Inhibition Of Inflammatory Pathways Research Articles

Saffron (Crocus sativus) and its constituents for pain management: A review of current evidence.

Pain can become a chronic and deliberating experience with a significant burden. In preclinical and clinical studies, Saffron (Crocus sativus L.) has shown analgesic activities. Considering the unsatisfactory results of current therapeutic management for chronic pain conditions, we aimed to review saffron's analgesic activity and underlying mechanisms. Saffron showed antinociceptive activities in formalin-, carrageenan-, and capsaicin-induced experimental pain models. Saffron analgesic activities affected several targets, including ion channels of nociceptors; the adrenergic system and central histaminic system; inhibition of inflammatory pathways, apoptotic pathways, and oxidative stress; regulation of NO pathway, and the endocannabinoid system. Clinical studies showed analgesia of Saffron in rheumatoid arthritis, after-pain following childbirth, dysmenorrhea, and fibromyalgia. Our literature review showed that saffron can be beneficial as an adjunct therapy to commonly used analgesics in practice, particularly in chronic pain conditions.

Inhibition of microRNA-33b specifically ameliorates abdominal aortic aneurysm formation via suppression of inflammatory pathways

Abdominal aortic aneurysm (AAA) is a lethal disease, but no beneficial therapeutic agents have been established to date. Previously, we found that AAA formation is suppressed in microRNA (miR)-33-deficient mice compared with wild-type mice. Mice have only one miR-33, but humans have two miR-33 s, miR-33a and miR-33b. The data so far strongly support that inhibiting miR-33a or miR-33b will be a new strategy to treat AAA. We produced two specific anti-microRNA oligonucleotides (AMOs) that may inhibit miR-33a and miR-33b, respectively. In vitro studies showed that the AMO against miR-33b was more effective; therefore, we examined the in vivo effects of this AMO in a calcium chloride (CaCl2)-induced AAA model in humanized miR-33b knock-in mice. In this model, AAA was clearly improved by application of anti-miR-33b. To further elucidate the mechanism, we evaluated AAA 1 week after CaCl2 administration to examine the effect of anti-miR-33b. Histological examination revealed that the number of MMP-9-positive macrophages and the level of MCP-1 in the aorta of mice treated with anti-miR-33b was significantly reduced, and the serum lipid profile was improved compared with mice treated with control oligonucleotides. These results support that inhibition of miR-33b is effective in the treatment for AAA.

Anti-Inflammatory and Active Biological Properties of the Plant-Derived Bioactive Compounds Luteolin and Luteolin 7-Glucoside.

Flavonoids are interesting molecules synthetized by plants. They can be found abundantly in seeds and fruits, determining the color, flavor, and other organoleptic characteristics, as well as contributing to important nutritional aspects. Beyond these characteristics, due to their biochemical properties and characteristics, they can be considered bioactive compounds. Several interesting studies have demonstrated their biological activity in different cellular and physiological processes in high-order organisms including humans. The flavonoid molecular structure confers the capability of reacting with and neutralizing reactive oxygen species (ROS), behaving as scavengers in all processes generating this class of molecules, such as UV irradiation, a process widely present in plant physiology. Importantly, the recent scientific literature has demonstrated that flavonoids, in human physiology, are active compounds acting not only as scavengers but also with the important role of counteracting the inflammation process. Among the wide variety of flavonoid molecules, significant results have been shown by investigating the role of the flavones luteolin and luteolin-7-O-glucoside (LUT-7G). For these compounds, experimental results demonstrated an interesting anti-inflammatory action, both in vitro and in vivo, in the interaction with JAK/STAT3, NF-κB, and other pathways described in this review. We also describe the effects in metabolic pathways connected with inflammation, such as cellular glycolysis, diabetes, lipid peroxidation, and effects in cancer cells. Moreover, the inhibition of inflammatory pathway in endothelial tissue, as well as the NLRP3 inflammasome assembly, demonstrates a key role in the progression of such phenomena. Since these micronutrient molecules can be obtained from food, their biochemical properties open new perspectives with respect to the long-term health status of healthy individuals, as well as their use as a coadjutant treatment in specific diseases.

Phase II trial of moderate dose omega-3 acid ethyl esters for colorectal cancer prevention in patients with lynch syndrome (COLYNE).

TPS209 Background: Lynch syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome and is responsible for about 3% of newly diagnosed CRC. It is caused by germline mutations in one of the DNA mismatch repair (MMR) genes, and patients with LS carry a lifetime risk of CRC ranging between 10% and 70%. The role of inflammation in driving this malignant transformation is now well established and retrospective studies have revealed a potential chemo-preventative role for omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), possibly via inhibition of inflammatory pathways associated with the development of defective MMR CRC tumors. While patients with LS have the highest risk of developing CRC, the majority of chemoprevention trials are focused on sporadic CRC. Effective interventions to reduce the risk of developing CRC in this population are limited to close surveillance and surgical prophylaxis. There is an unmet need for safe, effective, and non-invasive chemo-preventive interventions in patients with LS. Methods: This pilot study is a single-arm, open-label, phase 2 clinical trial of omega-3 acid ethyl esters (generic Lovasa; 2 grams orally once daily) for adult patients (≥ 18 years of age) with confirmed LS (based on germline testing of the MMR genes panel: MLH1, MSH2, MSHS6, PMS2 or deletion in EPCAM gene). Patients who are not candidate for elective endoscopy and/or with prior history of right sided or pan-colectomy are excluded. Thirty-four patients are expected to enroll, with a primary objective to determine the feasibility (defined as 80% retention rate) of 12 months of treatment with 2 grams capsules of omega-3 acid ethyl esters daily. Secondary endpoints include safety and tolerability of the intervention. Correlative aims include pre and post treatment assessment of colon mucosal tissue proliferation (right sided colon specimens will be evaluated for markers of proliferation (Ki-67) and apoptosis (Caspase-3)), the effect of omega-3 acid ethyl esters on inflammatory markers in serum, urine and feces (PGE-2, COX-2, β-catenin levels, and EPA:AA ratios), and gene expression related to proliferation, apoptosis and cell survival in colon tissue (NF-κB/Wnt pathways). The impact of omega-3 acid ethyl esters on intestinal microbiota will also be assessed (16S rRNA-based profiling). Correlative Colon tissue, serum, urine and feces samples are collected at baseline and at 12 months. The study is actively enrolling with 20 patients enrolled at the time of submission. Clinical trial information: NCT03831698.

Effects of supplementing a healthy diet with pecan nuts or extra-virgin olive oil on inflammatory profile of patients with stable coronary artery disease: a randomised clinical trial.

The consumption of nuts and extra-virgin olive oil has been associated with suppression of inflammatory pathways that contribute to atherosclerosis, but its role on the modulation of the inflammatory profile in patients with established coronary artery disease (CAD) is unclear. The aim of this study was to evaluate the effects of adding pecan nuts or extra-virgin olive oil to a healthy diet on inflammatory markers in patients with stable CAD. In this randomised clinical trial, 204 patients were enrolled to three study groups: sixty seven to control group (CG: healthy diet), sixty eight to pecan nuts group (PNG: 30 g/d of pecans + healthy diet) and sixty nine to extra-virgin olive oil group (OOG: 30 ml/d of extra-virgin olive oil + healthy diet). High-sensitivity C-reactive protein (hs-CRP, in mg/l), fibrinogen (mg/dl), IL 2, 4, 6, 10 (pg/ml) and interferon-γ (IFN-γ, in pg/ml), IL-6/IL-10, IL-2/IL-4 and IFN-/γIL-4 ratios were evaluated at baseline and after the follow-up (12 weeks). As main results, after adjustment for sex, statin used and relative body weight variation, there were no differences between groups regarding inflammatory markers at the end of the study. IL-6 levels (primary outcome) were reduced in 12 weeks when compared with baseline in all study groups (CG: difference: -0·593 (se = 0·159) pg/dL; PNG: difference: -0·335 (se = 0·143) pg/dl; OOG: IL-6 difference: -0·325 (se = 0·143) pg/dl). In conclusion, there was no significant effect of including pecan nuts or extra virgin olive oil to a healthy diet on inflammatory markers in individuals with CAD.

Role of GLP-1 Analogs in the Management of Diabetes and its Secondary Complication.

The cardiovascular complications of Type 2 Diabetes Mellitus (T2DM) including myocardial infarction, heart failure, peripheral vascular disease and, stroke and retinopathy, nephropathy and neuropathy are microvascular complications. While the newer therapies like glitazones or even Dipeptidyl- peptidase-IV (DPP-IV) inhibitors increase the risk of therapy, the Glucagon Like Peptide-1 Receptor Agonists (GLP-1RAs), were reported as suitable alternates. The GLP-1RAs reduce Major Adverse Cardiovascular Events (MACE), have anti-atherogenic potential, and possess pleiotropic activity. The GLP-1RAs were found to improve neuroprotection, enhance neuronal growth, reduce the incidence of stroke, and improve central insulin resistance. The GLP-1RAs are beneficial in improving the glycemic profile, preventing macroalbuminuria and reducing the decline in eGFR and enhancing renal protection. The renal benefits of add-on therapy of GLP-1RAs with SGLT-2 inhibitors have composite renal outcomes such as suppression of inflammatory pathways, improvement in natriuresis, diuresis, found to be nephroprotective. Improvement in glycemic control with a reduction in body weight and intraglomerular pressure and prevention of tubular injury makes the GLP-1RAs as suitable add-on therapies in improving cardiorenal outcomes. Obesity, an important contributor to insulin resistance and a reduction in weight, is an essential therapeutic option in addressing diabetic-obesity. It also reduces the damage to blood-retinal-barrier, thus beneficial in halting the development of diabetic retinopathy. In diabetic complications, glycemic control, addressing insulin resistance through weight loss, controlling atherosclerosis through anti-inflammatory effects and cardio-renal-neuro protection, makes GLP-1RAs a suitable therapeutic strategy on long-term treatment of T2DM. This review discusses the role of GLP-1RAs in diabetes, the dosage, mono or combination therapy with other antidiabetics in long-term treatment and its effect in uncontrolled diabetes.

Bioinformatic and biochemical studies of formononetin against liver injure

Formononetin is a promising bioactive phytoestrogen with evident pharmacological properties. However, the potential hepatoprotective benefit is evidenced limitedly in experiments. This study was designed to investigate the hepatoprotective mechanism and benefit of formononetin against liver injury via network pharmacology combined with biochemical determination. The computational data from network pharmacology identified the crucial genes of formononetin against liver injury, listed as TNF-α, NFκB-p65, TLR3, RELA, TRAF6, IKBKG, IKBKB, TNFRSF1A. And the anti-liver injury of formononetin were mainly involved in suppression of inflammatory pathways, including TNF signaling pathway, NF-κB signaling pathway, Toll-like receptor signaling pathway. In animal investigation, formononetin-dosed mice showed reduced body weight loss and hepatomegaly, meliorated liver function, suppressed hepatotoxicity and inflammatory reaction. Furthermore, the down-regulated expressions of TNF-α, NFκB-p65, TLR3 mRNAs and proteins in the livers of formononetin-dosed mice were detected accordingly. Therefore, we concluded that computational findings based on network pharmacology reveal the pharmacological targets, biological processes, and molecular mechanisms of formononetin against liver injury before some of findings were partially certified in vivo. Overall, formononetin may be a potential active component to prevent or treat liver injury.

Dieckol alleviates dextran sulfate sodium-induced colitis via inhibition of inflammatory pathway and activation of Nrf2/HO-1 signaling pathway.

Ulcerative colitis (UC) is the major type of inflammatory ailment with elevated prevalence worldwide. Dieckol (DEK) is a phlorotannin that is extensively found in marine algae and has been found to have different pharmacological properties. Nevertheless, the impact of DEK in UC has not been investigated earlier. Therefore, we appraised DEK's function in dextran sulfate sodium (DSS)-induced UC in the mouse. An overall of 30 mice was randomized into 5 equal groups. Control mice treated with a standard diet (group I), colitis mice challenged with 3% of DSS through drinking water for 7 consecutive days (group II), DEK was supplemented via oral gavage from day 1 to 10 at the dosages of 5, 10, and 15 mg/kg b.wt, respectively. All animals were sacrificed on the 11th day. The body weight (bwt), colon length, disease activity index, malondialdehyde (MDA), myeloperoxidase (MPO), and histological features were observed using suitable techniques, and COX-2 expression was investigated by immunohistochemistry. Moreover, TNF-α, IL-1β, p65, IκBα, HO-1, and Nrf2 expressions were measured using ELISA and RT-PCR techniques, respectively. DEK treatment to the colitis mice considerably lessened, DSS-challenged alterations in body weight, DAI, colonic length shortening and histological changes. DEK exhibited potent antioxidant effects due to the reduced MDA and MPO, and Nrf2 expression markers while the HO-1 marker was augmented. Additionally, DEK also suppressed the expression s of TNF-α, IL-1β, and the p-p65, p-IκBα, and p65 and augmented the expression of IκBα, which eventually proved the anti-inflammatory potential of DEK against the DSS-challenge. Based on these results, DEK has been found effective in mitigating colitis, conceivably alleviating colon inflammation through the NF-κB inhibition and triggering of Nrf2/HO-1 signaling cascade.

Nutrition and Psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by accelerated tumor necrosis factor-α/interleukin-23/interleukin-17 axis, hyperproliferation and abnormal differentiation of epidermal keratinocytes. Psoriasis patients are frequently associated with obesity, diabetes, dyslipidemia, cardiovascular diseases, or inflammatory bowel diseases. Psoriasis patients often show unbalanced dietary habits such as higher intake of fat and lower intake of fish or dietary fibers, compared to controls. Such dietary habits might be related to the incidence and severity of psoriasis. Nutrition influences the development and progress of psoriasis and its comorbidities. Saturated fatty acids, simple sugars, red meat, or alcohol exacerbate psoriasis via the activation of nucleotide-binding domain, leucine-rich repeats containing family, pyrin domain-containing-3 inflammasome, tumor necrosis factor-α/interleukin-23/interleukin-17 pathway, reactive oxygen species, prostanoids/leukotrienes, gut dysbiosis or suppression of regulatory T cells, while n-3 polyunsaturated fatty acids, vitamin D, vitamin B12, short chain fatty acids, selenium, genistein, dietary fibers or probiotics ameliorate psoriasis via the suppression of inflammatory pathways above or induction of regulatory T cells. Psoriasis patients are associated with dysbiosis of gut microbiota and the deficiency of vitamin D or selenium. We herein present the update information regarding the stimulatory or regulatory effects of nutrients or food on psoriasis and the possible alleviation of psoriasis by nutritional strategies.

Overexpression of MicroRNA-16 Alleviates Atherosclerosis by Inhibition of Inflammatory Pathways.

Background Our previous study demonstrated that the expression of miR-16 was downregulated in the cell and animal models of atherosclerosis (AS), a main contributor to coronary artery disease (CAD). Overexpression of miR-16 inhibited the formation of foam cells by exerting anti-inflammatory roles. These findings indicated miR-16 may be an anti-atherogenic and CAD miRNA. The goal of this study was to further validate the expression of miR-16 in CAD patients and explore its therapeutic roles in an AS animal model. Methods A total of 40 CAD patients and 40 non-CAD people were prospectively registered in our study. The AS model was established in ApoE-/- mice fed a high-fat diet. The model mice were randomly treated with miR-16 agomiR (n = 10) or miR-negative control (n = 10). Hematoxylin-eosin staining was conducted for histopathological examination in thoracic aorta samples. ELISA and immunohistochemistry were performed to determine the expression levels of inflammatory factors (IL-6, TNF-α, MCP-1, IL-1β, IL-10, and TGF-β). qRT-PCR and western blotting were carried out to detect the mRNA and protein expression levels of PDCD4, miR-16, and mitogen-activated protein kinase pathway-related genes. Results Compared with the normal control, miR-16 was downregulated in the plasma and peripheral blood mononuclear cell of CAD patients, and its expression level was negatively associated with IL-6 and the severity of CAD evaluated by the Gensini score, but positively related with IL-10. Injection of miR-16 agomiR in ApoE-/- mice reduced the formation of atherosclerotic plaque and suppressed the accumulation of proinflammatory factors (IL-6, TNF-α, MCP-1, and IL-1β) in the plasma and tissues but promoted the secretion of anti-inflammatory factors (IL-10 and TGF-β). Mechanism analysis showed overexpression of miR-16 might downregulate target mRNA PDCD4 and then activate p38 and ERK1/2, but inactivate the JNK pathway. Conclusions Our findings suggest miR-16 may be a potential diagnostic biomarker and therapeutic target for atherosclerotic CAD.

Neuroprotective effect of Umbelliferone against Cerebral ischemia/Reperfusion induced neurological deficits: in-vivo and in-silico studies

Inflammatory pathway is the significant marker of neuro-inflammation and plays a significant role in the expansion of cerebral ischemia/reperfusion injury. Umbelliferone (UF), 7-hydroxy coumarin, has been already proved for its anti-inflammatory and anti-oxidative effects against ischemic brain injury in the rodent model, but its underlying pharmacological mechanism for neuro-protection remain unclear. In this study, we try to explore the neuro-protective effect of umbelliferone against ischemia/Reperfusion induced neurological deficits in rats and explore the underlying mechanism. Inserting thread into the middle cerebral artery was used to induce the ischemic stroke model. The rats were treated with the umbelliferone (5, 10 and 20 mg/kg) for 14 days prior to the ischemic stroke. At the end of the experimental study, brain infarction volume, neurological score, brain edema, pro-inflammatory cytokines, inflammatory mediator were estimated in the region of brain and serum. The mRNA expression of Toll-like receptor-4 (TLR4), myeloid differentiation factor 88 (MyD88), Fas and FasL were also estimated at the end of the study. Dose dependently treatment of umbelliferone down-regulated the neurological score, brain infarction, inflammatory mediator (TNF-α, IL-1β, IL-6, COX-2, NF-kB and PGE2) in the serum and brain tissue as compared to I/R induced control group rats. Umbelliferone also reduced the expression of TRL4, MyD88, Fas and FasL as compared to I/R control group rats. Umbelliferone also decreased the level of nuclear factor kappa B (NF-kB) compared to MACO control group rats. Collectively, the obtained result showed that the umbelliferone protected the brain against the ischemic injury in the rats through the inhibition of inflammatory pathway. Communicated by Ramaswamy H. Sarma

Pomegranate protects renal proximal tubules during gentamicin induced-nephrotoxicity in rats

Objective: The aim of present study was to evaluate the nephroprotective effect of pomegranate in gentamicin induced-nephrotoxicity in rats.
 Methods: Thirty Sprague Dawley Male rat were used, which randomly divided into 3 groups, 10 rats in each group. Group1 (n=10): Rats treated with distilled water for 12 days.Group2 (n=10): Rats treated with distilled water + Gentamicin .Group3 (n=10): Rats treated with pomegranate + gentamicin. Blood urea, serum creatinine, serum malondialdehde (MDA), superoxide dismutase (SOD) , glutathione reductase (GSH) , Neutrophil Gelatinase Associated Lipocalin (NGAL) , kidney injury molecules (KIM-1) and Cystatin-c were measured .
 Results: Blood urea and serum creatinine were significantly elevated in gentamicin group compared to the control p=0.007 and p=0.04 respectively. Also estimated GFR was significantly decreased in gentamicin group compared to the control p=0.04. Cystatin-c serum level and MDA serum level were increased but SOD and GSH were decreased insignificantly in gentamicin group compared to the control p>0.05. Pomegranate reduced blood urea significantly p=0.002. Pomegranate improves endogenous anti-oxidant capacity since; it increase GSH significantly compared to gentamicin group p=0.02. There were insignificant effects on MDA and SOD. Moreover, pomegranate reduce serum levels of KIM-1and NGAL in gentamicin group p<0.05.
 Conclusion: Pomegranate attenuates gentamicin induced-nephrotoxicity through potentiation of endogenous anti-oxidant capacity and inhibition of inflammatory pathway.

Siegesbeckia Orientalis L. Extract Attenuates Postoperative Cognitive Dysfunction, Systemic Inflammation, and Neuroinflammation.

A proportion of patients experience acute or even prolonged cognitive impairment after surgery, a condition known as postoperative cognitive dysfunction (POCD). It is characterized by impairment in different cognitive domains and neuroinflammation has been implicated as one of the inciting factors as strategies targeting inflammation tend to improve cognitive performance. Siegesbeckia Orientails L. (S. Orientails) is a common Chinese medicinal herb used for managing chronic inflammatory diseases. We investigated if pretreatment with S. Orientails before surgery confers any neuroprotective effects in postoperative animals in terms of reducing inflammation and mitigating cognitive impairment. Three-month-old male C57BL/6N mice were fed different doses of S. Orientails extract for 14 days before they underwent a laparotomy. After cognitive testing they were sacrificed on postoperative day (POD) 3. Our results showed that animals with extract pretreatment demonstrated memory improvement in a dose-dependent manner compared with control. Further, evidence for the attenuation of systemic and neuroinflammation was found in the pretreated animals, along with the inhibition of inflammatory pathways and significantly reduced tau phosphorylation in the hippocampus. Taken together, these results demonstrated a neuroprotective effect of S. Orientails in postoperative animals, indicating a therapeutic potential of S. Orientails in minimizing POCD and the possibility of utilizing this traditional Chinese medicine perioperatively.

16 - Endothelial nitric oxide synthase plays a protective role against myocardial infarction

Redox signaling has been implicated in the loss of proliferative/regenerative ability of cardiomyocytes (CMs) after birth. This is one of the main reasons why a mature, aged heart cannot regenerate following an extensive inschemic event, such as myocardial infarction (MI). Based on our previous studies on the roles played by endothelial nitric oxide synthase (eNOS) on endothelial cell (EC) and CM proliferation, we hypothesized that eNOS signaling could play a protective role against MI. For this, we used an MI mouse model (permanent LAD ligation). These mice were injected in the muscle wall with different combinations of ECs and CMs isolated from either WT or KO eNOS neonatal mice. Cells were first co-cultured in hanging drops for ~5 days until formation of 3D vascularized cardiac spheroids (VCSs) and then transplanted in adult MI mice. Infarcted animals received either vehicle (media) or a suspension of VCSs in media. Adult mice received VCSs generated by co-culturing either: i) WT CMs and WT ECs; or ii) WT CMs and KO ECs; or iii) KO CMs and WT ECs. Our analysis 28 days following the procedure showed that the higher ejection fraction measured in VCS-injected mice compared with animals receiving media-only (61% ± 4% and 41% ± 11%, respectively) was dependent on eNOS presence in both ECs and CMs. Specifically, genetic deletion of eNOS in either KO ECs or KO CMs in group (ii) and (iii) reduced the ejection fraction to 40% ± 5% and 46% ± 2%, respectively. Therefore, our results strongly suggest that eNOS may play a major role via both an autocrine and paracrine mechanism. Current studies are focusing on evaluating the mechanism(s) for this eNOS-mediated protective role, possibly by promoting angiogenesis and/or proliferation, together with inhibition of inflammatory pathways. A better understanding of the eNOS-mediated protective role may have significant therapeutical impact in heart failure patients.

Duodenal chemosensing.

Luminal chemosensing is a term used to describe how small molecules in the gut lumen interact with the host through surface receptors or via transport into the submucosa. In this review, we have summarized recent advances of understanding luminal chemosensing in the gastroduodenal mucosa, with a particular emphasis on how chemosensing affects mucosal protective responses and the metabolic syndrome. In the past decade, data have supported the hypothesis that gut luminal chemosensing not only is important for the local or remote regulation of gut function but also contributes to the systemic regulation of metabolism, energy balance and food intake. We have provided examples of how luminal nutrients such as long-chain fatty acids (LCFAs), endogenous compounds such as bile acids, bacterial metabolites such as short-chain fatty acids (SCFAs) and bacterial components such as lipopolysaccharide (LPS) activate cognate receptors expressed on key effector cells such as enteroendocrine cells and inflammatory cells in order to profoundly affect organ function through the initiation or suppression of inflammatory pathways, altering gut barrier function and nutrient uptake, altering gut motility and visceral pain pathways, and preventing mucosal injury. These recent discoveries in this area have provided new possibilities for identifying novel molecular targets for the treatment of mucosal injury, metabolic disorders and abnormal visceral sensation. Understanding luminal chemosensory mechanisms may help to identify novel molecular targets for the treatment and prevention of mucosal injury, metabolic disorders and abnormal visceral sensation.

Hydrogen sulfide supplement attenuates the apoptosis of retinal ganglion cells in experimental glaucoma

Glaucoma is a group of neurodegenerative eye diseases characterized by progressive impairment of visual function due to loss of retinal ganglion cells (RGC). As hydrogen sulfide (H2S) was reported to play a role in the process of glaucomatous neuropathy and improve RGC survival in experimental glaucoma, the authors aimed to investigate the anti-apoptosis effect of H2S supplement in a rat glaucoma model, and further tried to explore the involved factors in the neuroprotection. A chronic ocular hypertension (COH) rat model induced by intracameral injection of cross-linking hydrogel was employed to simulate glaucoma and 288 rats were subjected to experimental procedures in the present study. After 4 weeks of sodium hydrosulfide (NaHS) administration following COH induction, the apoptosis of RGC isolated from experimented rats as well as apoptosis of neurons in ganglion cell layer (GCL), intrinsic apoptotic pathway activity, mitochondrial function, glial activation, NF-κB pathway activity, NADPH oxidase activity, autophagy activity and TNF-α level in retina were evaluated. The results showed that H2S supplement effectively attenuated the apoptosis of RGC in experimental glaucoma, and the neuroprotection by H2S might correlate with preservation of mitochondrial function, attenuation of oxidative stress, suppression of glial activation, inhibition of inflammatory pathways and downregulation of autophagy. Our study indicated that H2S supplement resulted in significant neuroprotection through attenuation of RGC apoptosis which might be linked with multiple factors in experimental glaucoma. The new therapeutic strategy might potentially contribute to benefit glaucoma treatment, which is worth further concerns.

Effect of Delayed Digital Hypothermia on Lamellar Inflammatory Signaling in the Oligofructose Laminitis Model.

BackgroundIn the oligofructose (OF) model of sepsis‐related laminitis (SRL), digital hypothermia (“cryotherapy”) initiated before the onset of clinical signs is reported not only to limit lamellar injury, but also to cause marked inhibition of lamellar inflammatory signaling.Hypothesis/ObjectivesBecause hypothermia also has been reported to be protective when not initiated until the onset of lameness in the OF model of SRL, we hypothesized that the lamellar protection conferred by hypothermia is caused by local lamellar inhibition of inflammatory signaling as described when hypothermia was initiated earlier in the disease process.AnimalsEight Standardbred geldings aged 3–11 years with no lameness and no abnormalities of the feet detectable by gross or radiographic examination.MethodsUsing the OF model of SRL, lamellar mRNA concentrations of proinflammatory cytokines, chemokines, and endothelial adhesion proteins were compared between samples from treated limbs (CRYO, submerged in ice water for 36 hour starting at the onset of lameness), untreated limbs (NON‐CRYO, opposite limb from CRYO limbs maintained at ambient temperature), and untreated limbs from normal horses in which laminitis was not induced (CON).ResultsAlthough OF administration resulted in increases in lamellar mRNA concentrations of several inflammatory mediators in NON‐CRYO limbs (vs CON), digital hypothermia had no significant effect on these increases.Conclusions and Clinical ImportanceThe lack of inflammatory inhibition in lamellar tissue samples in our study indicates that the protective effects of digital hypothermia instituted at the onset of clinical signs of laminitis do not arise from inhibition of inflammatory pathways.

Protective effect of Schizandrin B against damage of UVB irradiated skin cells depend on inhibition of inflammatory pathways

ABSTRACTSchizandrin B is extracted from Schisandra chinensis (Turcz.) Baill. This study evaluated the photoprotective effect of Schizandrin B on oxidative stress injury of the skin caused by UVB-irradiation and the molecular mechanism of the photoprotective effect of Schizandrin B, and we firstly found that Schizandrin B could block Cox-2, IL-6 and IL-18 signal pathway to protect damage of skin cells given by UVB-irradiation. In the research, we found that Schizandrin B can attenuate the UVB-induced toxicity on keratinocytes and dermal fibroblasts in human body, and can outstandingly eliminated intracellular ROS produced by UVB-irradiation. These results demonstrate that Schizandrin B can regulate the function of decreasing intracellular SOD's activity and increasing the expression level of MDA in HaCaT cells result from the guidance of UVB, and it markedly reduced the production of inflammatory factors such as Cox-2, IL-6 or IL-18, decreased the expression level of MMP-1, and interdicted degradation process of collagens in UVB-radiated cells. Therefore, skin keratinocytes can be effectively protected from UVB-radiated damage by Schizandrin B, and UVB-irradiation caused inflammatory responses can be inhibited by attenuating process of ROS generating.

The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice

Background and aimsGata6 is required to complete and maintain acinar differentiation in the mouse pancreas. Pancreas-specific Gata6 ablation during development causes extensive and persistent acinar-ductal metaplasia, which is considered an...

Nuclear receptors in inflammation control: Repression by GR and beyond

Inflammation is a protective response of organisms to pathogens, irritation or injury. Primary inflammatory sensors activate an array of signaling pathways that ultimately converge upon a few transcription factors such as AP1, NFκB and STATs that in turn stimulate expression of inflammatory genes to ultimately eradicate infection and repair the damage. A disturbed balance between activation and inhibition of inflammatory pathways can set the stage for chronic inflammation which is increasingly recognized as a key pathogenic component of autoimmune, metabolic, cardiovascular and neurodegenerative disorders. Nuclear receptors (NRs) are a large family of transcription factors many of which are known for their potent anti-inflammatory actions. Activated by small lipophilic ligands, NRs interact with a wide range of transcription factors, cofactors and chromatin-modifying enzymes, assembling numerous cell- and tissue-specific DNA–protein transcriptional regulatory complexes with diverse activities. Here we discuss established and emerging roles and mechanisms by which NRs and, in particular, the glucocorticoid receptor (GR) repress genes encoding cytokines, chemokines and other pro-inflammatory mediators.