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Aim Hepatic ischemia reperfusion injury (HIRI) is a leading cause of mortality post liver transplantation, hypovolemic shock and trauma. In this study, we tested, on molecular bases, the possible protective role of two different derivatives of 2-oxindole in a preclinical model of HIRI in rats. HIRI was operated in male Wistar albino rats and prophylactic treatment with oxindole-curcumin (Coxi) or oxindole-vanillin (Voxi) was carried out before the operation. The biochemical and histopathological investigations, in addition to the mechanistic characterizations of the effect of the tested drugs were performed. HIRI was assured with elevated liver enzymes and marked changes in histopathological features, inflammatory response and oxidative stress. Pretreatment with Coxi and Voxi improved the hepatic histopathological alterations, reduced the elevated serum liver enzymes level and hepatic Malondialdehyde (MDA) content, increased the hepatic Superoxide Dismutase (SOD) activity and reduced Glutathione (GSH) content, downregulated the expression of TNF-α, IL-6, Nod-Like Receptor p3 (NLRP3), Cleaved caspase1, Cleaved caspase 3 proteins, alongside the expression level of IL-1β, ICAM-1, VCAM-1 and BAX genes, attenuated NF-кB p-P65 Ser536 and Myeloperoxidase (MPO)-positive neutrophils, and activated the PI3K/AKT pathway. Coxi and Voxi have promising hepatoprotective activity against HIRI in rats through ameliorating the biochemical and histopathological alterations, attenuating inflammatory and oxidative stress status by modulating the inflammatory TNF-α/ICAM-1, the pyroptosis NLRP3/Caspase-1, and the antioxidant PI3K/AKT pathways. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: Osteoarthritis (OA) is a chronic joint disease characterized by osteoproliferation and the degeneration and destruction of articular cartilage. Platelet-rich plasma (PRP) is rich in various growth factors that have been reported to promote bone defect repair. This study examined the specific role and mechanism of PRP in OA. Methods: OA model cells were created by treating articular chondrocytes with IL-1β. After treatment of the model cells with PRP or/and a T-box transcription factor 3 (TBX3)-overexpression plasmid, TBX3 expression was monitored via RT-qPCR, western blotting, and immunofluorescence assays. IL-1β, IL-33, and Caspase-3 levels were detected with ELISA kits. Levels of NLRP3, Caspase-1, MMP9, MMP13, and COL2A1 expression were evaluated by western blotting, and cell proliferation was assessed by the CCK-8 assay. Results: Our results showed that TBX3 expression was upregulated in IL-1β-induced articular chondrocytes. IL-1β stimulation induced inflammation and the production of matrix metalloproteinases, activated Caspase-3 and the NLRP3/Caspase-1 pathway, inhibited the proliferation of articular chondrocytes; however, all those affects mediated by IL-1β could be markedly reversed by PRP. We also found that PRP alleviated IL-1β-induced inflammation, apoptosis, and extracellular matrix degradation in articular chondrocytes by inhibiting TBX3. Our findings suggest that PRP alleviates OA progression in vitro by downregulating TBX3. Conclusion: PRP suppressed OA progression in vitro by inhibiting TBX3, which may be its mechanism of action in treating OA. [ABSTRACT FROM AUTHOR]

Ketamine is an anesthetic drug that is widely used in human and veterinary medicine. In the developmental stage, long-term exposure to ketamine may cause serious side effects. MCC950 and VX765 play protective roles in many disease models by regulating the NLRP3/Caspase-1 pathway. This study aims to explore the potential protective effect of MCC950 and VX765 on ketamine-induced liver injury in neonatal rats and clarify its underlying mechanism. After administration of MCC950 and VX765 in a ketamine-induced liver injury rat model, liver function and inflammatory factors were determined, and immunohistochemistry and western blotting were performed. We found that ketamine caused liver injury in 7-day-old SD rats, decreased liver function indexes, and increased inflammation. MCC950 and VX765 effectively alleviated liver damage and inflammation, and downregulated the expression of proteins such as NLRP3, Caspase-1, and GSDMD-N. In summary, these results indicated that MCC950 and VX765 could have potential protective effects on ketamine-induced liver injury through inhibiting the NLRP3/Caspase-1 pathway. [ABSTRACT FROM AUTHOR]

Xiaojin Feng,1,2 Jialing Hu,1 Fenfang Zhan,1 Deqiang Luo,3 Fuzhou Hua,1,2 Guohai Xu1,2 1Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China; 2Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang, Jiangxi 330006, People’s Republic of China; 3Department of Intensive Care Unit, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of ChinaCorrespondence: Guohai Xu; Fuzhou HuaDepartment of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of ChinaTel +86-791-86299131Email xuguohai1@sina.com; 415134607@qq.comPurpose: Neuroinflammation is an essential causative factor in the pathogenesis and progression of cognitive impairment. The present study aims to evaluate the critical role of microRNA-138-5p (miR-138-5p) in hippocampal neuroinflammation and cognitive impairment through the NLRP3/caspase-1 signaling pathway in rats.Material and Methods: We established the cognitive impairment rat model and RM (Rat microglia) microglial cellular inflammation model by intracerebroventricular (icv) injection or stimulation of lipopolysaccharide (LPS). Morris water maze (MWM) and Y-maze tests were performed to assess the cognitive behaviors. Quantitative real-time polymerase chain reaction (qRT-PCR), Enzyme-linked immune-sorbent assay (ELISA) and Western blot analysis were utilized to evaluate mRNA or protein expression. Bioinformatic analysis and dual-luciferase reporter gene assay were performed to verify the targeting relationship between NLRP3 and miR-138-5p. Besides, Hematoxylin and eosin (H&E) staining and immunohistochemistry were applied to observe the neuronal morphology and detect the positive cells of the hippocampus, respectively.Results: Compared to the control groups, LPS-treated rats exhibited significantly impaired learning and memory in MWM and Y-maze tests. The expression of NLRP3, caspase-1 and pro-inflammation cytokines (IL-1β and IL-18) were upregulated, while miR-138-5p was downregulated both in rat hippocampus and RM cells treated with LPS. MiR-138-5p is downregulated in microarray data of cognitive impairment animals and could directly target the 3ʹ-UTR of NLRP3. Furthermore, upregulation of miR-138-5p improved impaired cognitive functions, while inhibited hippocampal neuroinflammation demonstrated by decreased expression of NLRP3/caspase-1 axis, pro-inflammation cytokines and microglial activation. This study demonstrates for the first time that miR-138-5p suppresses the hippocampal NLRP3/caspase-1 signaling pathway activation in cognition impaired rats.Conclusion: The low expression of miR-138-5p after LPS administration may contribute to the activation of the NLRP3/caspase-1 pathway, leading to hippocampal neuroinflammation and cognitive impairment in rat models. These findings indicate a promising therapeutic avenue for cognitive disorders.Keywords: microRNA-138-5p, NLRP3/caspase-1, neuroinflammation, cognitive impairment, microglial activation

Objectives: Osteoarthritis (OA) is a chronic joint disease characterized by osteoproliferation and the degeneration and destruction of articular cartilage. Platelet-rich plasma (PRP) is rich in various growth factors that have been reported to promote bone defect repair. This study examined the specific role and mechanism of PRP in OA. Methods: OA model cells were created by treating articular chondrocytes with IL-1β. After treatment of the model cells with PRP or/and a T-box transcription factor 3 (TBX3)-overexpression plasmid, TBX3 expression was monitored via RTqPCR, western blotting, and immunofluorescence assays. IL-1β, IL-33, and Caspase-3 levels were detected with ELISA kits. Levels of NLRP3, Caspase-1, MMP9, MMP13, and COL2A1 expression were evaluated by western blotting, and cell proliferation was assessed by the CCK-8 assay. Results: Our results showed that TBX3 expression was upregulated in IL-1β-induced articular chondrocytes. IL-1β stimulation induced inflammation and the production of matrix metalloproteinases, activated Caspase-3 and the NLRP3/Caspase-1 pathway, inhibited the proliferation of articular chondrocytes; however, all those affects mediated by IL-1β could be markedly reversed by PRP. We also found that PRP alleviated IL-1β-induced inflammation, apoptosis, and extracellular matrix degradation in articular chondrocytes by inhibiting TBX3. Our findings suggest that PRP alleviates OA progression in vitro by downregulating TBX3. Conclusion: PRP suppressedOA progression in vitro by inhibiting TBX3, which may be its mechanism of action in treating OA. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?How does miR‐302a‐3p play a role in hypoxia–reoxygenation‐induced pyroptosis of renal tubular epithelial cells?What is the main finding and its importance?Hypoxia–reoxygenation treatment upregulated the expression of miR‐302a‐3p in HK‐2 cells, and then inhibited the transcription of FMRP translational regulator 1 (FMR1), so as to promote the activation of the NLRP3 inflammasome and aggravate the pyroptosis of HK‐2 cells. miR‐302a‐3p was used as a molecular target in this study, which provides a new theoretical basis for the treatment of renal failure. Hypoxia–reoxygenation (H/R) induction can affect miRNA expression and then control NLR family pyrin domain containing 3 (NLRP3) inflammasome‐mediated pyroptosis. This study investigated the mechanism of miR‐302a‐3p in H/R‐induced renal tubular epithelial cell (RTEC) pyroptosis. Human HK‐2 RTECs were induced by H/R. Lactate dehydrogenase content, cell activity and pyroptosis, and levels of NLRP3, GSDMD‐N, caspase‐1, interleukin (IL)‐1β, IL‐18, superoxide dismutase, and malondialdehyde were detected to verify the effect of H/R on HK‐2 cells. The NLRP3 inflammasome action was evaluated after H/R‐induced HK‐2 cells were treated with BAY11‐7082, an inflammasome inhibitor. After inhibiting miR‐302a‐3p expression, the changes of pyroptosis were observed. The binding relation between miR‐302a‐3p and FMRP translational regulator 1 (FMR1) was verified. A function‐rescue experiment verified the role of FMR1 in the regulation of pyroptosis. H/R‐induced HK‐2 cells showed significant pyroptosis injury, and the NLRP3 inflammasome was activated. After inhibiting the NLRP3 inflammasome, H/R‐induced apoptosis was inhibited. After H/R treatment, miR‐302a‐3p in HK‐2 cells was increased, and miR‐302a‐3p downregulation limited H/R‐induced NLRP3 inflammasome‐mediated pyroptosis. FMR1 is the target of miR‐302a‐3p. Inhibition of FMR1 alleviated the inhibition of H/R‐induced HK‐2 cell pyroptosis by miR‐302a‐3p inhibitor. Collectively, inhibiting miR‐302a‐3p can weaken its targeted inhibition on FMR1, thereby inhibiting the activation of NLRP3 inflammasomes and reducing caspase‐1‐dependent pyroptosis in HK‐2 cells. [ABSTRACT FROM AUTHOR]

Ketamine is an anesthetic drug that is widely used in human and veterinary medicine. In the developmental stage, long-term exposure to ketamine may cause serious side effects. MCC950 and VX765 play protective roles in many disease models by regulating the NLRP3/Caspase-1 pathway. This study aims to explore the potential protective effect of MCC950 and VX765 on ketamine-induced liver injury in neonatal rats and clarify its underlying mechanism. After administration of MCC950 and VX765 in a ketamine-induced liver injury rat model, liver function and inflammatory factors were determined, and immunohistochemistry and western blotting were performed. We found that ketamine caused liver injury in 7-day-old SD rats, decreased liver function indexes, and increased inflammation. MCC950 and VX765 effectively alleviated liver damage and inflammation, and downregulated the expression of proteins such as NLRP3, Caspase-1, and GSDMD-N. In summary, these results indicated that MCC950 and VX765 could have potential protective effects on ketamine-induced liver injury through inhibiting the NLRP3/Caspase-1 pathway.

Objective To investigate the effects of Xianfang Huoming decoction on inflammation and oxidative stress levels and the activity of Nod-like receptor protein 3（NLRP3）/cysteine aspartic protease-1（Caspase-1）pathway in synovitis rats. Methods Eighty rat models of balloon synovitis in the back were established by subcutaneous injection of lipopolysaccharide（LPS）. In addition,15 rats were used as the control group（we injected equal volume of sterile equilibrium salt solution into the balloon）. The 75 successfully modeled rats were randomly divided into the model group（intragastric administration of distilled water）,indomethacin group（5 mg/kg,positive control）,low-dose,medium-dose and high-dose Xianfang Huoming decoction groups（crude drug：4. 6,9. 2,and 18. 4 g/kg, with 15 in each group,and meanwhile, the control group was set up（intragastric administration of distilled water；each group was given by gavage,once a day,for 7 consecutive days. At 24 h after the last administration,the amount of exudate from balloon in the back and the number of leukocytes in the lavage fluid were detected；the levels of malondialdehyde（MDA）,catalase（CAT）,superoxide dismutase（SOD）,reduced glutathione（GSH）in lavage fluid,tumor necrosis factor-α（TNF-α）,and interleukin-6 （IL-6）in lavage fluid and serum were detected by enzyme-linked immunosorbent assay（ELISA）；HE staining was used to detect the pathological characteristics of synovium；and the expression levels of TNF-α,IL-6,NLRP3 and Caspase-1 were detected by Western blotting. Results Compared with those in the control group,the amount of air bag exudate,the number of leukocytes in the lavage fluid,levels of MDA and CAT in the lavage fluid,and TNF-α and IL-6 in lavage fluid and serum of rats in the model group were significantly higher（all P<0. 05）,the content of SOD and GSH in lavage fluid was significantly lower（both P<0. 05）,the synovial tissue was seriously proliferated and disordered,and a large number of inflammatory cells infiltrated and aggregated,the expression levels of TNF-α,IL-6,NLRP3, and Caspase-1 in the synovial tissues were significantly higher（all P<0. 05. Compared with those in the model group,the amount of air bag exudate, the number of leukocytes in lavage fluid,levels of MDA and CAT in the lavage fluid,and the expression levels of TNF-α and IL-6 in the lavage fluid and serum of rats in the low-dose,medium-dose and high-dose Xianfang Huoming decoction groups were significantly lower（all P< 0. 05, the content of SOD and GSH in the lavage fluid was significantly higher（both P<0. 05）,the infiltration of inflammatory cells in synovial tissue was gradually alleviated,and the expression levels of TNF-α,IL-6,NLRP3 and Caspase-1 in the synovial tissues were significantly lower,with a dose-dependent manner（ all P<0. 05). There were no significant differences in the above indexes between the indomethacin group and highdose Xianfang Huoming decoction group（all P>0. 05. Conclusion Xianfang Huoming decoction can regulate the oxidative stress factor level in the balloon lavage fluid of synovitis rats,reduce the expression levels of inflammatory factors in the synovial tissues,and alleviate the synovial tissue damage in the synovitis rats,which may be related to the down-regulation of NLRP3/Caspase-1 pathway. [ABSTRACT FROM AUTHOR]

Objective: To observe the effect of electroacupuncture (EA) on the pyrolysis of dopaminergic neurons in rats with Parkinson's disease (PD), so as to explore its underlying molecular mechanism., Methods: Male SD rats were randomly divided into the sham operation, model, EA, MCC950 and EA+MCC950 groups, with 12 rats in each group. The PD rat model was established by two-point injection of 6-OHDA. Rats in the MCC950 group were injected with MCC950 at the dose of 10 mg/kg, once a day; for rats of EA group, EA was applied to "Taichong" (LR3) and "Fengfu"(GV16) for 30 min, once a day; rats in the EA+ MCC950 group were given MCC950 injection and EA once a day. All above interventions were performed for 2 weeks. After the intervention, the behavioral changes of rats were observed using rotating induction experiment, rotating rod experiment and open field experiment; the positive expressions of dopaminergic neuronal markers tyrosine hydroxylase (TH) and α-Synuclein (α-Syn) in substantia nigra striatum were detected by immunohistochemistry; the damage of dopaminergic neurons in substantia nigra striatum was observed after HE staining; immunopositive coexpression of brain nucleotide-binding oligomerization domain like receptor protein 3 (NLRP3), Caspase-1 and ionized calcium binding adapter1 (Iba-1) were detected by immunofluorescence double staining; the levels of interleukin (IL)-1β and IL-18 in brain tissues were detected by ELISA; the protein expression levels of NLRP3, Cleaved Caspase-1 and apoptosis-associated speck-like protein containing a CARD (ASC) in the substantia nigra striatum were detected by Western blot., Results: Compared with the sham operation group, the number of rotations of rotating induction experiment, the residence time in the central area of open field experiment, the positive expression of α-Syn, the positive co-expressions of NLRP3/Iba-1 and Caspase-1/Iba-1, the contents of IL-1β and IL-18 in brain tissues, and the protein expression levels of NLRP3, ASC and Cleaved Caspase-1 in substantia nigra striatum were significantly increased ( P <0.05), while the drop latency of rotating rod experiment, the rearing times and the total distance of open field experiment, and the positive expression of TH in substantia nigra striatum were significantly decreased ( P <0.05) in the model group. Compared with the model group, the above mentioned markers were reversed in EA, MCC950 and EA+MCC950 groups ( P <0.05), and the improvement of the EA+MCC950 group was more obvious than those of the MCC950 and EA groups. In the model group, the neurons were disorderly arranged, the number of neurons was reduced, the cytoplasm was swollen, and some of them were vacuolar degeneration; while the degree of neuronal arrangement disorder, cytoplasmic swelling and the vacuolar degeneration were reduced in varying degrees in the MCC950, EA and EA+MCC950 groups., Conclusion: The ameliorative effect of EA on dopaminergic neuron damage in PD rats may be related to its effects in inhibiting NLRP3/Caspase-1 mediated neuronal pyrosis.

Excessive molybdenum (Mo) and cadmium (Cd) cause toxic effects on animals, but their joint effects on pyroptosis in kidney of ducks remain unclear. 160 healthy 7-day-old ducks were randomly divided into four groups which were fed with basal diet containing different dosages of Mo or/and Cd for 16 weeks. On the 4th, 8th, 12th and 16th weeks, kidney tissue and serum were collected. The results showed that Mo or/and Cd could significantly elevate their contents in kidney, disturb the homeostasis of trace elements, cause renal function impairment and histological abnormality, and oxidative stress as accompanied by increasing hydrogen peroxide (H 2 O 2) and malondialdehyde (MDA) concentrations and decreasing glutathione peroxidase (GSH-Px), catalase (CAT) and total-superoxide dismutase (T-SOD) activities. Simultaneously, Mo or/and Cd could markedly increase interleukin-1β (IL-1β), interleukin-18 (IL-18) contents and the expression levels of pyroptosis-related genes (NOD-like receptor protein-3 (NLRP3), Caspase-1, apoptosis-associated speck-like protein (ASC), NIMA-related kinase 7 (NEK7), Gasdermin A (GSDMA), Gasdermin E (GSDME), IL-1β and IL-18) and proteins (NLRP3, Caspase-1 p20, ASC and Gasdermin D (GSDMD)). Moreover, the changes of above these indicators were more obvious in combined group. Taken together, the results illustrate that Mo and Cd might synergistically lead to oxidative stress and induce pyroptosis via NLRP3/Caspase-1 pathway, whose mechanism is somehow related to Mo and Cd accumulation in duck kidneys. Excess molybdenum (Mo) or/and cadmium (Cd) exposure can cause trace elements imbalance and oxidative stress in duck kidneys, which ultimately lead to histological abnormality, and pyroptosis by NOD-like receptor protein-3 (NLRP3)/Caspase-1 pathway. Moreover, the two metals may have a synergistic effect. [Display omitted] • The joint effects of molybdenum (Mo) and cadmium (Cd) on pyroptosis were assessed in duck kidney. • Mo and Cd disturbed the homeostasis of trace elements. • Mo and Cd caused oxidative stress and damage to kidney. • Mo and Cd caused pyroptosis by NOD-like receptor protein-3 (NLRP3)/Caspase-1 axis. • Mo and Cd exhibited synergic interactions. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of morin-regulated NLRP3/Caspase-1 pathway on experimental autoimmune thyroiditis in rats., Methods: The rats were randomly assigned to 6 groups: control group, experimental autoimmune thyroiditis group (EAT), low-, medium- and high-dose morin groups (post-modeling gavage of 50, 100 and 200 mg/kg morin hydrate per day for 6 weeks) and tripterygium wilfordii polyglycosides group (LGT group, post-modeling gavage of 6.25 mg/kg tripterygium wilfordii polyglycosidesper day for 6 weeks). Except for the control group, the rat model of experimental autoimmune thyroiditis was established by subcutaneous injection of 0.1 mL incomplete Freund's adjuvant containing porcine thyroglobulin. The levels of serum thyroglobulin (TgAb), thyroid peroxidase antibody (TPOAb), triiodothyronine (T3) and tetraiodothyronine (T4) in serum were detected by radioimmunoassay. The mRNA levels of interleukin-17 ( IL -17), interleukin-4 ( IL -4) and interferon γ ( INF - γ ) were detected by reverse transcription-polymerase chain reaction. The levels of serum protein carbonyl content, 8-hydroxydeoxyguanosine (8-OHdG), and malondialdehyde (MDA) activity were checked with test kits. Expressions of NLRP3, apoptosis-related speck-like protein (ASC), and Caspase-1 were detected by Western blot., Results: Compared with the EAT group, serum levels of TPOAb, TgAb, T3, and T4 in low-, medium- and high-dose Morin groups and LGT group were reduced ( P <0.01) and the mRNA levels of IL -17, INF-γ and IL -4 were increased ( P <0.01), the protein hydroxyl content, MDA activity, and 8-OHdG levels were reduced ( P <0.01). The levels of NLRP3, ASC and Caspase-1 were reduced ( P <0.01), the levels of 8-OHdG were significantly reduced ( P <0.01), and the levels of NLRP3, ASC and Caspase-1 were significantly reduced ( P <0.01). There were statistically significant differences between the data from the low-dose and the medium-dose Morin groups and the data of the LGT group ( P <0.05), while data from the high-dose Morin group showed no significant difference compared with the data of the LGT group. Data from low-, medium- and high-dose Morin groups showed no statistically significant differences ( P <0.05)., Conclusion: The findings suggest that Morin improved experimental autoimmune thyroiditis in rats through regulating NLRP3/Caspase-1 pathway., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)