IL-6 In Rats Research Articles

Trelagliptin relieved cognitive impairment of diabetes mellitus rats: Involvement of PI3K/Akt/GSK-3β and inflammation pathway

Cognitive impairment frequently coexists with diabetes. Trelagliptin is a once-weekly taking selective dipeptidyl peptidase-4 (DPP-4) inhibitor and a long-term effective hypoglycemic medicine; nonetheless, its effects for the treatment of diabetes-related cognitive impairment have only sometimes been explored. In this study, a DM model was built using streptozotocin (STZ) and a high-fat diet (HFD). The morris water maze test on DM rats revealed a considerably reduced capacity for spatial learning and memory, but trelagliptin was able to restore function. Trelagliptin could lower the mRNA expression of inflammatory factors such IL-1β, TNF-α, and IL-6 in DM rats. It could also reduce the ratio of p-IKKα/IKKα, and the immunofluorescence result of NF-κB also demonstrated a drop. Trelagliptin partially restored dendritic spines and prevented the loss or shrinkage of neurons, respectively, according to the results of Nissl's staining and golgi staining. Furthermore, PI3K/Akt/GSK-3β has been activated, and synaptic plasticity has been modified during this process. In conclusion, trelagliptin improved the cognitive lesion in DM rats by suppressing the activation of the inflammatory route and by activating the PI3K/Akt/GSK-3β pathway at the same time, as well as interacting with the pathways that protect neurons, which still need further research.

The regulatory effect of Angelicae Sinensis Radix on neuroendocrine-immune network and sphingolipid metabolism in CUMS-induced model of depression

Ethnopharmacological relevanceConventional antidepressants therapy remains unsatisfactory due to the disadvantages of delayed clinical onset of action and side effects. Traditional Chinese Medicine (TCM) with good efficacy and higher safety have received much attention. Angelicae Sinensis Radix (AS), a well-known TCM, has been proved to exhibit the efficacy of antidepression recently. Aim of the studyThe purpose of this study was to investigate the potential anti-depressant mechanisms of AS based on chronic unpredictable mild stress (CUMS) rat model. Materials and methodsIn this study, behavioral experiments, molecular biology techniques, and ultra performance liquid chromatography-triple-time of flight mass spectrometer (UPLC-Triple-TOF/MS) were combined to explore the potential antidepressant mechanisms of AS based on CUMS rat model. ResultsThe results demonstrated that AS could reduce the contents of serum hypothalamic-pituitary-adrenal (HPA) axis hormones in CUMS rats, including corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol (CORT). In addition, AS regulated the percentage of CD4+ T lymphocytes, the ratio of CD4+/CD8+, and the levels of serum cytokines such as IL-1β, IL-4, IL-6, and TNF-α in CUMS rats. Lipidomics showed that 31 lipids were related to depression and AS could regulate the lipid metabolism alteration induced by CUMS, particularly sphingolipid metabolism. Finally, the key proteins in sphingolipid metabolic pathways in hippocampus of CUMS rats could be back-regulated by AS, including serine palmitoyl transferase (SPTLC2), ceramide synthase (CerS2), sphingomyelinase (SPHK1), and neutral sphingomyelinase (nSMase). ConclusionAS could alleviate NEI network disorder and restore the levels of sphingolipid metabolites and key proteins in CUMS rats. The underlying mechanism by which AS relieved depression-like behavior in CUMS rats may be through modulation of NEI and disturbances in sphingolipid metabolism.

Modulation of PPAR-γ, SREBP-1c and inflammatory mediators by luteolin ameliorates β-cell dysfunction and renal damage in a rat model of type-2 diabetes mellitus.

Natural products have been recommended as a complementary therapy for type 2 diabetes mellitus (T2DM) due to constraints of safety and tolerability of existing anti-diabetic agents. Luteolin exhibits anti-diabetic and anti-inflammatory effects. Hence, the impact of luteolin on glucose homoeostasis and organ damage was investigated in high-fat diet (HFD) and streptozotocin (STZ) induced T2DM in rats. Male Wistar rats were maintained on HFD (provided 55% energy as fat) for 10days. Subsequently, a single dose of 40mg/kg STZ was injected intraperitoneally on the 11th day. Seventy-two hours after STZ administration, diabetic rats with established hyperglycemia (fasting serum glucose > 200mg/dL) were randomized into different groups having six rats each and orally administered either 0.5% hydroxy propyl cellulose or pioglitazone (10mg/kg) or luteolin (50mg/kg or 100mg/kg) once daily for 28days, while continuing HFD for respective groups. Luteolin significantly reduced hyperglycaemia, homoeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) levels, and improved hypoinsulinemia and HOMA of b-cell function (HOMA-B) in a dose-dependent manner. Increased TNF-α, IL-6 and NFκB levels in diabetic rats were significantly regulated. Additionally, luteolin significantly augmented PPAR-γ expression while attenuating sterol regulatory element binding protein-1c (SREBP-1c) expression. Histopathological scrutiny validated that luteolin effectively attenuated HFD-STZ-induced injury in pancreatic β-cells and kidneys to near normalcy. Our study showed that luteolin ameliorated hyperglycemia and improved hypoinsulinemia, β-cell dysfunction, and renal impairment in HFD-STZ-induced diabetic rats by attenuating inflammation and dysregulated cytokine secretion through modulation of PPAR-γ, TNF-α, IL-6 and NF-kB expression and down-regulation of SREBP-1c.

Fucoidan from Ericaria crinita Alleviates Inflammation in Rat Paw Edema, Downregulates Pro-Inflammatory Cytokine Levels, and Shows Antioxidant Activity.

Fucoidans are sulfated polysaccharides detected mainly in the cell walls of brown seaweeds. Here, we examined the effects of single doses of fucoidan derived from Ericaria crinita (formerly Cystoseira crinita) on carrageenan-induced paw inflammation in rats. The serum levels of TNF-α, IL-1β, IL-6, and IL-10 of rats with LPS-induced systemic inflammation after 14 days of treatment were also evaluated. Subchronic treatment with fucoidan from E. crinita attenuated the inflammation during the late phase of the degraded carrageenan-induced paw edema (3rd to 5th hour after carrageenan injection) with peak activity at the 3rd hour after the application. Both doses of fucoidan from E. crinita (25 and 50 mg/kg bw) significantly decreased the levels of all tested pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) in the serum of rats with a model of system inflammation but had no effect on the anti-inflammatory cytokine IL-10. The results showed that the repeated application of fucoidan has a more prominent effect on the levels of some pro-inflammatory cytokines in serum in comparison to a single dose of the sulfated polysaccharide. This reveals the potential of E. crinita fucoidan as an anti-inflammatory agent. Furthermore, E. crinita fucoidan exhibited in vitro antioxidant capacity, determined by 2,2-diphenyl-1-picryl-hydrazyl radical scavenging and ferric reducing antioxidant power assays as follows: IC50 = 412 µg/mL and 118.72 μM Trolox equivalent/g, respectively.

The Effect of Coconut Water on Decreasing MDA and IL-6 Levels in Male Wistar Rats Induced with High-Fat Diet

Dyslipidemia is a condition in which there are abnormal levels of lipids in the blood, including increased levels of cholesterol, LDL (Low-Density Lipoprotein), and triglyceride levels, as well as decreased HDL levels (High-Density Lipoprotein) which causes oxidative stress. Oxidative stress results in tissue damage which triggers an inflammatory reaction that releases proinflammatory cytokines such asInterleukin-6 (IL-6) which increases in blood endothelial cells and triggers Malondialdehyde (MDA) which increases as a result presence of lipid oxidation in tissues. This condition can be neutralized by consuming antioxidants from outside the body such as young coconut water. This research aims to know the effect of giving young coconut water on the rate of MDA and IL-6 in male Wistar rats who are given a high-fat diet. The research method is a posttest-only control group design. The subjects of the study were 24 male Wistar rats which were randomly divided into 4 groups. Group K1 was given standard feed and distilled water. Group K2 was given a high-fat diet without coconut water. Groups K3 and K4 were given a highfat diet and young coconut water at doses of 4mL/200gBW/day and 8mL/200gBW/day, respectively. The study was conducted for 29 days by taking blood to check MDA levels using the TBARS and IL-6 methods using the ELISA method. The lowest average of MDA level was in the K3 group (0.071 ng/L) and the lowest average of IL-6 level was in the K4 group (4.377 ppm). Kruskal Wallis test result showed the p-value of MDA was 0.004 ppm and at IL-6 levels was 0.020 ng/L. Differences in MDA levels between groups K1-K2 (0.004), K2-K3 (0.004), and -K4 (0.004). Differences in IL-6 levels between groups K2-K3 (0.016), K2-K4 (0.004). The administration of coconut water can significantly reduce the levels of MDA and IL-6 in male Wistar rats induced with a high-fat diet.

Houttuynia cordata Thunb repairs steroid-induced avascular necrosis of the femoral head through regulating NF-κB signaling pathway

To investigate the influences of Houttuynia cordata Thunb (HCT) in steroid-induced avascular necrosis of the femoral head (SANFH), we conducted a comprehensive study evaluating the effects of HCT on various aspects. Cell Counting Kit-8 assay was used to examine bone marrow stem cells (BMSCs) cell viability. Flow cytometry and lactate dehydrogenase detection assay were conducted to determine cell apoptosis. The levels of apoptosis-related proteins, osteogenic-related markers, inflammatory factors, and nuclear factor kappa B (NF-κB) pathway-associated proteins were determined via western blotting. Hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick-end labeling assays were utilized to verify the effects of HCT in SANFH rats. Our findings revealed that HCT could enhanced cell viability and arrested cell apoptosis in dexamethasone (Dex)-treated BMSCs. Dex increased the levels of cleaved caspase-3, Bcl2-associated X, interleukin (IL)-1β, IL-18, IL-6, p65, and inhibitor of NF-κB kinase β (IKKβ), while this promoting trend was weakened by HCT. Moreover, pyrrolidine dithiocarbamate (PDTC, an inhibitor of NF-κB signaling pathway) further increased the inhibitory role of apoptosis and the levels of IL-1β, IL-18, and IL-6 and the promotional effect of the levels of RUNX2 and ALP in Dex-treated BMSCs. The in-vivo assays showed that HCT decreased the percentage of empty lacunae, apoptosis, and the levels of IL-1β, IL-18, IL-6, p65, and IKKβ in SANFH rats. In conclusion, our study demonstrated that HCT relieved SANFH, which might be possibly achieved by NF-κB pathway.

Effect of Plant Extracts Combinations on TNF-α, IL-6 and IL-10 Levels in Serum of Rats Exposed to Acute and Chronic Stress.

Oxydative stress, anxiety and depression are associated with changes in cytokine levels. Natural products, including individual and combined plant extracts, have the potential to be used in the treatment of neuropsychiatric disorders. The goal of this study is to investigate the effects of two combined plant extracts, rich in flavonoids, on the levels of the cytokines TNF-α, IL-6, and IL-10 in rats subjected to models of acute cold stress and chronic unpredictable stress. The study utilized common medicinal plants such as Valeriana officinalis, Melissa officinalis, Crataegus monogyna, Hypericum perforatum, and Serratula coronata, which were combined in two unique combinations-Antistress I and Antistress II. The compositions of the used extracts were determined by HPLC methods. Pro- and anti-inflammatory cytokines in rats' serum were measured with Enzyme-linked immunosorbent assay. The results from the acute stress model revealed that the individual extract of Crataegus monogyna decreased levels of TNF-α, while Serratula coronata, Hypericum perforatum, and Valeriana officinalis effectively reduced IL-6 levels. Both combinations, Antistress I and Antistress II, were effective in reducing TNF-α and IL-6 levels, with Antistress II also increasing IL-10 levels. In the chronic stress model, Hypericum perforatum extract decreased the levels of the pro-inflammatory cytokines TNF-α and IL-6, whereas extracts of Serratula coronata and Valeriana officinalis only reduced TNF-α levels. The two combined extracts, Antistress I and Antistress II, decreased TNF-α and IL-6 levels, while Antistress I also reduced the levels of the anti-inflammatory cytokine IL-10. The combinations of plant extracts used in our experiment have not been previously studied or documented in the available literature. However, based on our own experimental results, we can draw the conclusion that the combinations exhibit a more pronounced effect in reducing cytokine levels compared to the individual plant extracts.

Effect of zinc and probiotics supplementation on IL-6 and tissue neutrophil levels in rats exposed to cigarette smoke

Introduction: Cigarette smoke exposure can cause inflammation, inducing the release of acute phase cytokines, such as IL-6, that will then trigger the recruitment of neutrophils, which are mostly phagocytic cells. Zinc and probiotics are known to have beneficial effects against inflammation. This study was conducted to investigate the effect of zinc and probiotics supplementation on IL-6 and tissue neutrophil levels in rats exposed to cigarette smoke. Methods: In a randomised, experimental study with post-test control group design, thirty 2 to 3-month-old male Wistar rats, each weighing 180-220 g, were divided into five groups: control group without treatment (C); exposed to cigarette smoke [C (-)]; exposed to cigarette smoke and received zinc (Z); exposed to cigarette smoke and received probiotics (P); and exposed to cigarette smoke and received a combination of zinc and probiotics (ZP). Results: Mean tissue neutrophil levels in Z, P, and ZP groups were 43.43±2.01, 34.67±1.32, and 29.77±5.05 cells, respectively. There were significant differences between supplementation intake and tissue neutrophil levels in each group compared to C (-) group (p<0.05). Meanwhile, only IL-6 level in the ZP group (6.02 pg/mL) decreased significantly compared to C (-) group (10.61 pg/mL). Conclusion: These results suggest that a combination of zinc and probiotics have an anti-inflammatory effect as measured by IL-6 and neutrophil levels.

The Effect of secretome-hypoxia mesenchymal-stem-cells and vitamin-d3 in type-2 diabetes-mellitus induced periodontitis rats

Background: A systemic metabolic disorder by insulin resistance, type-2 diabetes mellitus (T2DM), is characterised by an increased level of reactive oxygen species (ROS) and decreased superoxide dismutase (SOD), which is associated with the activation of proinflammatory cytokine pathways such as tumor necrosis (TNF)-α. This condition usually stimulates inflammation of the periodontal tissue (periodontitis). Vitamin-D3 can inhibit the release of inflammatory mediator and reduce the risk of chronic periodontitis. Purpose this study to determine the effect of the secretome-hypoxia mesenchymal-stem-cells (SH-MSCs)-Vitamin-D3 combination on the expression of SOD, IL-10, and TNF-α genes in T2DM periodontitis-induced rats.
 Method: 30 rats were randomly divided into five groups; normal sham condition, positive control, SH-MSCs group, vitamin-D3 group, and combination of SH-MSCs and vitamin D3 group. SH-MSCs were injected at doses of 150 uL in the gingival. In addition, vitamin D3 5000 IU 2.25 mcg were administrated orally. After 35 days, all rats were sacrificed, and qRT-PCR from gingival tissue was performed to identify the expression of SOD, IL-10 and TNF-α genes 
 Results: The results a significant increase in SOD and IL-10 gene expression (p

Water extracts of Tibetan medicine Wuweiganlu attenuates experimental arthritis via inducing macrophage polarization towards the M2 type

Ethnopharmacological relevanceWuweiganlu (WGL) is a well-known formulation described in the “Four Medical Scriptures of Tibetan medicine”, which is mainly used for the treatment of Rheumatoid Arthritis (RA) and other chronic ailments prescribed by Tibetan medicine. Nonetheless, the active constituents present in the water extracts of Wuweiganlu (WGLWE) specifically targeting arthritis treatment are largely unknown. Aim of the studyThe aim of this study is to explore the effects and underlying mechanisms of the active components in WGLWE on RA. Materials and methodsWe utilized ultra-performance liquid chromatography coupled with Q-TOF mass spectrometry (UPLC-Q-TOF-MS) to identify the main chemical compositions of WGLWE. The polarization effect of WGLWE on bone marrow-derived macrophages (BMDM) was determined. A rat model of collagen-induced arthritis (CIA) was established by injecting an emulsion of bovine type II collagen mixed with an equal volume of incomplete Freund's adjuvant into the tail, paw and back of rats. A WGLWE-based ointment was topically applied to the legs and paws of the rats for 30 days. The rats' ankles were photographed to measure the degree of swelling. Micro-CT was used to image the knee joint and paw of rats, and the bone mineral density (BMD) and bone volume fraction (BV/TV) of knee joint in rats were analyzed. High-frequency ultrasound imaging of the rat knee joint was performed to observe knee joint effusion. Further, the serum levels of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), IL-10, and arginine (Arg-1) in CIA rats were detected by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry (IHC) and immunofluorescence (IF) co-staining were employed to detect the expression levels of inflammatory factors in synovium. ResultsA total of 28 main components were identified in WGLWE, and these compounds can directly bind to the inflammatory pathway proteins such as JAK2, NFκB and STAT3. In vitro experiments demonstrated that WGLWE promoted the transformation of M1 macrophages into M2 macrophages and suppressed the release of proinflammatory cytokines TNF-α and IL-6. In vivo studies showed that WGLWE effectively reduced ankle swelling, alleviated knee joint effusion, and improved BV/TV while also reducing synovial inflammation levels. Furthermore, WGLWE compounds induced the transition of M1-type macrophages to M2-type macrophages in synovial tissue, resulting in decreased secretion of inflammatory factors TNF-α, WGLWE improved the synovial inflammatory state. ConclusionOur results indicated that WGLWE alleviated joint inflammation in CIA rats and the underlying mechanism may be related to inducing the transformation of bone marrow-derived M1 macrophages to M2 macrophages, leading to an increase in the secretion of anti-inflammatory factors and a decrease in pro-inflammatory factors. Therefore, WGLWE may be used as a potential herbal preparation for the treatment of RA.

Chemical Characterization and Ameliorating Effect of Centratherum anthelminticum Extract against Polycystic Ovary Syndrome in Wistar Rats.

Polycystic ovary syndrome (PCOS) in females is an endocrine pathological condition of reproductive age which is usually caused by insulin resistance, hyperlipidemia, and oxidative stress. This research was aimed at evaluating the therapeutic effect of the Centratherum anthelminticum seed extract (CA) against PCOS in rodents as it is traditionally used to treat diabetes, inflammation, and gynecological problems. The CA was chemically characterized by high-performance liquid chromatography-diode array detection (HPLC-DAD). For the induction of PCOS, a high-fat diet (HFD) was given to all female Wistar rats for nine weeks except the normal control group, which was given a normal chow diet. Estradiol valerate was given to all rats except normal control. After the induction of PCOS, oral metformin (300 mg/kg) was given to the standard group, while CA was orally administered to diseased rats at 250, 500, and 750 mg/kg/day for 28 days. HPLC-DAD analysis revealed that kaempferol-3-pcoumaroylglucoside was present in the highest amount (146.8 ± 1.8 mg/g) of the extract followed by ferulic acid and malvidin-3-(6-caffeoyl)-glucoside. The in vivo results revealed a marked reduction in cholesterol and triglyceride levels in CA treatment groups. A significant rise was observed in progesterone and follicle stimulating hormone with a decrease in luteinizing hormone in the treatment groups as compared to disease control, which indicated normalization of the estrus cycle. The decrease in insulin resistance was characterized by low serum insulin levels in treatment groups. Treatment with CA also reduced inflammatory markers, such as IL-6 and NF-κB in PCOS rats. NrF2 and oxidative stress markers such as catalase, superoxide dismutase, malondialdehyde, and reduced glutathione were also improved by CA in the ovary of diseased rats. Histopathological examination showed the different developmental stages of normal follicles in CA-treated diseased rats which were indicative of a normal fertile estrous cycle. Overall, the results confirmed the efficacy of CA against PCOS in treating estradiol-HFD-induced PCOS due to its antidiabetic, anti-inflammatory, antihyperlipidemic, and antioxidant properties.

Effect of acupuncture at "Houxi" (SI3) and"Huantiao" (GB30) on high mobility group box 1 protein in spinal nerve trunk of rats with lumbar disc herniation

To observe the effect of acupuncture at "Houxi"(SI3) and "Huantiao"(GB30) on high mobility group box 1(HMGB1) protein and mRNA in spinal nerve trunk(SNT) of rats with lumbar disc herniation(LDH), so as to explore the mechanisms of acupuncture at this paired points on the treatment for LDH. SD rats were randomly divided into sham operation, model, conventional acupuncture(CA) and paired points(PP) groups (with 8 rats in each group). The LDH model was established by injection of autologous suspension made from rats' own nucleus pulsus into the epidural space. Rats in the CA group received acupuncture treatment at bilateral "Weizhong"(BL40), "Dachangshu"(BL25) and "Shenshu"(BL23), while rats in the PP group received acupuncture at bilateral SI3 and GB30, 30 min each time, once daily for 14 consecutive days. The thermal pain threshold of bilateral hind feet of rats was detected by thermal pain stimulator. The contents of serum IL-1β, IL-6 and IL-8 of rats were detected by ELISA. Western blot and immunofluorescence were used to detect the expression of HMGB1 protein in the lumbar(L)5 SNT of rats. The relative expression of HMGB1 mRNA in L5 SNT was determined by qPCR. HE staining was used to observe the morphological changes of L5 SNT. Compared with the sham operation group, the thermal pain threshold of bilateral hind feet in the model group was decreased (P<0.05); compared with the model group, the thermal pain threshold of bilateral hind feet in the CA group and the PP group were increased (P<0.05). The expressions of HMGB1 protein and mRNA in L5 SNT, and the contents of serum IL-1β, IL-6 and IL-8 of rats in the model group were significantly increased(P<0.000 1, P<0.001) in contrast to the sham operation group. The expressions of HMGB1 protein and mRNA in L5 SNT, and the levels of serum IL-1β, IL-6 and IL-8 were significantly decreased (P<0.01, P<0.000 1, P<0.001, P<0.05) in the CA and PP group, in comparison with those of the model group. Compared with the CA group, the above indexes of rats in the PP group recovered more significantly (P<0.05,P<0.001, P<0.01,P<0.000 1). The histomorphological results showed scattered and various-sized nerve fibers, vacuolation, a large number of disintegrating myelin sheath and lysed Schwann cells in the model group. Myelin sheaths regeneration, regularly-arranged nerve fibers were seen in the CA group and the PP group, with more obvious histopathological recovery observed in the PP group than the CA group. Acupuncture intervention inhibites the expressions of HMGB1 protein and mRNA in rats with LDH, and further reduces the production of IL-1β, IL-6 and IL-8, which is beneficial to inflammatory response inhibition and pain alleviation. The therapeutic effect of the PP group is more obvious than that of the CA group.

Xuebijing injection protects against sepsis-induced myocardial injury by regulating apoptosis and autophagy via mediation of PI3K/AKT/mTOR signaling pathway in rats.

Apoptosis and autophagy are significant factors of sepsis induced myocardial injury (SIMI). XBJ improves SIMI by PI3K/AKT/mTOR pathway. Present study is devised to explore the protective mechanism of XBJ in continuous treatment of SIMI caused by CLP. Rat survival was first recorded within 7 days. Rats were randomly assigned to three groups: Sham group, CLP group, and XBJ group. The animals in each group were divided into 12 h group, 1 d, 2 d, 3 d and 5 d according to the administration time of 12 hours, 1 day, 2 days, 3 days or 5 days, respectively. Echocardiography, myocardial injury markers and H&E staining were used to detect cardiac function and injury. IL-1β, IL-6 and TNF-α in serum were measured using ELISA kits. Cardiomyocyte apoptosis was assayed by TUNEL staining. Apoptosis and autophagy related proteins regulated by the PI3K/AKT/mTOR signaling pathway were tested using western blot. XBJ increased the survival rate in CLP-induced septic Rat. First of all, the results of echocardiography, H&E staining and myocardial injury markers (cTnI, CK, and LDH levels) showed that XBJ could effectively improve the myocardial injury caused by CLP with the increase of treatment time. Moreover, XBJ significantly decreased the levels of serum inflammatory cytokines IL-1β, IL-6 and TNF-α in SIMI rats. Meanwhile, XBJ downregulated the expression of apoptosis-related proteins Bax, Cleaved-Caspase 3, Cleaved-Caspase 9, Cytochrome C and Cleaved-PARP, while upregulated the protein levels of Bcl-2 in SIMI rats. And, XBJ upregulated the expression of autophagy related protein Beclin-1 and LC3-II/LC3-I ratio in SIMI rats, whereas downregulated the expression of P62. Finally, XBJ administration downregulated the phosphorylation levels of proteins PI3K, AKT and mTOR in SIMI rats. Our results showed that XBJ has a good protective effect on SIMI after continuous treatment, and it was speculated that it might be through inhibiting apoptosis and promoting autophagy via, at least partially, activating PI3K/AKT/mTOR pathway in the early stage of sepsis, as well as promoting apoptosis and inhibiting autophagy via suppressing PI3K/AKT/mTOR pathway in the late stage of sepsis.

Effects of ACTH6-9-Pro-Gly-Pro Peptide on the Levels of Pro- and Anti-Inflammatory Cytokines in Wistar Rats under Conditions of Chronic Restraint Stress.

We evaluated the effect of ACTH6-9-Pro-Gly-Pro (ACTH6-9-PGP) peptide on the serum levels of pro- and anti-inflammatory cytokines in experimental animals under conditions of chronic restraint stress. Stress exposure over 2 weeks led to an increase in the levels of IL-1β, IL-6, and IFNγ in rats. Daily intraperitoneal injection of ACTH6-9-PGP in a dose of 5 μg/kg before stress exposure significantly decreased the levels of IL-6 and IFNγ by 4.8 and 49.3% respectively. Administration of the peptide in a dose of 50 μg/kg decreased the levels of IL-1β and IFNγ by 51.2 and 39.7%, respectively. However, no changes in the cytokine levels were observed after injection of the peptide in a dose of 500 μg/kg. Thus, ACTH6-9-PGP administered in doses of 5 and 50 μg/kg prevented the stress-induced changes in the levels of pro- and inflammatory cytokines.

Indole-3-carbinol ameliorated the thioacetamide-induced hepatic encephalopathy in rats

Indole-3-carbinol (I3C) is reported to have hepatic and neuroprotective properties. However, the I3C role in the protection of the liver and brain in the pathological condition of hepatic encephalopathy has not been investigated. Therefore, in the present study, we have assessed the hepatic and neuroprotective roles of I3C against thioacetamide (TAA)- induced hepatic encephalopathy in Wistar rats. TAA (300 mg/kg) was intraperitoneally administered to Wistar rats to induce hepatic encephalopathy. The elevated levels of ammonia in the blood, liver, and brain were substantially lowered by I3C treatment (25, 50, and 100 mg/kg, oral, 7 days). I3C significantly ameliorated the TAA-induced liver dysfunction by decreasing the alanine transaminase, aspartate transaminase, and alkaline phosphatase enzymes and reduced the elevated cytochrome P4502E1 (CYP2E1) activity in the liver and brain. Further, I3C alleviated mitochondrial dysfunction and oxidative stress in the brain. I3C treatment improved the anti-inflammatory cytokine interleukin (IL)− 10 while reducing inflammatory cytokines such as tumor necrosis factor-1 and IL-6 in hepatic encephalopathy rats. I3C reduced the levels of apoptotic indicators mediated by the mitochondria, including cytochrome c, caspase 9, and caspase 3. Concurrently, I3C mitigated the liver and brain histological abnormalities in hepatic encephalopathy rats. Therefore, the present study concluded that the I3C protected the liver and brain from TAA-induced hepatic encephalopathy injury by inhibiting CYP2E1 enzyme activity and decreasing ammonia, oxidative stress, inflammation, and apoptosis. The present study provides preclinical validation of I3C use as hepatic and neuroprotective for hepatic encephalopathy management.

Genistein Effect on Estrogen Receptor especially Interleukin-6 and Tumor Necrosis Factor-α in Mice Model of Endometriosis: a Systematic Review and Meta-analysis

Introduction: Endometriosis is the endometrial tissue proliferation outside the uterine space. Anti-angiogenic agents from different groups of substances are currently being discussed as promising therapies for the treatment of endometriosis in the future, one of which is therapy using the phytoestrogen genistein. At the molecular level, genistein's effects on cells include inhibition of proliferation, induction of differentiation, apoptosis, and cell arrest in the cell cycle, which are related to the transforming growth factor. Genistein inhibits cell growth by modulating the signal-transforming growth factor pathway. Methods: We searched PubMed, Scopus, Cochrane Library and Proquest from its inception to December 2022 to collect observational and interventional studies of Genistein consumption in endometriosis mice. Two authors independently screened the literature according to the inclusion and exclusion criteria, extracted data, and assessed the risk of bias. Safety analysis was assessed through TNF-α and IL-6 values of estrogen expression. Results: No significant difference in the values of IL-6 and TNF-α in rats with endometriosis that were given genistein at these three doses. However, if analyzed further, the IL-6 outcome compared to the 0.78mg/day dose most affected the IL-6 value between the two groups, and the TNF-α output compared to the 0.78 mg/day dose most affected the TNF-α value between the two groups. So, a genistein dose of 0.78 mg/day can affect IL-6 and TNF-α in mice with endometriosis. Conclusion: Genistein modulated estrogen expression of TNF-α and IL-6 at all doses, but the best dose for its effect was 0.78 mg/day.

Network pharmacology and experimental studies for deciphering the molecular targets and mechanisms of Chaihu Shugan powder in the treatment of functional dyspepsia.

Chaihu Shugan powder (CSP) is a prevalent prescription product used in the treatment functional dyspepsia (FD) in China. However, the underlying pharmacological mechanisms involved in the treatment of FD remain unclear. To explore the key components of CSP and their molecular targets and mechanisms in the treatment of FD. Active compounds for CSP were identified from the TCMSP and SymMap databases, and the relevant targets were predicted. FD-related targets were obtained from the CTD database. In addition, using the protein-protein interactions (PPI) analysis, the common targets were obtained. Furthermore, the compound-target networks were created with Cytoscape. Finally, molecular docking was performed to identify the core targets and validate them experimentally. In total, 78 active compounds and 671 related targets of CSP were obtained. PPI network analysis identified 15 key FD-related compound targets. Molecular docking revealed that sitosterol and hyndarin exhibited good binding activities with AKT1 and IL6, respectively. Animal experiments have shown that CSP effectively increased the protein levels of AKT1 and reduced the serum levels of IL-6 in FD rats. This study provides a theoretical evidence for the analysis of the molecular targets and mechanisms of the action of CSP in FD.

Extraction, Structural Characterization, and In Vivo Anti-Inflammatory Effect of Alginate from Cystoseira crinita (Desf.) Borry Harvested in the Bulgarian Black Sea.

The aim of this study was to identify the chemical composition and sequential structure of alginate isolated from C. crinita harvested in the Bulgarian Black Sea, as well as its effects in histamine-induced paw inflammation in rats. The serum levels of TNF-α, IL-1β, IL-6, and IL-10 in rats with systemic inflammation, and the levels of TNF-α in a model of acute peritonitis in rats were also investigated. The structural characterization of the polysaccharide was obtained by FTIR, SEC-MALS, and 1H NMR. The extracted alginate had an M/G ratio of 1.018, a molecular weight of 7.31 × 104 g/mol, and a polydispersity index of 1.38. C. crinita alginate in doses of 25 and 100 mg/kg showed well-defined anti-inflammatory activity in the model of paw edema. A significant decrease in serum levels of IL-1β was observed only in animals treated with C. crinita alginate in a dose of 25 mg/kg bw. The concentrations of TNF-α and IL-6 in serum were significantly reduced in rats treated with both doses of the polysaccharide, but no statistical significance was observed in the levels of the anti-inflammatory cytokine IL-10. A single dose of alginate did not significantly alter the levels of the pro-inflammatory cytokine TNF-α in the peritoneal fluid of rats with a model of peritonitis.

Euphorbium total triterpenes improve Freund's complete adjuvant-induced arthritis through PI3K/AKT/Bax and NF-κB/NLRP3 signaling pathways.

Euphorbium is the resinous secretion of Euphorbia resinifera Berg. According to the record, Euphorbium was first used by Roman doctors to treat the emperor's joint pain. In China, it is applied in folk medicine to treat damp-cold or mucous diseases, such as arthralgia and ascites, etc. This herb is used for rheumatoid arthritis and skin tumors in the folklore of northeastern Brazil. Triterpenes are mainly characteristic constituents of Euphorbium, and possibly possess anti-rheumatoid arthritis. To explore the preventive effect of Euphorbium total triterpenes (TTE) on Freund's complete adjuvant (FCA) induced arthritis in rats and its mechanism. TTE was extracted and isolated from Euphorbium, and its components were analyzed by HPLC. The safety of TTE was evaluated by an acute toxicity test in mice. Arthritis was induced in rats by injecting 0.2mL FCA into the right hind paw toe, except for the control group, which was given the same volume of physiological saline. Tripterygium Glycosides (TG, 7.5mg/kg) and TTE (32, 64 and 128mg/kg) were administered by gavage for 30 days. Body weights, paw swelling, and arthritic scores were measured during the experiment process. After 30 days, blood and joints were harvested to determine various indicators of arthritis. The contents of euphol and euphorbol in TTE were 47.03% and 18.77% respectively, and the maximal feasible dose of TTE in mice is 12 g/kg. The experimental results showed that arthritis indicators in rats deteriorated after FCA inducement compared with the control group. After treatment with TTE, the swelling degree and histopathological change of the hind paws in rats were significantly improved as well as arthritic score; the serum TNF-α, CRP, IL-1β, IL-6, IL-18 and RF levels in rats were significantly reduced; The expression of PI3K, AKT, P-AKT, Bcl-2, NF-κB, NLRP3 and Pro-caspase-1 protein in joint tissue were down-regulated, and the expression of Bax protein was up-regulated. The results suggested that TTE possessed anti-arthritis effects, and its mechanism may be related to its anti-inflammatory and immunomodulatory properties, as well as regulation of PI3K/AKT/Bax and NF-κB/NLRP3 signaling pathway.

Zinc accumulation aggravates cerebral ischemia/reperfusion injury by promoting inflammation.

Intracellular zinc accumulation has been shown to be associated with neuronal death after cerebral ischemia. However, the mechanism of zinc accumulation leading to neuronal death in ischemia/reperfusion (I/R) is still unclear. Intracellular zinc signals are required for the production of proinflammatory cytokines. The present study investigated whether intracellular accumulated zinc aggravates I/R injury through inflammatory response, and inflammation-mediated neuronal apoptosis. Male Sprague-Dawley rats were treated with vehicle or zinc chelator TPEN 15 mg/kg before a 90-min middle cerebral artery occlusion (MCAO). The expressions of proinflammatory cytokines TNF-α, IL-6, NF-κB p65, and NF-κB inhibitory protein IκB-α, as well as anti-inflammatory cytokine IL-10 were assessed at 6 or 24 h after reperfusion. Our results demonstrated that the expression of TNF-α, IL-6, and NF-κB p65 increased after reperfusion, while the expression of IκB-α and IL-10 decreased, suggesting that cerebral ischemia triggers inflammatory response. Furthermore, TNF-α, NF-κB p65, and IL-10 were all colocalized with the neuron-specific nuclear protein (NeuN), suggesting that the ischemia-induced inflammatory response occurs in neurons. Moreover, TNF-α was also colocalized with the zinc-specific dyes Newport Green (NG), suggesting that intracellular accumulated zinc might be associated with neuronal inflammation following cerebral I/R. Chelating zinc with TPEN reversed the expression of TNF-α, NF-κB p65, IκB-α, IL-6, and IL-10 in ischemic rats. Besides, IL-6-positive cells were colocalized with TUNEL-positive cells in the ischemic penumbra of MCAO rats at 24 h after reperfusion, indicating that zinc accumulation following I/R might induce inflammation and inflammation-associated neuronal apoptosis. Taken together, this study demonstrates that excessive zinc activates inflammation and that the brain injury caused by zinc accumulation is at least partially due to specific neuronal apoptosis induced by inflammation, which may provide an important mechanism of cerebral I/R injury.