3-Cinnamoyl-4-hydroxy-6-methyl-2H-pyran-2-one ameliorates diabetic peripheral neuropathy in type 2 diabetes mellitus rats via PI3K/Akt signaling pathway

Purpose: To investigate the curative effects of 3-cinnamoyl-4-hydroxy-6-methyl-2H-pyran-2-one (CHMP) on streptozotocin (STZ)-induced model of diabetic SD rats, and the underlying mechanism. Method: Diabetes was induced in rats using single intraperitoneal injection of STZ. Subsequently, diabetic and non-diabetic rats were randomly grouped into five experimental groups. Six weeks after the STZ-injection, the diabetic animals were orally administered test compound (CHMP) at two doses of 10 and 20 mg/kg body weight for 6 weeks. Thereafter, the rats were anesthetised, and body weight, blood sugar, and motor nerve conduction velocity (MNCV) were determined. Moreover, real time-polymerase chain reaction (RT-PCR) and western blot analysis were used to assay the expression levels of genes in PIK3/Akt pathway and Glut4. Results: Treatment of diabetic rats with CHMP significantly reduced levels of fasting blood glucose and enhanced average rat body weight, relative to diabetic control (p ˂ 0.05). Motor nerve conduction velocity (MNCV) was remarkably increased in CHMP-treated rats (54.2 ± 2.2), when compared to the diabetic control rats (46 ± 4.1, p < 0.01). Results from RT-PCR and western blot indicated increased expressions of PI3K, Akt and IRS-1, and down regulation of GSK-3B expression in skeletal muscle. The CHMP treatment also upregulated the Glut4 expression in skeletal muscle. Conclusion: These findings show that CHMP may be beneficial in the management of diabetic neuropath

ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages

The mammalian ATP-binding cassette transporters A1 and A7 (ABCA1 and -A7) show sequence similarity to CED-7, a Caenorhabditis elegans gene that mediates the clearance of apoptotic cells. Using RNA interference or gene targeting, we show that knock down of macrophage ABCA7 but not -A1 results in defective engulfment of apoptotic cells. In response to apoptotic cells, ABCA7 moves to the macrophage cell surface and colocalizes with the low-density lipoprotein receptor–related protein 1 (LRP1) in phagocytic cups. The cell surface localization of ABCA7 and LRP1 is defective in ABCA7-deficient cells. C1q is an opsonin of apoptotic cells that acts via phagocyte LRP1 to induce extracellular signal–regulated kinase (ERK) signaling. We show that ERK signaling is required for phagocytosis of apoptotic cells and that ERK phosphorylation in response to apoptotic cells or C1q is defective in ABCA7-deficient cells. These studies reveal a major role of ABCA7 and not -A1 in the clearance of apoptotic cells and therefore suggest that ABCA7 is an authentic orthologue of CED-7

AAGAB is an assembly chaperone regulating AP1 and AP2 clathrin adaptors

Multimeric cargo adaptors such as AP2 play central roles in intracellular membrane trafficking. We recently discovered that the assembly of the AP2 adaptor complex, a key player in clathrin-mediated endocytosis, is a highly organized process controlled by alpha- and gamma-adaptin-binding protein (AAGAB, also known as p34). In this study, we demonstrate that besides AP2, AAGAB also regulates the assembly of AP1, a cargo adaptor involved in clathrin-mediated transport between the trans-Golgi network and the endosome. However, AAGAB is not involved in the formation of other adaptor complexes, including AP3. AAGAB promotes AP1 assembly by binding and stabilizing the &gamma; and &sigma; subunits of AP1, and its mutation abolishes AP1 assembly and disrupts AP1-mediated cargo trafficking. Comparative proteomic analyses indicate that AAGAB mutation massively alters surface protein homeostasis, and its loss-of-function phenotypes reflect the synergistic effects of AP1 and AP2 deficiency. Taken together, these findings establish AAGAB as an assembly chaperone for both AP1 and AP2 adaptors and pave the way for understanding the pathogenesis of AAGAB-linked diseases. &nbsp;</p

Role for nuclear interleukin-37 in the suppression of innate immunity

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Extracellular and nuclear roles of IL-37 after spinal cord injury

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Comprehensive landscape-style investigation of the molecular mechanism of acupuncture at ST36 single acupoint on different systemic diseases

The principle of acupoint stimulation efficacy is based on traditional meridian theory. However, the molecular mechanisms underlying the therapeutic effects of acupoints in treating diseases remain unclear in modern scientific understanding. In this study, we selected the ST36 acupoint for investigation and summarized all relevant literature from the PubMed database over the past 10 years. The results indicate that stimulation of ST36 single acupoints has therapeutic effects mainly in models of respiratory, neurological, digestive, endocrine and immune system diseases. And it can affect the inflammatory state, oxidative stress, respiratory mucus secretion, intestinal flora, immune cell function, neurotransmitter transmission, hormone secretion, the network of Interstitial Cells of Cajal (ICC) and glucose metabolism of the organism in these pathological states. Among them, acupuncture at the ST36 single point has the most prominent function in regulating the inflammatory state, which can mainly affect the activation of MAPK signaling pathway and drive the ''molecular-cellular'' mode involving macrophages, T-lymphocytes, mast cells (MCs) and neuroglial cells as the core to trigger the molecular level changes of the acupuncture point locally or in the target organ tissues, thereby establishing a multi-system, multi-target, multi-level molecular regulating mechanism. This article provides a comprehensive summary and discussion of the molecular mechanisms and effects of acupuncture at the ST36 acupoint, laying the groundwork for future in-depth research on acupuncture point theory

Activation of Host-NLRP3 Inflammasome in Myeloid Cells Dictates Response to Anti-PD-1 Therapy in Metastatic Breast Cancers

Tumor-associated inflammation leads to dysregulated cytokine production that promotes tumor immune evasion and anti-tumor immunity dysfunction. In advanced stage breast cancer, the proinflammatory cytokine IL-1β is overexpressed due to large proportions of activated myeloid cells in the tumor microenvironment (TME). Here, we demonstrate the role of the host nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing 3 (NLRP3) inflammasome in metastatic breast cancer. In vitro, we show that stimulation of THP-1 cells with conditioned media collected from MDA-MB-468 cells induced NLRP3 activation and increased Pdcd1l1 expression. In vivo, mice deficient in NLRP3 orthotopically implanted with metastatic breast cancer cell line (E0771) showed significant reduction in tumor growth (p p ® reduced expression of Pdcd1l1 (p Casp1 (p Il1b (p ® showed reduced infiltration of myeloid-derived suppressor cells (MDSCs) (p + T cells (p p p < 0.05). These data define NLRP3 activation as a key driver of immune suppression in metastatic breast cancers. Furthermore, this study suggests NLRP3 as a valid target to increase efficacy of immunotherapy with checkpoint inhibitor in metastatic breast cancers

Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue

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