Expression Of NF-κB Research Articles

Chemoprotective Effect of Myrrhone against Diethylnitrosamine and Ferric Nitrile Induced Renal Cancer via Alteration of HO-1/Nrf2 and TRL4/NF-κB Signaling Pathway.

. Following a single dose of intraperitoneal DEN (200 mg/kg) and a twice-weekly administration of Fe-NTA, rats were administered either an oral dose of myrrhone (5, 10, or 15 mg/kg). The body weights and food intake of the rats were monitored at regular intervals, and the levels of renal cancer markers, antioxidants, inflammatory markers, and other parameters were assessed. Additionally, histopathological studies were conducted on the renal tissues, and the mRNA expression of Bax, Bcl-2, HO-1, SOD2, mtDNA, ATP8, PGC-1α, TRL4, and NF-κB was analyzed. . The dosage-dependent administration of myrrhone demonstrated a remarkable suppression of tumor incidence and an improvement in body weight and food intake. Myrrhone markedly decreased the level of ODC, Thymidine [3H] incorporation, and renal parameters such as creatinine, uric acid, BUN, Kim-1, Cysc-C, and LDH. Additionally, myrrhone significantly altered the levels of MDA, GSH, GPx, CAT, and SOD, as well as inflammatory cytokines such as TNF-α, INF-γ, IL-1β, IL-6, and IL-10, and inflammatory parameters such as COX-2, PGE2, TGF-β1, NF-κB, and iNOS. Furthermore, myrrhone significantly decreased the histopathological score and improved the condition of histopathology. Finally, myrrhone significantly altered the mRNA expression of Bax, Bcl-2, HO-1, SOD2, mtDNA, ATP8, PGC-1α, TRL4, and NF-κB. : The result clearly showed the chemoprotective effect of myrrhone against diethylnitrosamine and ferric nitrile induced Renal Cancer via alteration of HO-1/Nrf2 and TRL4/NF-κB Signaling pathway.

Chlorogenic Acid Ameliorates CCl4-induced Liver Fibrosis by Modulating the PI3K/AKT/mTOR Autophagy Pathway.

Liver fibrosis represents a serious risk to global health by impairing quality of life and elevating the chances of hepatocellular carcinoma, while the intricate role of autophagy can either alleviate or worsen fibrosis depending on its functioning. Herein, we aimed to investigate the therapeutic effect of chlorogenic acid in CCl4-induced hepatic fibrosis and explore the autophagy pathway as the possible molecular target of chlorogenic acid. Rats were injected with carbon tetrachloride (1ml/kg) to induce liver fibrosis for 10 weeks. In the current study, the liver fibrosis rats were treated daily with chlorogenic acid (20, 40, and 60 mg/kg) for 30 days. Liver function tests, renal function tests, lipid peroxidation, antioxidant enzyme, anti-inflammatory NF-κB level, and autophagy pathway parameters (PI3K, AKT, mTOR, LC3, and Beclin-1) were assessed. CCl4 elevated serum AST and ALT activity, and hepatic malondialdehyde, PI3K, AKT, and mTOR expressions. It decreased LC3, Beclin-1 expression, and hepatic glutathione level. The results indicated that chlorogenic acid treatment ameliorated the hepatic functions. It declined serum AST and ALT activities, improved hepatic GSH concentration, decreased lipid peroxidation, and downregulated PI3K, AKT, and mTOR protein expressions in hepatic tissue. Moreover, chlorogenic acid increased the hepatic expression of LC3 and Beclin-1. It also significantly decreased NF-kB expression. Chlorogenic acid showed promise in reducing liver damage in rats caused by CCl4 by influencing the autophagy process and adjusting levels of antioxidant and inflammatory markers.

Afobazole alleviates streptozotocin-induced diabetic nephropathy in rats via hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic properties: Role of the S1R/Nrf2 antioxidant axis.

Sigma-1 receptor (S1R) activation was recently identified as a promising target for preventing diabetic nephropathy (DN) by mitigating hypoxia, oxidative stress, and inflammation. This study aimed to investigate the potential reno-protective effect of the S1R agonist afobazole against streptozotocin (STZ)-induced DN in rats compared to metformin. Rats were split into six groups: the normal control group; the diabetic control group received STZ (55mg/kg i.p.); the other four groups received STZ and were treated with different doses of either afobazole (10, 15, and 20mg/kg) or metformin (200mg/kg). Metabolic parameters and renal function were assessed. Expression levels of oxidative stress markers and inflammatory cytokines were measured using ELISA, apoptosis-related proteins were evaluated using immunohistochemistry, and gene expression of S1R, Nrf2, NF-κB, and TLR-4 was determined. Histopathological analysis was performed on kidney tissues. Both afobazole and metformin exerted hypoglycemic effects, alleviating renal injury, reducing blood urea nitrogen (BUN) and serum creatinine, and restoring oxidant/antioxidant balance in diabetic rats. Both treatments boosted renal S1R and Nrf2 levels, suppressed inflammatory proteins and cytokines, and reduced apoptotic features. The study revealed that afobazole provided nephroprotection in STZ-induced DN through a hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic potential mediated by activating the S1R/Nrf2 antioxidant axis. The 15mg/kg dose elicited the most pronounced nephroprotective effects, outperforming other treatment groups.

Methyl 3-Bromo-4,5-dihydroxybenzoate Attenuates Inflammatory Bowel Disease by Regulating TLR/NF-κB Pathways.

Inflammatory bowel disease (IBD) is characterized by uncontrolled, chronic relapsing inflammation in the gastrointestinal tract and has become a global healthcare problem. Here, we aimed to illustrate the anti-inflammatory activity and the underlying mechanism of methyl 3-bromo-4,5-dihydroxybenzoate (MBD), a compound derived from marine organisms, especially in IBD, using a zebrafish model. The results indicated that MBD could inhibit the inflammatory responses induced by CuSO4, tail amputation and LPS in zebrafish. Furthermore, MBD notably inhibited the intestinal migration of immune cells, enhanced the integrity of the gut mucosal barrier and improved intestinal peristalsis function in a zebrafish IBD model induced by trinitro-benzene-sulfonic acid (TNBS). In addition, MBD could inhibit ROS elevation induced by TNBS. Network pharmacology analysis, molecular docking, transcriptomics sequencing and RT-PCR were conducted to investigate the potential mechanism. The results showed that MBD could regulate the TLR/NF-κB pathways by inhibiting the mRNA expression of TNF-α, NF-κB, IL-1, IL-1β, IL6, AP1, IFNγ, IKKβ, MyD88, STAT3, TRAF1, TRAF6, NLRP3, NOD2, TLR3 and TLR4, and promoting the mRNA expression of IL4, IκBα and Bcl-2. In conclusion, these findings indicate that MBD could be a potential candidate for the treatment of IBD.

NF-κB-Specific Suppression in Cardiomyocytes Unveils Aging-Associated Responses in Cardiac Tissue.

Background/Objectives: Aging is associated with structural and functional changes in the heart, including hypertrophy, fibrosis, and impaired contractility. Cellular mechanisms such as senescence, telomere shortening, and DNA damage contribute to these processes. Nuclear factor kappa B (NF-κB) has been implicated in mediating cellular responses in aging tissues, and increased NF-κB expression has been observed in the hearts of aging rodents. Therefore, NF-κB is suspected to play an important regulatory role in the cellular and molecular processes occurring in the heart during aging. This study investigates the in vivo role of NF-κB in aging-related cardiac alterations, focusing on senescence and associated cellular events. Methods: Young and old wild-type (WT) and transgenic male mice with cardiomyocyte-specific NF-κB suppression (3M) were used to assess cardiac function, morphology, senescence markers, lipofuscin deposition, DNA damage, and apoptosis. Results: Kaplan-Meier analysis revealed reduced survival in 3M mice compared to WT. Echocardiography showed evidence of eccentric hypertrophy, and both diastolic and systolic dysfunction in 3M mice. Both aged WT and 3M mice exhibited cardiac hypertrophy, with more pronounced hypertrophic changes in cardiomyocytes from 3M mice. Additionally, cardiac fibrosis, senescence-associated β-galactosidase activity, p21 protein expression, and DNA damage (marked by phosphorylated H2A.X) were elevated in aged WT and both young and aged 3M mice. Conclusions: The suppression of NF-κB in cardiomyocytes leads to pronounced cardiac remodeling, dysfunction, and cellular damage associated with the aging process. These findings suggest that NF-κB plays a critical regulatory role in cardiac aging, influencing both cellular senescence and molecular damage pathways. This has important implications for the development of therapeutic strategies aimed at mitigating age-related cardiovascular diseases.

Esmolol upregulates the α7 nAChR/STAT3/NF-κB pathway by decreasing the ubiquitin and increasing the ChAT+CD4+ T lymphocyte to alleviate inflammation in septic cardiomyopathy.

Esmolol has been demonstrated to mitigate inflammation damage and T lymphocyte apoptosis in septic cardiomyopathy. It has been established that the activation of α7 nicotinic acetylcholine receptor (nAChR) by cluster of differentiation 4(CD4) + T lymphocytes expressing choline acetyltransferase (ChAT) can prevent excessive inflammation and reduce splenocyte apoptosis in septic cardiomyopathy. Given the similar anti-inflammatory effects, we hypothesized that esmolol might be associated with α7 nAChR and thereby exert its cardioprotective functions. In the cecal ligation puncture (CLP)-induced rat septic cardiomyopathy model, esmolol was found to attenuate myocardial injury as evidenced by Hematoxylin and Eosin (HE) staining, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay, and the reduced concentration of interleukin (IL)-1, IL-6, and Tumor Necrosis Factor (TNF)-α detected by enzyme-linked immunosorbent assay (ELISA). Western blotting (WB) revealed that esmolol enhanced the expression of α7 nAChR, elevated the level of Phosphorylated-Signal transducer and activator of transcription 3 (P-STAT3)/STAT3, and decreased the level of Nuclear factor-κB (NF-κB), which led to the reduction of plasma IL-1, IL-6, and TNF-α. Methyl lycaconitine Citrate (MLA, an α7 nAChR inhibitor) suppressed the level of P-STAT3/STAT3, while stattic (a STAT3 inhibitor) inhibited the level of P-STAT3/STAT3 and up-regulated the expression of NF-κB. Real-time quantitative PCR (RT-qPCR) results indicated no significant difference in the mRNA level of α7 nAChR, but immunofluorescence and WB results verified the upregulation of α7 nAChR by esmolol and the reduction of ubiquitin induced by esmolol. In the spleen, esmolol decreased splenocyte apoptosis and increased the expression of α7 nAChR as shown by immunofluorescence. In isolated CD4+ T cells obtained through magnetic cell separation, esmolol enhanced the expression of ChAT mRNA. In conclusion, esmolol upregulates α7 nAChR by decreasing ubiquitin and increasing ChAT+CD4+ T lymphocytes and then increases the P-STAT3/STAT3 which inhibits NF-κB thus alleviating inflammation in septic cardiomyopathy.

Bacillus subtilis MZ-01 alleviates diarrhea caused by ETEC K88 by reducing inflammation and promoting intestinal health.

The purpose of this study was to investigate the effects of Bacillus subtilis supplementation on the health of weaned piglets and whether Bacillus subtilis supplementation can reduce the damage of piglets induced by ETEC K88. The experiment was designed with a 2×2 factorial arrangement, comprising the control (CON) group, Bacillus subtilis (PRO) group, Escherichia coli K88 (ETEC) group, and Bacillus subtilis+ETEC (PRO+ETEC) group. Regardless of the presence of ETEC, the addition of PRO increased the piglets' final body weight (FW), average daily gain (ADG), and daily feed intake (ADFI). Additionally, PRO primarily achieves a reduction in heat-stable enterotoxin (ST) levels, suppresses the expression of NF-κB, TLR4, and MyD88 mRNA in the jejunum and ileum, lowers pro-inflammatory factors in the blood and small intestine, enhances the expression of tight junction proteins in the small intestine, improves the composition of the colonic microbiota, increases colonic short-chain fatty acids (SCFAs) contents, thereby alleviates diarrhea and mitigates bodily damage caused by ETEC K88 infection. The addition of Bacillus subtilis MZ-01 alleviated ETEC K88-induced piglet diarrhoea by reducing heat-stable enterotoxin levels, decreasing pro-inflammatory factors in the blood and intestine, and enhancing the intestinal barrier and tight junction proteins.

Berberine Inhibits the Disruption of the Blood-Brain Barrier and Glial Cell Activation in a Rat Model of Acute Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a complex neurological disorder in individuals with liver diseases, necessitating effective neuroprotective interventions to alleviate its adverse outcomes. Berberine (BBR), a natural compound with well-established anti-fibrotic and neuroprotective properties, has not been extensively studied in the context of glial activation under hyperammonaemic conditions. This study evaluates the neuroprotective potential of BBR in a thioacetamide (TAA)-induced HE rat model, focusing on its effects on glial activation and NLRP3 inflammasome signalling. Neurological impairments were assessed using open field tests and sensory analysis. Western blotting was performed to evaluate the expression of glial and neuronal markers, tight junction proteins and NLRP3 inflammasome components in the cortex and hippocampus. Histopathological and molecular changes were further examined using H&E, immunohistochemistry and immunofluorescence staining. BBR treatment significantly improved behavioural abnormalities and reduced systemic ammonia levels in TAA-exposed rats. It restored blood-brain barrier integrity, as evidenced by reduced tight junction protein degradation. BBR inhibited the expression of NLRP3 inflammasome markers, including caspase-1, IL-1β, ASC, and NF-κB, while reducing glial cell activation (IBA-1 and GFAP). Notably, BBR diminished NLRP3 expression in glial cells, indicating its potent anti-inflammatory effects. Additionally, BBR preserved neuronal integrity, as demonstrated by the maintained expression of MAP-2 and NeuN and reduced cleaved Gasdermin D levels. These findings suggest that BBR alleviates behavioural and molecular abnormalities in HE through NLRP3 inflammasome inhibition, highlighting its potential as a therapeutic agent for managing HE.

Anti-Inflammatory and Anti-Fibrotic Effects of a Mixture of Polyphenols Extracted from "Navelina" Orange in Human Hepa-RG and LX-2 Cells Mediated by Cannabinoid Receptor 2.

Navelina oranges (Citrus sinensis) are rich in phytonutrients and bioactive compounds, especially flavonoids like hesperidin. This study investigates the anti-inflammatory and anti-fibrotic properties of hesperidin (HE) and a polyphenol mixture from Navelina oranges (OE) in human hepatocytes (Hepa-RG) and hepatic stellate cells (LX-2), in order to elucidate the underlying molecular mechanisms. In Hepa-RG cells, HE treatment increased expression of cannabinoid receptor 2 (CB2R), which was associated with down-regulation of p38 mitogen-activated protein kinases (p38 MAPK) but had minimal impact on cyclooxygenase-2 (COX-2) and transforming growth factor-β (TGF-β) levels. Conversely, OE treatment not only enhanced CB2R levels and reduced p38 MAPK, but also promoted a significant reduction in both COX-2 and TGF-β levels, suggesting that OE might be more effective in mitigating inflammatory and fibrotic processes than HE. In LX-2 cells, HE treatment caused a notable decrease in both COX-2 and TGF-β levels, reflecting its efficacy in targeting fibrosis-associated inflammation. OE treatment, on the other hand, reduced Nuclear Factor-Kappa B p65 (NF-κB) expression, a critical transcription factor involved in inflammatory responses, though it did not significantly affect COX-2. LX-2 cells induced to fibrosis with TGF-β and treated with HE and OE showed a reduction in the expression levels of several fibrosis markers. In addition, HE and OE showed antioxidant effects by increasing protein levels of Cu, Zn superoxide dismutase (SOD1), Mn superoxide dismutase (SOD2) and catalase (CAT) and influencing the state of lipid peroxidation. Further research is needed to explore the effects of the treatments in activated hepatic stellate cells and in vivo liver disease models.

Genetic and molecular mechanisms of hydrocephalus.

Hydrocephalus is a neurological condition caused by aberrant circulation and/or obstructed cerebrospinal fluid (CSF) flow after cerebral ventricle abnormal dilatation. In the past 50 years, the diagnosis and treatment of hydrocephalus have remained understudied and underreported, and little progress has been made with respect to prevention or treatment. Further research on the pathogenesis of hydrocephalus is essential for developing new diagnostic, preventive, and therapeutic strategies. Various genetic and molecular abnormalities contribute to the mechanisms of hydrocephalus, including gene deletions or mutations, the activation of cellular inflammatory signaling pathways, alterations in water channel proteins, and disruptions in iron metabolism. Several studies have demonstrated that modulating the expression of key proteins, including TGF-β, VEGF, Wnt, AQP, NF-κB, and NKCC, can significantly influence the onset and progression of hydrocephalus. This review summarizes and discusses key mechanisms that may be involved in the pathogenesis of hydrocephalus at both the genetic and molecular levels. While obstructive hydrocephalus can often be addressed by removing the obstruction, most cases require treatment strategies that involve merely slowing disease progression by correcting CSF circulation patterns. There have been few new research breakthroughs in the prevention and treatment of hydrocephalus.

Effects of Seaweed Polysaccharide on the Growth and Physiological Health of Largemouth Bass, Micropterus salmoides.

A seven-week trial was designed to evaluate the effects of dietary seaweed polysaccharide (SP) supplementation on the growth performance and physiological health of largemouth bass. The results reveal that the 0.05SP group showed the best growth performance. The mRNA expression levels of tor, 4ebp1, and igf1 genes were remarkably down-regulated in the 0.15SP and 0.2SP groups compared to the control group. The CAT activities were significantly increased in the 0.05SP and 0.1SP groups, and the GSH-Px activity was increased in the 0.15SP group. The expression of the immune response-related gene nfκb was significantly down-regulated in the 0.1SP group, and those of tnfα and il-8 were at the maximum in the control group. Moreover, the expression of il-10 in the 0.15SP and 0.2SP groups was significantly down-regulated. Furthermore, endoplasmic reticulum stress (ERS)-related expression of atf6 was the highest in the control group. Furthermore, the chopα and bax expression levels in the 0.15SP and 0.2SP groups were significantly down-regulated compared with other groups. In addition, the highest expression level of bcl-xl was observed in the 0.15SP group. Finally, the quadratic regression analysis of antioxidant, immune, and ERS core parameters (CAT, nf-κb, and bcl-xl) determined 0.06-0.11% to be the optimal SP supplemental level in largemouth bass diets.

Effect of bromelain on ischemia-reperfusion injury in the torsion model created in polycystic and normal ovarian tissues.

Due to its increased volume, polycystic ovarian tissue is more prone to torsion than normal ovarian tissue. In treating ovarian torsion, detorsion is applied to ensure oxygenation of hypoxic tissues. However, the resulting oxygen radicals cause tissue damage. Bromelain is a substance obtained from pineapple, and studies in the literature show it is used as an antioxidant. This study aimed to evaluate the damage caused by ischemia-reperfusion (I/R) in the torsion-detorsion model created in normal and polycystic ovarian tissue and investigate the role of bromelain in this damage. Polycystic ovarian tissue was created by applying dihydroepiandrosterone sulfate to rats. Afterward, a torsion-detorsion model was used for all rats. The rats were divided into six groups: the polycystic ovary sham-operated group (P-S), the normal ovary sham-operated group (N-S), the polycystic ovary ischemia/reperfusion group (P-IR), the normal ovary ischemia/reperfusion group (N-IR), the polycystic ovary ischemia/reperfusion group treated with bromelain (P-IRB), and the normal ovary ischemia/reperfusion group treated with bromelain (N-IRB). After the procedure, tissues were collected for histopathological examination, and MDA, TUNEL, and NF-κB levels were measured. This study detected significant decreases in MDA and NF-κB levels and apoptotic cell numbers assessed by TUNEL staining in groups with IR damage and given bromelain compared to the control groups. The number of TUNEL-positive cells was found to be highest in the P-IR group (8.80 ± 2.98) and significantly lower in the bromelain-administered P-IRB (1.04 ± 1.09) and N-IRB (0.52 ± 0.58) groups (p< 0.05). NF-κB expression was also high in P-IR and N-IR groups, while it was significantly decreased in bromelain-treated groups (P-IRB and N-IRB) (p< 0.05). In addition, IR damage was more pronounced in polycystic ovary tissue than in normal ovary tissue. Ischemia perfusion damage may be more pronounced in polycystic ovarian tissue than in normal ovarian tissue. Bromelain may be preferred to prevent I/R injury caused by ovarian torsion. It is also thought that bromelain may function in treating polycystic ovaries, and further studies can be conducted on this subject.

Lipid Coating Modulates Effects of Nanoceria on Oxidative Metabolism in Human Embryonic Lung Fibroblasts: A Case of Cardiolipin.

The unique redox properties of nanoscale cerium dioxide determine its diverse application in biology and medicine as a regulator of oxidative metabolism. Lipid modifiers of the nanoparticle surface change their biochemical properties and bioavailability. Complexes with lipids can be formed upon contact of the nanoparticles with the membrane. The effects of lipid coating on nanoceria have not been studied yet. Here, we assessed the effect of bare and cardiolipin-coated CeO2 on the expression of oxidative metabolism genes in human embryonic lung fibroblasts. Cell viability, mitochondrial activity, intracellular reactive oxygen species, NOX4, NRF2, and NF-κB expression, oxidative DNA damage/repair, autophagy, and cell proliferation were studied. We used an MTT assay, fluorescence microscopy, real-time reverse transcription polymerase chain reaction, and flow cytometry. At a concentration of 1.5 μM, bare and cardiolipin-coated nanoceria penetrated into cells within 1-3 h. Cell survival, mitochondrial activity, and the proliferative effect were similar for bare and cardiolipin-coated nanoceria. Intracellular ROS, activation of NOX4, NRF2, and NF-kB, DNA oxidative damage, and DNA break/repair were different. Cardiolipin-coated nanoceria induced intracellular oxidative stress and short-term activation of these genes and DNA damage/break/repair. Unlike bare nanoceria, cardiolipin-coated nanoceria induced autophagy. Thus, the effects of cardiolipin-coated nanoceria are determined by both the nanoceria itself and cardiolipin. Presumably, the differences in properties are due to lipid peroxidation of cardiolipin. This effect needs to be taken into account when developing nanoceria-based drugs targeting mitochondria.

Ferulic acid mediates microbial fermentation of arabinoxylan to enhance host immunity by suppressing TLR4/NF-κB signaling.

The study was conducted to explore the relationship between arabinoxylan (AX) structure and microbial fermentation characteristics, and reveal molecular mechanism of AX on regulating immune function of the host. Results indicated that the group of wheat bran AX showed greater activity of feruloyl esterase, production of short chain fatty acids and ferulic acid compared with the blank group (P < 0.05). The AX increased sIgA concentration and protein expression of protein expression of TLR4 and NF-κB (p65), but decreased mRNA expression of pro-inflammatory cytokines in the ileum of weaned pig model, leading to the reduced diarrhea (P < 0.05). The AX increased an abundance of Bifidobacterium pseudocatenulatum, production of butyric acid and ferulic acid in the ileal digesta of pigs (P < 0.05). In a LPS-treated mouse model, butyric acid and ferulic acid combination increased IL-10 concentration and abundance of Bifidobacterium pseudocatenulatum, but reduced mRNA expression of IL-6 and gene expression of TLR4 and NF-κB (p65) in the jejunum. In summary, AX is fermented by gut microbiota to produce ferulic acid, as well as butyric acid, which improved host immunity by promoting relative abundance of Bifidobacterium pseudocatenulatum and suppressing activation of TLR4/NF-κB signaling.

Combination of inorganic nitrate and vitamin C prevents collagen-induced arthritis in rats by inhibiting pyroptosis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by synovial inflammation, cartilage damage, and bone loss. Although effective treatments are currently lacking, early interventions hold promise for alleviating RA symptoms. Inorganic nitrates and vitamin C (VC) are essential bioactive substances abundant in fruits and vegetables. Notably, nitrates and VC exhibit synergistic effects in a series of physiological and pathological conditions. In this study, we aim to examine the combination of nitrate and VC for preventing RA in a collagen-induced arthritis (CIA) rat model. Nitrate partly reduced foot swelling and arthritis scores and was more effective when combined with VC. Histopathological and radiological analyses revealed that nitrate + VC treatment alleviated synovial hyperplasia and bone loss. Additionally, nitrate + VC lowered the levels of TNF-α and IL-1β in serum as well as synovial tissue, decreased the expression of NF-κB and reduced the number of macrophages in synovial tissue. Compared to the CIA group, nitrate + VC decreased the levels of NLRP3 and GSDMD in macrophages, thus inhibiting pyroptosis. According to in vitro experiments, nitrate inhibited the activation of the NLRP3/caspase-1/GSDMD pathway in macrophages by conversion into nitrite. VC reduced the expression and phosphorylation of NF-κB in macrophages and thus reduced the expression levels of TNF-α and IL-1β. Therefore, nitrate/nitrite and VC may exert synergistic effects by blocking the interaction between NF-κB and NLRP3, further alleviating the inflammation and pyroptosis of macrophages, which provides a new strategy for RA prevention.

Pink1/Parkin signaling mediates pineal mitochondrial autophagy dysfunction and its biological role in a comorbid rat model of depression and insomnia

Using a chronic unpredictable mild stress (CUMS) combined with multi-platform water environment sleep deprivation (SD) as an animal model, the occurrence and development of human depression combined with insomnia were simulated. The abnormal mitochondrial autophagy signaling caused by the putative kinase 1/Parkin E3 ubiquitin protein ligase (Pink1/Parkin) signaling pathway directly affects the normal secretion of melatonin by the pineal gland, which may explain the pathogenesis of depression combined with insomnia. This study aims to explore the depression-like behavior, sleep changes, central oxidative stress response, pineal mitochondrial autophagy damage, melatonin secretion, histopathological changes of the pineal gland, and the expression of Pink1/Parkin signaling-related factors in CUMS+SD rats. The results showed that the levels of reactive oxygen species (ROS) in cerebrospinal fluid of CUMS+SD rats significantly increased along with the inflammatory factors Interleukin-1β (IL-1β) and nuclear factor kappa-B (NF-κB) in cerebrospinal fluid. In addition, the number of pineal gland cells significantly decreased, cell boundaries became blurred, cell volume shrank, and apoptotic bodies appeared in the pineal gland tissue under HE staining, indicating pineal gland inflammation. Sleep deprivation further disrupted the levels of autophagy damage factors, including histamine (MDA), glutathione (GSH), and catalase (CAT), in the cerebrospinal fluid of CUMS + SD rats. Transmission electron microscopy of the pineal gland in CUMS+SD rats revealed damage to mitochondrial autophagy. The levels of 5-hydroxytryptamine (5-HT) and aromatic amine-N-acetyltransferase (AANAT) in the cerebrospinal fluid, as well as melatonin levels in the pineal gland, were significantly decreased. Additionally, the expression of IL-1β, NF-κB, Pink1, and Parkin in the pineal gland of CUMS+SD rats significantly increased. The expression of microtubule-associated protein 1 light chain 3-β (LC3), selective autophagy adaptor protein (P62), cytochrome c oxidase IV (COXIV), and mitochondrial outer membrane translocation enzyme 20 (TOM20) proteins downstream of the Pink1/Parkin signaling pathway was enhanced, while the expression of downstream brain-derived neurotrophic factor (BDNF), Beclin 1, and BCL2 interacting protein 3 (BNIP3) proteins was negatively regulated. Pink1/Parkin signaling may specifically respond to mitochondrial autophagy damage in the pineal gland, affecting the normal synthesis and secretion of melatonin in the pineal gland. In summary, mitochondrial autophagy damage in the pineal gland affects the normal secretion of melatonin in CUMS+SD rats, which is closely related to the specific autophagy signaling impairment of Pink1/Parkin pathway, which may mediate the occurrence of depression combined with insomnia.

Identification of Key Chondrocyte Apoptosis-Related Genes in Osteoarthritis Based on Weighted Gene Co-Expression Network Analysis and Experimental Verification.

Osteoarthritis (OA) is the primary cause of disability worldwide. Chondrocyte apoptosis has important implications for OA onset and progression. This work was designed to explore the mechanisms of chondrocyte apoptosis in OA and identify key chondrocyte apoptosis-related genes (CARGs). GSE32317 and GSE55235 datasets were acquired from the Gene Expression Omnibus (GEO) database. OA-associated module genes were determined via weighted gene co-expression network analysis (WGCNA) in GSE32317. CARGs were acquired from public databases. ClusterProfiler was employed for GO and KEGG analyses. Protein-protein interaction (PPI) network establishment was realized via the STRING database and Cytoscape, and the hub genes were screened by MCC, MNC, and DMNC algorithms of cyto-Hubba. The diagnostic values of the hub CARGs in OA in GSE55235 were verified via receiver operating characteristic (ROC) curve analysis. C28/I2 cells were stimulated with IL-1Β to establish the in vitro OA model. WGCNA identified 9,141 OA-related genes and 248 CARGs, resulting in 75 CARGs in OA. GO and KEGG analyses demonstrated that the 75 CARGs were primarily enriched in response to lipopolysaccharide, transcription regulator complex, and DNA-binding transcription factor binding, along with NF-kappa B and TNF signaling pathways. NFKB1 and ICAM1 were identified as the hub CARGs in OA through the three algorithms, which showed favorable prognostic values for OA. Notably, both bioinformatics analysis and in vitro assays revealed upregulated NFKB1 and ICAM1 expression in OA. NFKB1 and ICAM1 were the hub CARGs in OA, and might serve as diagnostic signatures and therapeutic targets for OA therapy.

Combined injection of pristane and Bacillus Calmette-Guerin Vaccine successfully establishes a lupus model with atherosclerosis.

Cardiovascular disease (CVD) induced by atherosclerosis (AS) is the main fatal complication of systemic lupus erythematosus (SLE). Establishing an appropriate animal model of SLE with AS is of great value for investigating the pathogenesis and therapeutic targets of SLE-CVD. In the present work, pristane was injected intraperitoneally into C57BL/6J mice to establish the SLE model and Bacillus Calmette-Guerin Vaccine (BCG) was injected intradermally one month later to enhance immunity and induce AS. Both pristane or pristane and BCG treated C57BL/6J mice exhibit a classical lupus-like phenotype which manifested as proteinuria and high levels of serum anti-ANA and anti-dsDNA autoantibodies, in conjunction with pathological changes in spleen and kidney, complement C3 deposition in the kidney, overactivation of T and B cells, a decreased proportion of splenic CD19+ B cells, and an increased frequency of CD19-CD138+ plasma cells, CD19+CD27+ memory B cells, CD3+CD4+ helper T (Th) cells, and CD3+CD4+CXCR5+PD-1+ T follicular helper cells. The combined pristane and BCG challenge aggravated AS in SLE mice, which had an enlarged thymus gland, an increased T cell proliferative vitality, an expanded Th cell pool, severe perivascular lymphocytes, and CD68+ macrophage infiltration, in addition to an intimal lipid deposition, and further elevation of Toll-like receptor 2 (TLR2), TLR4, and the transcription factor nuclear factor-κB (NF-κB) expression in kidney tissue and blood vessels when comparing with pristane or BCG injection alone. Pristane combined BCG challenge is able to establish a validated SLE-AS mouse model in C57BL/6J mice.

Effects of Cordyceps cicadae Polysaccharide on Gut Microbiota, the Intestinal Mucosal Barrier, and Inflammation in Diabetic Mice.

Background: Polysaccharides produced by the edible fungus Cordyceps cicadae can regulate blood sugar levels and may represent a suitable candidate for the treatment of diabetes and its complications. However, there is limited information available about the mechanism of how C. cicadae polysaccharide (CCP) might improve diabetic conditions. Methods: This study investigated its effects on the intestinal microbiota, intestinal mucosal barrier, and inflammation in mice with type 2 diabetes mellitus (T2DM) induced by streptozotocin, and its potential mechanisms. Results: Compared with the DC (diabetes model control group), CCPH oral treatment significantly increased the number of beneficial bifidobacteria, bifidobacteria, and lactobacilli (p < 0.01), restored the diversity of intestinal microorganisms in diabetic mice, and the proportions of Firmicutes and Bacteroidetes (34.36%/54.65%) were significantly lower than those of the DC (52.15%/32.09%). Moreover, CCPH significantly reduced the content of endotoxin (lipopolysaccharide, LPS) and D-lactic acid(D-LA) (p < 0.05), the activities of antioxidant enzymes and total antioxidant capacity were significantly increased (p < 0.01), and the content of proinflammatory cytokines TNF-α, IL-6, and IL-1β were reduced by 42.05%, 51.28%, and 52.79%, respectively, compared with the DC. The TLR4/NF-κB signaling pathway, as a therapeutic target for diabetic intestinal diseases, plays a role in regulating the inflammatory response and protecting the intestinal barrier function. Molecular mechanism studies showed that oral treatment with CCPH down-regulated the expression of NF-κB, TLR-4, and TNF-α genes by 18.66%, 21.58%, and 34.87%, respectively, while up-regulating the expression of ZO-1 and occludin genes by 32.70% and 25.11%, respectively. CCPH regulates the expression of short-chain fatty acid levels, increases microbial diversity, and ameliorates mouse colon lesions by inhibiting the TLR4/NF-κB signaling pathway. Conclusions: In conclusion, it is demonstrated that in this murine model, the treatment of diabetes with C. cicadae polysaccharide can effectively regulate intestinal microbiota imbalance, protect intestinal mucosal barrier function, and reduce inflammation in vivo, suggesting this natural product can provide a suitable strategy for the treatment of T2D-induced gut dysbiosis and intestinal health.

NMDA receptors antagonists alleviated the acute phase of traumatic brain injury.

Traumatic brain injury (TBI) is a significant cause of mortality and disability worldwide. TBI has been associated with factors such as oxidative stress, neuroinflammation, and apoptosis, which are believed to be mediated by the N-methyl-D-aspartate (NMDA)-type glutamate receptor. Two NMDA receptor antagonists, ketamine and memantine, have shown potential in mitigating the pathophysiological effects of TBI. To conduct the study, a controlled cortical impact model was used to induce TBI in rats. The rats with TBI were then divided into three groups: a group receiving only TBI, a group receiving TBI along with memantine, and a group receiving TBI along with ketamine. After 24 hr, the levels of oxidative stress markers (such as SOD, MDA, and total thiol) in the brain tissue were measured. Immunohistochemical staining was also performed seven days after TBI to assess the activation of glial cells and the TLR-4/NF-κB neuroinflammatory pathway. The results indicated that treatment with memantine led to a reduction in MDA levels and an increase in SOD and total thiol levels. Memantine also decreased astrogliosis and down-regulated the TLR-4/NF-κB pathway. On the other hand, ketamine increased the levels of anti-oxidant markers but did not significantly affect the MDA level. Additionally, ketamine decreased the expression of NF-κB seven days after TBI. The findings suggest that NMDA receptor antagonists, such as ketamine and memantine, may have therapeutic effects on TBI by inhibiting oxidative stress and inflammatory responses.