Inhibition of Src homology 2 domain containing protein tyrosine phosphatase as the possible mechanism of metformin-assisted amelioration of obesity induced insulin resistance in high fat diet fed C57BL/6J mice.

SHP-1 (Src homology 2 domain containing protein tyrosine phosphatase) is a known negative regulator of insulin signaling and inflammation. To date, the molecular mechanism of metformin in modulating SHP-1 expression has remained elusive. In the present study, we have investigated the role of SHP-1 in relation to anti-hyperglycemic and anti-inflammatory actions of metformin in an obese phenotype mouse model. We observed that metformin treatment significantly reduced SHP-1 activity in obese mice, leading to improved insulin sensitivity. Additionally, metformin down regulated inflammatory markers like TLR2, TLR4, CD80, CD86, NF-κB, STAT1 and suppressed adipose tissue inflammation by efficiently polarizing adipose tissue macrophages toward anti-inflammatory state by way of indirect inhibition of SHP-1 mRNA and protein expressions. Our study suggests that metformin exerts its insulin sensitizing effects via inhibition of SHP-1 activity and expression.

Macrophage polarization: the link between inflammation and related diseases.

OBJECTIVE: In the present review, we try to critically evaluate the two faces of the macrophages and their roles in relation to gene alteration in some inflammatory conditions. The pros- and cons of each type of macrophage in immunologic outcomes are discussed. INTRODUCTION: If ''Diversity is the rule of nature'', macrophages have proven to be its obedient followers. A cell type that was classically considered to be activated by Interferon-c, under the influence of T(H)-1 type of response and a well-accepted warrior of cellular immunity to the intracellular pathogens is not as simple as once considered. Past decade has revolutionized this notion with the advent of T(H)-2 influenced alternatively activated macrophages, now established as wound repairing and tissue regenerating. METHODS: Literature survey was done to present a detailed study on this macrophage dichotomy and its relevance to immune disorders via expression of some critical genes, nuclear factor kappa-light-chain-enhancer of activated B cells, peroxisome proliferator-activated receptors and SH2-containing inositol-50-phosphatase 1, highly implicated in a myriad of immunological emergencies like inflammation, insulin resistance, wound healing, cancer, etc. CONCLUSION: The evaluation of macrophage dichotomy in these disorders may prove to be the first step towards the formulation of innovative therapeutic approaches.

Implication of protein tyrosine phosphatase SHP-1 in cancer-related signaling pathways.

The altered expression of SHP-1 (SH2 domain-containing protein tyrosine phosphatase) as a consequence of promoter hypermethylation or mutations has evidently been linked to cancer development. The notion of being a cancer drug target is conceivable as SHP-1 negatively regulates cell cycle and inflammatory pathways which are an inevitable part of oncogenic transformation. In the present review, we try to critically analyze the role of SHP-1 in cancer progression via regulating the above mentioned pathways with the major emphasis on cell cycle components and JAK/STAT pathway, commencing with the SHP-1 biology in immune cell signaling. Lastly, we have provided the future directions for researchers to encourage SHP-1 as a prognostic marker and curative target for this debilitating disease called as cancer.

Correction: Identification of protein targets and the mechanism of the cytotoxic action of Ipomoea turpethum extract loaded nanoparticles against breast cancer cells.

Correction for 'Identification of protein targets and the mechanism of the cytotoxic action of Ipomoea turpethum extract loaded nanoparticles against breast cancer cells' by Mohd Mughees et al., J. Mater. Chem. B, 2019, 7, 6048-6063.

Identification of protein targets and the mechanism of the cytotoxic action of Ipomoea turpethum extract loaded nanoparticles against breast cancer cells.

The shortcomings of the currently available anti-breast cancer agents compel the development of the safer targeted drug delivery for the treatment of breast cancer. The aim of the present study was to evaluate the anti-breast cancer potential of Ipomoea turpethum extract loaded nanoparticles (NIPAAM-VP-AA) against breast cancer, together with the identification of the key proteins responsible for the caused cytotoxicity. For this, we explored the tumor microenvironment for targeted drug delivery and synthesized (temperature and pH responsive) double triggered polymeric nanoparticles by the free radical mechanism and characterized them by DLS and TEM. The extract which emerged as the best extract, i.e. root extract, was loaded on the nanoparticles and the cytotoxicity was evaluated in breast cancer cell lines (MCF-7 and MDA-MB-231) by various cytotoxic assays like MTT assay, CFSE cell proliferation assay, apoptosis assay, cell cycle study and DAPI nuclear staining. The key protein targets responsible for the caused cytotoxicity were identified by nano-LC-MS/MS analysis. The proteome analysis revealed that most of the significantly differentially expressed proteins have a role in proliferation, vesicular trafficking, apoptosis and tumor suppression. Finally, the interaction among the highly differentially expressed proteins was identified by using the STRING online tool, which showed that I. turpethum nanoparticles caused apoptosis in MCF-7 and MDA MB-231 cells by targeting nucleolysin TIAR, serine/threonine-protein phosphatase PP1 and ubiquitin-60S ribosomal protein L40.

Targeted SHP-1 Silencing Modulates the Macrophage Phenotype, Leading to Metabolic Improvement in Dietary Obese Mice.

Chronic over-nutrition promotes adipocyte hypertrophy that creates inflammatory milieu leading to macrophage infiltration and their phenotypic switching during obesity. The SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1) has been identified as an important player in inflammatory diseases involving macrophages. However, the role of SHP-1 in modulating the macrophage phenotype has not been elucidated yet. In the present work, we show that adipose tissue macrophage (ATM)-specific deletion of SHP-1 using glucan particle-loaded siRNA improves the metabolic phenotype in dietary obese insulin-resistant mice. The molecular mechanism involves AT remodeling via reducing crown-like structure formation and balancing the pro-inflammatory (M1) and anti-inflammatory macrophage (M2) population. Therefore, targeting ATM-specific SHP-1 using glucan-particle-loaded SHP-1 antagonists could be of immense therapeutic use for the treatment of obesity-associated insulin resistance.

Alteration of adipose tissue immune cell milieu towards the suppression of inflammation in high fat diet fed mice by flaxseed oil supplementation.

The present study evaluates the effect of flaxseed oil (FXO) supplementation on adipose tissue macrophages (ATM's), E and D series resolvin (Rv) levels and adipose tissue inflammation. Male C57BL/6J mice were divided into five groups (n = 5): lean group (given standard chow diet), HFD group given high fat diet (approx. 18 weeks) till they developed insulin resistance and 4, 8 or 16 mg/kg group (HFD group later orally supplemented with 4, 8 or 16 mg/kg body weight flaxseed oil) for 4 weeks.The present study showed that FXO supplementation led to enhanced DHA, EPA, RvE1-E2, RvD2, RvD5- D6, IL-4, IL-10 and arginase 1 levels in ATMs together with altered immune cell infiltration and reduced NF-κB expression. The FXO supplementation suppresses immune cell infiltration into adipose tissue and alters adipose tissue macrophage phenotype towards the anti-inflammatory state via enhancement of E and D series resolvins, arginase 1 expression and anti-inflammatory cytokines level (IL-4 and IL-10.) leading to amelioration of insulin resistance in flaxseed oil supplemented HFD mice.

Amelioration of obesity-associated inflammation and insulin resistance in c57bl/6 mice via macrophage polarization by fish oil supplementation.

Enormous phenotypic plasticity makes macrophages the target cells in obesity-associated inflammatory diseases. Thus, nutritional components that polarize macrophages toward antiinflammatory phenotype can partially reverse inflammatory diseases like insulin resistance. In the present study, macrophage-polarizing and insulin-sensitizing properties of fish oil (FO) were evaluated in obese insulin-resistant c57bl/6 mice fed high-fat diet (HFD-IR) after oral supplementation with FO (4, 8 or 16mg/kg body weight) and compared to lean and HFD-IR mice. FO-supplemented HFD-IR mice exhibited reduced adiposity index, serum cholesterol and triglycerides and increased insulin sensitization and showed improved adipose tissue physiology under light and transmission electron microscopy. NF-κB/P65 expression showed a downward shift on FO supplementation. The surface marker of M1 macrophages (CD-86) and the TLR-4 expression reduced with the increased supplementation of FO. Expression of arginase 1, an important marker of M2 macrophages, increased in a dose-dependent manner in response to FO dosage, which was observed at protein level by the western blotting and at mRNA level by real-time PCR. The cytokine profile of adipose tissue macrophages showed a steep shift toward antiinflammatory ones (IL-4 and IL-10) from the inflammatory TNF-α, IFN-γ, IL-2 and IL-1ß. Thus, macrophage polarization seems to be the plausible mechanism via which FO alleviates obesity-induced inflammation and insulin resistance.

Balanced TH1 and TH2 immunopotentiating effects of silicates partly containing nanoparticles present in calcined serpentine.

Calcined Serpentine (CS) is used in various formulations of alternative systems of medicine as a tonic to vital organs and as an anti-inflammatory agent. The process of calcination or incineration is believed to render non-toxic, gently absorbable, adaptable and digestible properties to the mineral compounds. The present study characterized CS and also evaluated its immunostimulatory potential. CS was characterized by using transmission electron microscopy (TEM), X-ray powder diffraction, atomic absorption spectroscopy and CHNS analysis. The characterized CS was further evaluated for its immunomodulatory potential in Swiss mice. X-Ray diffraction analysis revealed that the CS contained silicates of magnesium, calcium and iron as major minerals. Elemental composition and heavy metal analyses showed a presence of various inorganic elements/heavy metals, albeit at levels well below daily permissive intake values. TEM analysis of the test CS revealed a presence of nano particles with an average size of 10-20 nm (≈ 26% of total material). Oral administration of CS to mice at 50, 75, 100 or 200 µg/kg body weight for 10 days led to enhanced levels of total IgG, IgG1, IgG2a and IgG2b in ovalbumin-immunized mice as well as ex vivo lymphocyte proliferation and levels of TH1 (IL-2, IFNγ) and TH2 (IL-4, IL-10) cytokines produced by their cultured splenocytes. Similarly, CS treatment resulted in enhanced delayed-type hypersensitivity responses in GRBC-primed hosts. CS also activated host peritoneal macrophages, as indicated by increases in phagocytic activity and in TLR-2, CD80 and CD86 expression. The CS did not affect liver, kidney and spleen histology. Taken together, the results indicated that absorbed CS was stimulatory of host cell-mediated immune responses. It is hypothesized for now that the immunomodulatory effect of CS may have been due, in part, to a presence of nanoparticles on the CS; further study is required to validate this viewpoint.

Protein tyrosine phosphatase SHP-1: resurgence as new drug target for human autoimmune disorders.

Recognition of self-antigen and its destruction by the immune system is the hallmark of autoimmune diseases. During the developmental stages, immune cells are introduced to the self-antigen, for which tolerance develops. The inflammatory insults that break the immune tolerance provoke immune system against self-antigen, progressively leading to autoimmune diseases. SH2 domain containing protein tyrosine phosphatase (PTP), SHP-1, was identified as hematopoietic cell-specific PTP that regulates immune function from developing immune tolerance to mediating cell signaling post-immunoreceptor activation. The extensive research on SHP-1-deficient mice elucidated the diversified role of SHP-1 in immune regulation, and inflammatory process and related disorders such as cancer, autoimmunity, and neurodegenerative diseases. The present review focalizes upon the implication of SHP-1 in the pathogenesis of autoimmune disorders, such as allergic asthma, neutrophilic dermatosis, atopic dermatitis, rheumatoid arthritis, and multiple sclerosis, so as to lay the background in pursuance of developing therapeutic strategies targeting SHP-1. Also, new SHP-1 molecular targets have been suggested like SIRP-α, PIPKIγ, and RIP-1 that may prove to be the focal point for the development of therapeutic strategies.