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  • br Diabetes and obesity fit

    2024-05-15


    Diabetes and obesity: fit or fat; sugar or not: the autophagic verdict Type 2 diabetes and obesity are among the most emerging health problems worldwide. The factors that are responsible for the establishment of diabetes include decreased CGP 57380 australia production, rise in adiposity, and an increase in insulin resistance in skeletal muscles. The increase in adiposity and insulin resistance are primarily attributed to defective mitochondria characterized by impaired beta-oxidation, accumulation of lipids, oxidative stress, and hence mitochondrial damage. Autophagy, specifically mitophagy, at this stage eliminates oxidative stress and damaged mitochondria, thus playing a protective role against the development of insulin resistance and increase in adiposity [35,36].
    Microbial pathogenesis, inflammation, and immunity: fight or flight: the autophagic response Autophagy controls the intracellular pathogens in response to different types of infections. In many cases, it has been noticed that eukaryotic pathogens use their autophagic machinery for successful pathogenesis. On the other hand, intracellular pathogens can be sequestered in autophagosome for their degradation by lysosomes. This selective elimination of invading pathogens through autophagy is termed as xenophagy. The induction of xenophagy results with protein ubiquitination present on the pathogen-associated phagosomes. The adapter proteins including NDP52, optineurin and p62 binds to the ubiquitinated protein which further escorts the autophagic proteins required for the autophagosome formation. NDP52 also cooperates with a β‐galactose‐binding lectin, galectin‐8. As a result of rupture of phagosomal membrane by pathogens, NDP52 and galectin-8 access the β‐galactose chain of phagosomes resulting in the induction of xenophagy [46,47]. This specific pathway can be linked to various aspects of adaptive and innate immunity, including antigen presentation, cytokine and interferon production, and lymphocyte development. The relationship between classical autophagic response and microbial infection to adapt inside the host system rules the consequence of host-microbe interaction for disease growth and progression [46]. Autophagy is activated in most bacterial infections. During Listeria monocytogenes and Staphylococcus aureus infections, it has been reported that TLR2 stimulation induces autophagy [47]. TLR9 recognizes the CpG motifs of bacteria, which activate AMPK signaling pathway thus stimulating autophagy [48]. A very recent experiment validated the antimycobacterial effect of calcimycin against Mycobacterium bovis BCG as a result of autophagic up-regulation through an increase in Atg1, Atg7, Atg3, and LC3-II conversion. The effect of calcimycin was observed to decrease in the presence of an autophagic inhibitor 3MA [49]. In contrast, there are certain microorganisms, such as Brucella abortus and Porphyromonas gingivalis, where autophagy plays a protective role. Here, autophagosomes are prevented from the fusion with the lysosomes so that the bacterial content is protected against the lysosomal hydrolases and the bacteria use their hydrolases to process the autophagosome as components for energy. The action of Legionella pneumophila is even more critical. The bacteria reach the autophagolysosomes that already contain hydrolytic enzymes such that the lytic enzymes process the host-sequestered products that are used by the bacteria for to live [50]. It has been inspected that the infection of Herpes simplex virus stimulates autophagy to remove the viral particles [51]. An experiment confirmed the aforesaid statement where deletion in the dendritic cell Atg5 of mice showed impaired CD4 + T cell priming of the viral antigen after Herpes infection resulting in rapid disease condition [52]. Microbial infection is accompanied by an activation of the immune system of the host system where autophagy serves as a part of innate immunity, thereby eliminating the foreign pathogens [53]. Inflammasomes are cytosolic proteins that are produced in response to the invading pathogens. After activation, it proteolytically cleaves the pro-inflammatory cytokines IL1B. The canonical inflammasome comprises of PYCARD/ASC adaptor, pro-CASP1 (caspase 1) and some proteins for sensing microbial products including NLRC4, NLRP1 and NLRP3 along with endogenous agonists especially mitochondrial ROS and lysosomal damage. After the assembly of inflammasome components, CASP1 cleaves pro-IL1B to make ready to be secreted from the cells. It has shown that autophagy inhibits inflammasome activation through clearance of the damaged mitochondria and other organelles thereby ROS generation cannot activate the inflammasomes [54]. The antimicrobial defensive role of autophagy is found to be controlled by Th1/Th2 polarization. The Th1 cytokines induce autophagy, whereas Th2 cytokines inhibit it [53]. The pathogen-associated molecular patterns (PAMPS), which are present on the surfaces of microbial pathogens, have been found to activate the autophagy through regulation of Toll-like receptors (TLRs), present on the surfaces of macrophages and dendritic cells, cellular sensors for PAMPS. Thus, the invading pathogens are removed by autophagy response [55]. Autophagy is also induced by the bacterial LPS and TLR4 ligands, which belong to the diverse group of PAMPs, in macrophages [56]. Contrary, LPS has been shown to induce the secretion of IL1-b and IL-18 during deficiency of Atg161L, an essential component for autophagosome formation [57]. Similarly, autophagy inhibitors have been found to increase the activation of LPS-induced inflammasomes [58]. Further evidence proves the fact that Atg5 deletion causes the enhancement of both interferon-alpha and interferon 1 in response to single-stranded RNA viruses [59]. Atg16l1 and Atg7 deletions, with a deficiency in Beclin1 and LC3B in monocytes and macrophages of the mouse, cause the enhanced secretion of IL-1beta and IL-18, the pro-inflammatory cytokines in response to LPS. However, deletions of Atg16l and Atg7 had no effect on the production of TNF and IFN-beta [60]. The Epstein-Barr virus infection demonstrated reduced MHC-II antigen presentation when Atg12 was genetically altered [61].