY2 KO mice were higher (WT: £二一13.325, P < 0.001; £=-4.889, P < 0.001; i=-10.442, P < 0.001; £=-3.500： P=0.003; £=-15.122： P < 0.001; CNPY2 KO： =一6.910, P < 0.001; =-4.962, P < 0.001;匸一7.457, P < 0.001; =-4.584： P < 0.001;匸一7.336, P < 0.001). The levels of TNF-ot, IL-6, p~IKBa/lKBot, p-NF~kB/NF-kB, NF-kB mRNA, TNF-ct mRNA, and IL-6 mRNA in liver were increased significantly (WT: £=-25.179; P < 0,001; £=-21.043, P < 0.001; £=-9.177, P < 0,001; i=-12.207, P < 0.001;匸一5205, P=0.002; *-6.910, P < 0.001; z =-4.802, P二0.003; CNPY2 KO： e-18.87& P < 0.001; =-21.840, P < 0.001; h--14.033： P < 0.001; =--12.511, P < 0.001;匸一6.870： P < 0.001; =-9.546, P < 0,001;匸一8.303, P < 0.001), HDL-C level decreased (WT: 11.695, P < 0.001; CNPY2 KO: £=6.59& P < 0.001), and hepatocyte steatosis with large amount of lipid droplets was observed. Compared with MOD group, the above-mentioned indexes were effectively improved in WT mice and CNPY2 KO mice in MOD+EX group. Compared with WT mice, the above -mentioned indexes of CNPY2 KO mice were improved effectively. Conclusion CNPY2 regulates NF-kB signal pathway and participates in the formation and development of NAFLD. Both CNPY2 gene deletion and aerobic exercise can improve NAFLD, which may be related to the decrease of liver CNPY2 expression, inhibition of NF-kB signal pathway, down-regulation of liver inflammatory cytokines and reduction of liver inflammation. [ABSTRACT FROM AUTHOR]

α-Actinin-4 is an actin-binding protein involved in a wide range of cellular processes. Along with actin and other proteins of the actin cytoskeleton, α-actinin-4 is found not only in the cytoplasm, but also in the nucleus of various types of cells. As a nuclear protein, it takes part in regulating the activity of some transcription factors. In particular, it can regulate the activity of the NF-kB factor, which largely determines the resistance of cancer cells to apoptosis and anticancer therapy. Our previous studies revealed that α-actinin-4 can influence the resistance of cancer cells to topoisomerase II inhibitors and determine the efficiency of DNA double-strand break repair by regulating the assembly of HRR and NHEJ protein complexes. In this work, we tried to answer the question of how α-actinin-4 is involved in the regulation of the double-stranded DNA breaks repair under genotoxic stress. Our results indicate that the effect of α-actinin-4 on the repair process in H1299 non-small-cell lung-cancer cells does not depend on the activity of the transcription factor NF-kB. We found that, in the nucleus of H1299 cells, α-actinin-4 is localized not only in the nucleoplasm, but also shows close association with chromatin. [ABSTRACT FROM AUTHOR]

ABSTRACT The primary challenge posed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is COVID-19-related mortality, often exacerbated by additional medical complications, such as COVID-19-associated kidney injuries (CAKIs). Up to half of COVID-19 patients experience kidney complications, with those facing acute respiratory failure and kidney injury having the worst overall prognosis. Despite the significant impact of CAKI on COVID-19-related mortality and its enduring effects in long COVID, the underlying causes and molecular mechanisms of CAKI remain elusive. In this study, we identified a functional relationship between the expression of the SARS-CoV-2 ORF3a protein and inflammation-driven apoptotic death of renal tubular epithelial cells in patients with CAKI. We demonstrate in vitro that ORF3a independently induces renal cell-specific apoptotic cell death, as evidenced by the elevation of kidney injury molecule-1 (KIM-1) and the activation of NF-kB-mediated proinflammatory cytokine (TNFα and IL-6) production. By examining kidney tissues of SARS-CoV-2-infected K18-ACE2 transgenic mice, we observed a similar correlation between ORF3a-induced cytopathic changes and kidney injury. This correlation was further validated through reconstitution of the ORF3a effects via direct adenoviral injection into mouse kidneys. Through medicinal analysis, we identified a natural compound, glycyrrhizin (GL4419), which not only blocks viral replication in renal cells, but also mitigates ORF3a-induced renal cell death by inhibiting activation of a high mobility group box 1 (HMGB1) protein, leading to a reduction of KIM-1. Moreover, ORF3a interacts with HMGB1. Overproduction or downregulation of hmgb1 expression results in correlative changes in renal cellular KIM-1 response and respective cytokine production, implicating a crucial role of HMGB1 in ORF3a-inflicted kidney injuries. Our data suggest a direct functional link between ORF3a and kidney injury, highlighting ORF3a as a unique therapeutic target contributing to CAKI.IMPORTANCEThe major challenge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the pandemic is COVID-19-related mortality, which has tragically claimed millions of lives. COVID-19-associated morbidity and mortality are often exacerbated by pre-existing medical conditions, such as chronic kidney diseases (CKDs), or the development of acute kidney injury (AKI) due to COVID-19, collectively known as COVID-19-associated kidney injuries (CAKIs). Patients who experience acute respiratory failure with CAKI have the poorest clinical outcomes, including increased mortality. Despite these alarming clinical findings, there is a critical gap in our understanding of the underlying causes of CAKI. Our study establishes a direct correlation between the expression of the SARS-CoV-2 viral ORF3a protein and kidney injury induced by ORF3a linking to CAKI. This functional relationship was initially observed in our clinical studies of COVID-19 patients with AKI and was further validated through animal and in vitro cellular studies, either by expressing ORF3a alone or in the context of viral infection. By elucidating this functional relationship and its underlying mechanistic pathways, our research deepens the understanding of COVID-19-associated kidney diseases and presents potential therapeutic avenues to address the healthcare challenges faced by individuals with underlying conditions.

ABSTRACT Lentiviruses encode a number of multi-functional accessory proteins, however, the primary role of the accessory protein Vpr remains unclear. As Vpr engages the host DNA damage response (DDR) at multiple steps, modulation of the DDR is considered central to the function(s) of Vpr. Vpr activates ataxia telangiectasia and Rad3 (ATR)-mediated DDR signaling, resulting in cell cycle arrest. However, the cellular consequences of Vpr-induced DNA damage, and the connection of Vpr-induced DNA damage to other Vpr functions, are unknown. Here, we determined that HIV-1 Vpr-induced DNA damage activates the ATM-NF-κB essential modulator (NEMO) pathway and alters cellular transcription via NF-κB/RelA. Through RNA-sequencing (RNA-seq) of cells expressing Vpr or mutants that separate the ability of Vpr to induce DNA damage from other DDR phenotypes, we identified that Vpr alters the transcriptome independent of cell cycle arrest. In tissue-cultured U2OS cells and primary human monocyte-derived macrophages (MDMs), we showed Vpr activates both ataxia telangiectasia mutated (ATM) and NF-κB/RelA signaling cascades. While inhibition of NEMO did not affect Vpr-induced DNA damage, it prevented NF-κB activation by Vpr, highlighting the importance of NEMO in Vpr-mediated transcriptional reprogramming. Virion-delivered Vpr was sufficient to induce DNA damage and activate ATM-NEMO dependent NF-κB transcription, suggesting that engagement of the DDR and transcriptional changes can occur early during viral replication. Together, our data uncover cellular consequences of Vpr-induced DNA damage and provide a mechanism for how Vpr activates NF-κB through DNA damage and ATM-NEMO signaling, which occur independent of cell cycle arrest. We propose this is essential to overcoming restrictive environments, such as in macrophages, to enhance viral replication.IMPORTANCEThe HIV accessory protein Vpr is multi-functional and required for viral replication in vivo, yet how Vpr enhances viral replication is unknown. Emerging literature suggests that a conserved function of Vpr is the engagement of the host DNA damage response (DDR). For example, Vpr activates DDR signaling, causes DDR-dependent cell cycle arrest, promotes degradation of various DDR proteins, and alters cellular consequences of DDR activation. However, a central understanding of how these phenotypes connect and how they affect HIV-infected cells remains unknown. Here, we found that Vpr-induced DNA damage alters the host transcriptome by activating an essential transcription pathway, NF-κB. This occurs early during the infection of primary human immune cells, suggesting NF-κB activation and transcriptome remodeling are important for establishing productive HIV-1 infection. Together, our study provides novel insights into how Vpr alters the host environment through the DDR, and what roles Vpr and the DDR play to enhance HIV replication.

Ferroptosis is an iron-dependent form of cell death, which finally culminates in lipid peroxidation and membrane damage. During the past decade, the interest in ferroptosis increased substantially and various regulatory components were discovered. The role of ferroptosis during inflammation and its impact on different immune cell populations is still under debate. Activation of inflammatory pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and hypoxia inducible factors (HIFs) are known to alter the ability of cells to undergo ferroptosis and are closely connected to iron metabolism. During inflammation, iron regulatory systems fundamentally change and cells such as macrophages and neutrophils adapt their metabolism towards iron sequestering phenotypes. In this review, we discuss how ferroptosis alters inflammatory pathways and how iron metabolism under inflammatory conditions affects immune cell ferroptosis.

Abstract In the face of recent advances in Cervical cancer (CC) treatment, therapeutic and surgical procedures for CC management are still inadequate. In the current study for the first time Andrographolide (Andro) has been explored for its multitarget therapeutic efficacy on NF-kB, COX-2, and PI3K/AKT expressions together in CC. The expression levels of NF-kB, COX-2, PI3K and PTEN in the CC patient samples, both at mRNA and protein levels have shown significant association with poor survival and increased tumor aggressiveness. The binding efficacy of Andro was investigated using molecular docking and molecular dynamic simulations, and the protein and ligand complex for NF-kB and COX-2 has shown high binding energy. Andro displayed cytotoxicity by impeding the in-vitro proliferation of CC cells. Andro significantly supressed the NF-kB, COX-2, and PI3K expression and enhanced the expression levels of PTEN at protein levels in-vitro. Andro induced apoptosis in a dose dependent manner and significantly inhibited the migration and invasion of CC cells. Andro exhibited similar activity in-vivo and suppressed the CC tumor growth in xenograft C57BL/6 mice model. The anti-tumor activity of Andro, both in-vitro and in-vivo has shown considerable downregulation of NF-kB and COX-2 and induced apoptosis through impeding the PI3K/AKT signalling pathway. These findings from the above study projects, administration of Andro as an effective alternate safe compound to curtail and impede cervical cancer progression.

Abstract Background Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by hypomorphic loss of function in the survival motor neuron (SMN) protein. SMA presents across a broad spectrum of disease severity. Unfortunately, genetic models of intermediate SMA have been difficult to generate in vertebrates and are thus unable to address key aspects of disease etiology. To address these issues, we developed a Drosophila model system that recapitulates the full range of SMA severity, allowing studies of pre-onset biology as well as late-stage disease processes. Results Here, we carried out transcriptomic and proteomic profiling of mild and intermediate Drosophila models of SMA to elucidate molecules and pathways that contribute to the disease. Using this approach, we elaborated a role for the SMN complex in the regulation of innate immune signaling. We find that mutation or tissue-specific depletion of SMN induces hyperactivation of the immune deficiency (IMD) and Toll pathways, leading to overexpression of antimicrobial peptides (AMPs) and ectopic formation of melanotic masses in the absence of an external challenge. Furthermore, the knockdown of downstream targets of these signaling pathways reduced melanotic mass formation caused by SMN loss. Importantly, we identify SMN as a negative regulator of a ubiquitylation complex that includes Traf6, Bendless, and Diap2 and plays a pivotal role in several signaling networks. Conclusions In alignment with recent research on other neurodegenerative diseases, these findings suggest that hyperactivation of innate immunity contributes to SMA pathology. This work not only provides compelling evidence that hyperactive innate immune signaling is a primary effect of SMN depletion, but it also suggests that the SMN complex plays a regulatory role in this process in vivo. In summary, immune dysfunction in SMA is a consequence of reduced SMN levels and is driven by cellular and molecular mechanisms that are conserved between insects and mammals.

Abstract Smoking is the major cause of cardiovascular diseases and cancer. It induces oxidative stress, leading to DNA damage and cellular senescence. Senescent cells increase the expression and release of pro-inflammatory molecules and matrix metalloproteinase, which are known to play a vital role in the initiation and progression of cardiovascular diseases and metastasis in cancer. The current study investigated the smoking induced cellular senescence and employed colchicine that blocked senescence in endothelial cells exposed to tobacco smoke condensate. Colchicine prevented oxidative stress and DNA damage in tobacco smoke-condensate-treated endothelial cells. Colchicin reduced β-gal activity, improved Lamin B1, and attenuated cell growth arrest markers P21 and P53. Colchicine also ameliorated the expression of SASP factors and inhibited the activation of NF-kB and MAPKs P38 and ERK. In summary, colchicine inhibited tobacco smoke condensate-induced senescence in endothelial cells by blocking the activation of NF-kB and MAPKs P38 and ERK. Graphical Abstract

As a consequence of chronic hyperglycemia, diabetes complications and tissue damage are exacerbated. There is evidence that natural phytochemicals, including resveratrol, a bioactive polyphenol, may be able to reduce oxidative stress and improve insulin sensitivity. However, resveratrol's limited bioavailability hampers its therapeutic effectiveness. By using liposomes, resveratrol may be better delivered into the body and be more bioavailable. The objective of this study was to assess the cardioprotective potential of liposome-encapsulated resveratrol (LR) in a streptozotocin-induced (STZ) diabetic rat model. Adult male Wistar rats were categorized into five groups: control, diabetic, resveratrol-treated (40 mg/kg), liposomal resveratrol (LR)-treated (20 mg/kg) and liposomal resveratrol (LR)-treated (40 mg/kg) for a five-week study period. We compared the effects of LR to those of resveratrol (40 mg/kg) on various parameters, including serum levels of cardiac markers, tissue levels of pro-inflammatory cytokines, nuclear transcription factor, oxidative stress markers, and apoptotic markers. LR treatment in STZ-diabetic rats resulted in notable physiological improvements, including blood glucose regulation, inflammation reduction, oxidative stress mitigation, and apoptosis inhibition. LR effectively lowered oxidative stress and enhanced cardiovascular function. It also demonstrated a remarkable ability to suppress NF-kB-mediated inflammation by inhibiting the pro-inflammatory cytokines TNF-α and IL-6. Additionally, LR restored the antioxidant enzymes, catalase and glutathione peroxidase, thereby effectively counteracting oxidative stress. Notably, LR modulated apoptotic regulators, including caspase, Bcl2, and Bax, suggesting a role in regulating programmed cell death. These biochemical alterations were consistent with improved structural integrity of cardiac tissue as revealed by histological examination. In comparison, resveratrol exhibited lower efficacy at an equivalent dosage. Liposomal resveratrol shows promise in alleviating hyperglycemia-induced cardiac damage in diabetes. Further research is warranted to explore its potential as a therapeutic agent for diabetic cardiovascular complications and possible cardioprotective effects.

In the face of recent advances in Cervical cancer (CC) treatment, therapeutic and surgical procedures for CC management are still inadequate. In the current study for the first time Andrographolide (Andro) has been explored for its multitarget therapeutic efficacy on NF-kB, COX-2, and PI3K/AKT expressions together in CC. The expression levels of NF-kB, COX-2, PI3K and PTEN in the CC patient samples, both at mRNA and protein levels have shown significant association with poor survival and increased tumor aggressiveness. The binding efficacy of Andro was investigated using molecular docking and molecular dynamic simulations, and the protein and ligand complex for NF-kB and COX-2 has shown high binding energy. Andro displayed cytotoxicity by impeding the in-vitro proliferation of CC cells. Andro significantly supressed the NF-kB, COX-2, and PI3K expression and enhanced the expression levels of PTEN at protein levels in-vitro. Andro induced apoptosis in a dose dependent manner and significantly inhibited the migration and invasion of CC cells. Andro exhibited similar activity in-vivo and suppressed the CC tumor growth in xenograft C57BL/6 mice model. The anti-tumor activity of Andro, both in-vitro and in-vivo has shown considerable downregulation of NF-kB and COX-2 and induced apoptosis through impeding the PI3K/AKT signalling pathway. These findings from the above study projects, administration of Andro as an effective alternate safe compound to curtail and impede cervical cancer progression. [ABSTRACT FROM AUTHOR]

Moringa oleifera Lam has been used as a medicinal plant in many Asian countries including Thailand. The plant has a variety of pharmacological effects such as antioxidant, anti-inflammation, hypolipidemic, anti-infection, anticancer, and antidiabetic. The leaves and young pods, which contain various nutritional compounds including proteins, fatty acids, and vitamins, are widely consumed. In this study, we investigated the effects of hexane, ethyl acetate, methanol and ethanol crude extracts of M. oleifera Lam leaves on the viability of microglial cells and on the lipopolysaccharide-induced microglial activation. which is widely used as a model for neuroinflammation. Our findings suggested that all of the crude extracts at concentrations ranging from 10-9 to 10-5 g/mL did not significantly affect the viability of microglial cells and exhibited similar effects. Subsequently, we focused on ethanol extract for investigation of the molecular mechanism involving neuroinflammation. We found that the ethanol extract of M. oleifera Lam leaves at the concentrations of 10-9 to 10-5 g/mL significantly reduced inducible nitric oxide synthase (iNOS) protein expression and nitric oxide (NO) production, accompanied by the reduction of phospho-NF-kB and phospho-IkBα expressions. The results suggested that the ethanol extract of M. oleifera Lam leaves reduced NO production through reduction of iNOS protein expression following the inhibition of NF-kB/IkBα signaling pathways. Our study underscored the therapeutic potential of M. oleifera Lam leaves extract in neurodegenerative diseases associated with neuroinflammation. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of adipocytes on the proliferation of human normal prostate epithelial cell (RWPE-1) and human normal prostate stromal immortalized cell(WPMY-1) and its potential mechanism. Methods Adipocyte conditioned medium (Adi-cm) was prepared and collected after lipogenesis induction, RWPE-1 and WPMY-1 cells were divided into the control group and the Adi-cm group, respectively・ The results of fat induction were verified by oil red 0 stainingT cell proliferation and cytotoxicity were detected by cck8 kit, cell migration ability was evaluated by scratching assay, RNA and protein levels of NF-kB, Bcl-2, Bax, IL-lp, BL-6 and TNF-a were detected by RT-PCR and western blot. Results Cell proliferation was significantly increased in the Adi-cm group, and no significant difference was found in cell migration. Expressions of NF-kB and inflammatory factors IL-lp, IL-6 and TNF-a were significantly increased in the Adi-cm group. NF-kB inhibitors could significantly inhibit the proliferation of the two types of prostate cells treated with Adi-cm, Conclusion Adipocytes can promote the proliferation of RWPE-1 and WPMY-1 cells by activating NF-kB and releasing inflammatory factors. [ABSTRACT FROM AUTHOR]

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Macrophages are tissue resident innate phagocytic cells that take on contrasting phenotypes, or polarization states, in response to the changing combination of microbial and cytokine signals at sites of infection. During the opening stages of an infection, macrophages adopt the proinflammatory, highly antimicrobial M1 state, later shifting to an anti-inflammatory, pro-tissue repair M2 state as the infection resolves. The changes in gene expression underlying these transitions are primarily governed by nuclear factor kappaB (NF-kB), Janus kinase (JAK)/signal transducer and activation of transcription (STAT), and hypoxia-inducible factor 1 (HIF1) transcription factors, the activity of which must be carefully controlled to ensure an effective yet spatially and temporally restricted inflammatory response. While much of this control is provided by pathway-specific feedback loops, recent work has shown that the transcriptional co-regulators of the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxy-terminal domain (CITED) family serve as common controllers for these pathways. In this review, we describe how CITED proteins regulate polarization-associated gene expression changes by controlling the ability of transcription factors to form chromatin complexes with the histone acetyltransferase, CBP/p300. We will also cover how differences in the interactions between CITED1 and 2 with CBP/p300 drive their contrasting effects on pro-inflammatory gene expression. [ABSTRACT FROM AUTHOR]

Vitamin C (VC) can be used to increase disease resistance in practice in intensive aquaculture. But it is still unconfirmed whether VC could alleviate inflammation and what dosage is suitable. This study investigated the effects of dietary VC on the immunity and enteritis of juvenile blunt snout bream (Megalobrama amblycephala) challenged with Aeromonas hydrophila. The fish were fed with VC levels ranging from 25.35 to 2231.98 mg/kg for 60 days. After that, fish fed with 150.65 mg/kg, 573.79 mg/kg, and 2231.98 mg/kg VC were challenged with A. hydrophila orally to simulate enteritis. The results showed that 285.39 and 573.79 mg/kg dietary VC significant improved growth performance and feed utilization. Dietary VC (573.79 and 1133.79 mg/kg) significantly enhanced the serum immune parameters, antioxidant enzymes' activities, and relative gene expressions of ikbα and cat in the liver in the 60-day feeding trail. The survival rate was significantly higher in 573.79 mg/kg dietary VC group than the other two treatments. Cytokines were activated after the bacteria challenge. Dietary 573.79 mg/kg VC caused significantly higher TNF-α level at 12 hpi and maintained a high level of IL-8 at 48 to 72 h compared to other treatments. In conclusion, more than 500 mg/kg VC was needed to maintain the health of blunt snout bream juveniles. Suitable VC would activate cytokines to increase disease resistance along with antioxidant enzymes. [ABSTRACT FROM AUTHOR]

Smoking is the major cause of cardiovascular diseases and cancer. It induces oxidative stress, leading to DNA damage and cellular senescence. Senescent cells increase the expression and release of pro-inflammatory molecules and matrix metalloproteinase, which are known to play a vital role in the initiation and progression of cardiovascular diseases and metastasis in cancer. The current study investigated the smoking induced cellular senescence and employed colchicine that blocked senescence in endothelial cells exposed to tobacco smoke condensate. Colchicine prevented oxidative stress and DNA damage in tobacco smoke-condensate-treated endothelial cells. Colchicin reduced β-gal activity, improved Lamin B1, and attenuated cell growth arrest markers P21 and P53. Colchicine also ameliorated the expression of SASP factors and inhibited the activation of NF-kB and MAPKs P38 and ERK. In summary, colchicine inhibited tobacco smoke condensate-induced senescence in endothelial cells by blocking the activation of NF-kB and MAPKs P38 and ERK. [ABSTRACT FROM AUTHOR]

Liver injury from paracetamol (acetaminophen) (APAP) is common worldwide. To prevent intoxication with a drug with high poisoning, treatment can be made possible with an easily accessible and harmless substance. This study aimed to investigate the hepatoprotective effects of Gossypin (GOS) in mice exposed to an overdose of APAP -the possible mechanism of action. Specifically, serum [alanine aminotransferase (ALT), aspartate transaminase (AST), and hepatic biochemical parameters (glutathione (GSH), malondialdehyde (MDA) and superoxide dismutase (SOD)] were evaluated. Protein and mRNA levels of inflammatory, apoptotic, and cytochrome factors, including TNF-α, IL-1β, IL-6, NFkB, and CYP2E1, were analyzed using real-time PCR. Pretreatment with GOS significantly reduced APAP-induced hepatic injury via oxidative stress. Along with potent antioxidant activity, GOS promoted APAP hepatic detoxification by regulating AST, ALT, GSH, MDA, and SOD activities and mRNA levels of the cytochrome CYP2E1 gene. The anti-inflammatory activity of GOS increases its production. TNF-α, IL-1β and IL-6, through possible NF-kB blockade, are also responsible for its hepatoprotective effect. Taken together, GOS has the potential to be developed as a preventive agent to be administered to patients suffering from APAP overdose. [ABSTRACT FROM AUTHOR]