Charlie Norwood VA Medical Center

About: Charlie Norwood VA Medical Center is a healthcare organization based out in Augusta, Georgia, United States. It is known for research contribution in the topics: Autophagy & Kidney. The organization has 349 authors who have published 490 publications receiving 16360 citations. The organization is also known as: Augusta VA Medical Center.

Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke.

Abstract: Background and purpose The role of autophagy in response to ischemic stroke has been confusing with reports that both enhancement and inhibition of autophagy decrease infarct size and improve post-stroke outcomes. We sought to clarify this by comparing pharmacologic modulation of autophagy in two clinically relevant murine models of stroke.

Type I interferon suppresses tumor growth through activating the STAT3-granzyme B pathway in tumor-infiltrating cytotoxic T lymphocytes

Abstract: Type I interferons (IFN-I) have recently emerged as key regulators of tumor response to chemotherapy and immunotherapy. However, IFN-I function in cytotoxic T lymphocytes (CTLs) in the tumor microenvironment is largely unknown. Tumor tissues and CTLs of human colorectal cancer patients were analyzed for interferon (alpha and beta) receptor 1 (IFNAR1) expression. IFNAR1 knock out (IFNAR-KO), mixed wild type (WT) and IFNAR1-KO bone marrow chimera mice, and mice with IFNAR1 deficiency only in T cells (IFNAR1-TKO) were used to determine IFN-I function in T cells in tumor suppression. IFN-I target genes in tumor-infiltrating and antigen-specific CTLs were identified and functionally analyzed. IFNAR1 expression level is significantly lower in human colorectal carcinoma tissue than in normal colon tissue. IFNAR1 protein is also significantly lower on CTLs from colorectal cancer patients than those from healthy donors. Although IFNAR1-KO mice exhibited increased susceptibility to methylcholanthrene-induced sarcoma, IFNAR1-sufficient tumors also grow significantly faster in IFNAR1-KO mice and in mice with IFNAR1 deficiency only in T cells (IFNAR1-TKO), suggesting that IFN-I functions in T cells to enhance host cancer immunosurveillance. Strikingly, tumor-infiltrating CTL levels are similar between tumor-bearing WT and IFNAR1-KO mice. Competitive reconstitution of mixed WT and IFNAR1-KO bone marrow chimera mice further determined that IFNAR1-deficient naive CTLs exhibit no deficiency in response to vaccination to generate antigen-specific CTLs as compared to WT CTLs. Gene expression profiling determined that Gzmb expression is down-regulated in tumor-infiltrating CTLs of IFNAR1-KO mice as compared to WT mice, and in antigen-specific IFNAR1-KO CTLs as compared to WT CTLs in vivo. Mechanistically, we determined that IFN-I activates STAT3 that binds to the Gzmb promoter to activate Gzmb transcription in CTLs. IFN-I induces STAT3 activation to activate Gzmb expression to enhance CTL effector function to suppress tumor development. Human colorectal carcinoma may use down-regulation of IFNAR1 on CTLs to suppress CTL effector function to evade host cancer immunosurveillance.

Specific mitochondrial calcium overload induces mitochondrial fission in prostate cancer cells

Abstract: Mitochondria are structurally complex organelles that undergo fragmentation or fission in apoptotic cells. Mitochondrial fission requires the cytoplasmic dynamin-related protein, Drp1, which translocates to the mitochondria during apoptosis and interacts with the mitochondrial protein, Fis1. Finely tuned changes in cellular calcium modulate a variety of intracellular functions; in resting cells, the level of mitochondrial calcium is low, while it is higher during apoptosis. Mitochondria take up Ca(2+) via the Uniporter and extrude it to the cytoplasm through the mitochondrial Na+/Ca(2+) exchanger. Overload of Ca(2+) in the mitochondria leads to their damage, affecting cellular function and survival. The mitochondrial Na+/Ca2+ exchanger was blocked by benzodiazepine, CGP37157 (CGP) leading to increased mitochondrial calcium and enhancing the apoptotic effects of TRAIL, TNFalpha related apoptosis inducing ligand. In the present study, we observed that increasing mitochondrial calcium induced mitochondrial fragmentation, which correlated with the presence of Drp1 at the mitochondria in CGP treated cells. Under these conditions, we observed interactions between Drp1 and Fis1. The importance of Drp1 in fragmentation was confirmed by transfection of dominant negative Drp1 construct. However, fragmentation of the mitochondria was not sufficient to induce apoptosis, although it enhanced TRAIL-induced apoptosis. Furthermore, oligomerization of Bak was partially responsible for the increased apoptosis in cells treated with both CGP and TRAIL. Thus, our results show that combination of an apoptogenic agent and an appropriate calcium channel blocker provide therapeutic advantages.