Agents and Actions

Poor dietary habits such as an over consumption of high fructose and high fat diet are considered as the major culprit for the induction of diabetes associated liver injury. Diabetes mellitus is a metabolic disorder that affects various vital organs of the body especially the kidney, brain, heart, and liver. The high fructose and high fat (HFHF) diet worsen the metabolic conditions by producing various pathogenic burdens such as oxidative stress, inflammation, etc. on liver. The hyperlipidemic and hyperglycemic conditions induced by HFHF diet leads to the generation of various proinflammatory mediators like TNFα, interleukin and cytokines. The systematic bibliographical literature survey was done with the help of PubMed, Google scholar and MedLine to identify all pathological and molecular concerened with HFHF induced diabetic liver injury. The consumption of HFHF diet leads to an increase in mitochondrial oxidative stress thereby decreases the liver protective antioxidants required for cell viability. HFHF diet disturbs lipid and lipoprotein clearance by elevating the level of apolipoprotein CIII and impairing the hydrolysis of triglyceride. As a result, there is an increase in free fatty acid concentration, triglycerides and diacylglycerol in the liver which further triggers the situation of insulin resistance. The focus of present review is based upon the various pathological, genetic and molecular mechanism involved in the development of high-fat high fructose diet induced diabetic liver injury. However, the current review also documented few shreds of evidence related to various microRNAs (miR-31, miR-33a, miR-34a, miR-144, miR-146b, miR-150) concerned to HFHF diet which play an important role in the pathogenesis of diabetes associated liver injury Dietary life style modification may prove beneficial in the management of various metabolic disorders.

Biogenic amines play an important role in regulating cell proliferation in the normal and neoplastic colon. Elevated histidine decarboxylase (HDC) activity has been measured in human colorectal tumors. H2 antagonists can suppress the growth of colorectal cancer and their inclusion in human therapy has been proposed. We studied the effects of histamine, cimetidine, mepyramine and α-fluoromethylhistidine (FMH) on the growth of colorectal tumors in ten patients in the 6-day mouse subrenal capsule assay (SRCA). The effect of the Hic antagonist DPPE was tested in two assays. In summary, a reduction of tumor size was achieved with histamine and DPPE. In addition, significant inhibition of tumor growth was seen in the FMH-treated animals. When pooled by their growth potential, as assessed by the growth of saline-treated controls, FMH and DPPE caused distinct tumor reduction in rapidly growing tumors. In the moderately growing tumors, histamine and mepyramine were the most effective.

The plasma histaminase activity in guinea-pigs was found to increase by experimental inflammation induced by a subcutaneous turpentine injection and carrageenan peritonitis. The histaminase activity was raised 24 hours after the injection and did not return to normal values before 2 weeks. It was also observed that the alteration in the erythrocytes sedimentation rate followed a similar time course as that of the plasma level of histaminase. No relationship existed between the increased histaminase activity and skin oedema or changes in body temperature. The kinetics of the increase of plasma histaminase activity during inflammation are discussed.

Fungal keratitis is a severe sight-threatening ocular infection, without effective treatment strategies available now. Calprotectin S100A8/A9 has recently attracted great attention as a critical alarmin modulating the innate immune response against microbial challenges. However, the unique role of S100A8/A9 in fungal keratitis is poorly understood. Experimental fungal keratitis was established in wild-type and gene knockout (TLR4−/− and GSDMD−/−) mice by infecting mouse corneas with Candida albicans. The degree of mouse cornea injuries was evaluated by clinical scoring. To interrogate the molecular mechanism in vitro, macrophage RAW264.7 cell line was challenged with Candida albicans or recombinant S100A8/A9 protein. Label-free quantitative proteomics, quantitative real-time PCR, Western blotting, and immunohistochemistry were conducted in this research. Herein, we characterized the proteome of mouse corneas infected with Candida albicans and found that S100A8/A9 was robustly expressed at the early stage of the disease. S100A8/A9 significantly enhanced disease progression by promoting NLRP3 inflammasome activation and Caspase-1 maturation, accompanied by increased accumulation of macrophages in infected corneas. In response to Candida albicans infection, toll-like receptor 4 (TLR4) sensed extracellular S100A8/A9 and acted as a bridge between S100A8/A9 and NLRP3 inflammasome activation in mouse corneas. Furthermore, the deletion of TLR4 resulted in noticeable improvement in fungal keratitis. Remarkably, NLRP3/GSDMD-mediated macrophage pyroptosis in turn facilitates S100A8/A9 secretion during Candida albicans keratitis, thus forming a positive feedback cycle that amplifies the proinflammatory response in corneas. The present study is the first to reveal the critical roles of the alarmin S100A8/A9 in the immunopathology of Candida albicans keratitis, highlighting a promising approach for therapeutic intervention in the future.

The aim of this study was to investigate whether microtubule acetylation is triggered by antigen stimulation and how it affects mast cell degranulation. The RBL-2H3 cell line was used as a model for mast cells. Acetylation of α-tubulin was analyzed by Western blotting. Intracellular distribution of α-tubulin and acetylated α-tubulin was observed by immunostaining. Degranulation was monitored by measuring the activity of β-hexosaminidase secreted into cell supernatants. Tukey–Kramer test was used to compare differences between groups. Microtubule acetylation proceeds globally in mast cell cytoplasm after antigen stimulation in addition to accelerated formation of microtubule-organizing centers. Pretreatment with 5Z-7-oxozeaenol (5 µmol/l), an inhibitor of TGF-β-activated kinase 1, which is a key activator of α-tubulin acetyltransferase 1, did not affect the distribution and acetylation of microtubules in resting cells; however, it significantly suppressed antigen-evoked microtubule acetylation and their reorganization, and subsequent degranulation (95.0 ± 1.2% inhibition, n = 3, P < 0.01). These results provided new insight into the post-translational modifications of microtubule to regulate mast cell degranulation.

In the present study, we investigated the relation between the inflammatory mediators such as nitric oxide, prostaglandins, and cysteinyl-leukotrienes with mucin release and the sympathetic system in submandibular glands from rats with experimental periodontitis. Submandibular glands from rats with experimental periodontitis. For the first experiment, rats were treated with hydrocortisone sc, 1 mg/kg for 3 days. All other experiments were carried out in isolated submandibular glands from untreated rats. Submandibular glands were treated with cysteinyl-leukotrienes, isoproterenol, NDGA, FPL 55712, L-NMMA, Nio, Nz, AMG, indomethacin, DuP 697 and atenolol. Nitric oxide synthase activity, prostaglandin and cysteinyl-leukotriene productions and mucin secretion were determined. The Newman–Keuls statistical test was applied after analysis of variance. In rats with periodontitis hydrocortisone-induced a 36.6% (P < 0.05) decrease in mucin release. Only cysteinyl-leukotriene production was increased in rats with ligature (79.2%, P < 0.001). Either the inhibition of cysteinyl-leukotriene production or the block of leukotriene receptor abolished the increase in mucin secretion by 25.6% (P < 0.05) and 37% (P < 0.01), respectively, in glands from rats with ligature. On the other hand, the presence of cysteinyl-leukotrienes in the incubation medium induced mucin release from submandibular glands. Atenolol diminished by 24% (P < 0.05), the increase in cysteinyl-leukotrienes observed in rats with periodontitis. Besides, isoproterenol induced cysteinyl-leukotriene production in both groups. In submandibular glands from rats with periodontitis, the increment in mucin release and cysteinyl-leukotrienes production are related events and both are associated with the sympathetic system.

Gastric acid secretion, whole blood histamine concentration and serum gastrin were measured in dogs, equipped with Heidenhain pouch, in response to feeding alone and in combination with antral histamine (AH) — Antramine-or with somatostatin. Feeding stimulated acid secretion, histamine and gastrin responses in a dose-related manner. Addition of antramine to feeding resulted in a potentiated acid and gastrin responses while histamine response corresponded to sum of individual responses to antramine and to feeding. Somatostatin reduced markedly acid and histamine responses, while gastrin response was unchanged. Serum gastrin and whole blood histamine appear to be agonistic factors responsible together for acid secretion. Somatostatin suppresses histamine response and would inhibit gastrin activity on acid secreting cells by this mean. Somatostatin and histamine might act antagonistically on gastrin which would be their common substrate, and thus they could intervene in a regulation process of acid secretion. In regard to synthetic histamine, native antral histamine — antramine — appears to be a better candidate for a physiological histamine regulation of acid secretion.