Metformin Decreases 2-HG Production through the MYC-PHGDH Pathway in Suppressing Breast Cancer Cell Proliferation

The biguanide drug metformin has been widely used for the treatment of type 2 diabetes, and there is evidence supporting the anticancer effect of metformin despite some controversy. Here, we report the growth inhibitory activity of metformin in the breast cancer (MCF-7) cells, both in vitro and in vivo, and the associated metabolic changes. In particular, a decrease in a well-known oncometabolite 2-hydroxyglutarate (2-HG) was discovered by a metabolomics approach. The decrease in 2-HG by metformin was accompanied by the reduction in histone methylation, consistent with the known tumorigenic mechanism of 2-HG. The relevance of 2-HG inhibition in breast cancer was also supported by a higher level of 2-HG in human breast cancer tissues. Genetic knockdown of PHGDH identified the PHGDH pathway as the producer of 2-HG in the MCF-7 cells that do not carry isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) mutations, the conventional producer of 2-HG. We also showed that metformin's inhibitory effect on the PHGDH-2HG axis may occur through the regulation of the AMPK-MYC pathway. Overall, our results provide an explanation for the coherent pathway from complex I inhibition to epigenetic changes for metformin's anticancer effect.Peer reviewe

Genome-Based Construction of the Metabolic Pathways of Orientia tsutsugamushi and Comparative Analysis within the Rickettsiales Order

Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular bacterium that belongs to the order of Rickettsiales. Recently, we have reported that O. tsutsugamushi has a unique genomic structure, consisting of highly repetitive sequences, and suggested that it may provide valuable insight into the evolution of intracellular bacteria. Here, we have used genomic information to construct the major metabolic pathways of O. tsutsugamushi and performed a comparative analysis of the metabolic genes and pathways of O. tsutsugamushi with other members of the Rickettsiales order. While O. tsutsugamushi has the largest genome among the members of this order, mainly due to the presence of repeated sequences, its metabolic pathways have been highly streamlined. Overall, the metabolic pathways of O. tsutsugamushi were similar to Rickettsia but there were notable differences in several pathways including carbohydrate metabolism, the TCA cycle, and the synthesis of cell wall components as well as in the transport systems. Our results will provide a useful guide to the postgenomic analysis of O. tsutsugamushi and lead to a better understanding of the virulence and physiology of this intracellular pathogen

Minocycline markedly reduces acute visceral nociception via inhibiting neuronal ERK phosphorylation

<p>Abstract</p> <p>Background</p> <p>Minocycline prevents the development of neuropathic and inflammatory pain by inhibiting microglial activation and postsynaptic currents. But, how minocycline obviates acute visceral pain is unclear. The present study investigated whether minocycline had an any antinociceptive effect on acetic acid-induced acute abdominal pain after intraperitoneal (i.p.) administration of saline or minocycline 1 hour before acetic acid injection (1.0%, 250 μl, i.p.).</p> <p>Results</p> <p>Minocycline (4, 10, or 40 mg/kg) significantly decreased acetic acid-induced nociception (0-60 minutes post-injection) and the enhancement in the number of c-Fos positive cells in the T5-L2 spinal cord induced by acetic acid injection. Also, the expression of spinal phosphorylated extracellular signal-regulated kinase (p-ERK) induced by acetic acid was reduced by minocycline pre-administration. Interestingly, intrathecal introduction of PD98059, an ERK upstream kinase inhibitor, markedly blocked the acetic acid-stimulated pain responses.</p> <p>Conclusions</p> <p>These results demonstrate that minocycline effectively inhibits acetic acid-induced acute abdominal nociception via the inhibition of neuronal p-ERK expression in the spinal cord, and that minocycline may have therapeutic potential in suppressing acute abdominal pain.</p

Inhibition of T Cell Receptor Signal Transduction by Tyrosine Kinase–interacting Protein of Herpesvirus saimiri

T cells play a central role in orchestrating immunity against pathogens, particularly viruses. Thus, impairing T cell activation is an important strategy employed by viruses to escape host immune control. The tyrosine kinase–interacting protein (Tip) of the T lymphotropic Herpesvirus saimiri (HVS) is constitutively present in lipid rafts and interacts with cellular Lck tyrosine kinase and p80 endosomal protein. Here we demonstrate that, due to the sequestration of Lck by HVS Tip, T cell receptor (TCR) stimulation fails to activate ZAP70 tyrosine kinase and to initiate downstream signaling events. TCR ζ chains in Tip-expressing T cells were initially phosphorylated to recruit ZAP70 molecule upon TCR stimulation, but the recruited ZAP70 kinase was not subsequently phosphorylated, resulting in TCR complexes that were stably associated with inactive ZAP70 kinase. Consequently, Tip expression not only markedly inhibited TCR-mediated intracellular signal transduction but also blocked TCR engagement with major histocompatibility complexes on the antigen-presenting cells and immunological synapse formation. These results demonstrate that a lymphotropic herpesvirus has evolved a novel mechanism to deregulate T cell activation to disarm host immune surveillance. This process contributes to the establishment and maintenance of viral latency

Elevated IFNA1 and suppressed IL12p40 associated with persistent hyperinflammation in COVID-19 pneumonia

IntroductionDespite of massive endeavors to characterize inflammation in COVID-19 patients, the core network of inflammatory mediators responsible for severe pneumonia stillremain remains elusive. MethodsHere, we performed quantitative and kinetic analysis of 191 inflammatory factors in 955 plasma samples from 80 normal controls (sample n = 80) and 347 confirmed COVID-19 pneumonia patients (sample n = 875), including 8 deceased patients. ResultsDifferential expression analysis showed that 76% of plasmaproteins (145 factors) were upregulated in severe COVID-19 patients comparedwith moderate patients, confirming overt inflammatory responses in severe COVID-19 pneumonia patients. Global correlation analysis of the plasma factorsrevealed two core inflammatory modules, core I and II, comprising mainly myeloid cell and lymphoid cell compartments, respectively, with enhanced impact in a severity-dependent manner. We observed elevated IFNA1 and suppressed IL12p40, presenting a robust inverse correlation in severe patients, which was strongly associated with persistent hyperinflammation in 8.3% of moderate pneumonia patients and 59.4% of severe patients. DiscussionAberrant persistence of pulmonary and systemic inflammation might be associated with long COVID-19 sequelae. Our comprehensive analysis of inflammatory mediators in plasmarevealed the complexity of pneumonic inflammation in COVID-19 patients anddefined critical modules responsible for severe pneumonic progression

Prognostic Value of Postoperative CEA Clearance in Rectal Cancer Patients with High Preoperative CEA Levels

PURPOSE: We determined the prognostic value of carcinoembryonic antigen (CEA) clearance after tumor resection with serial evaluation of postoperative CEA levels in rectal cancer. METHODS: Between 1994 and 2004, we retrospectively reviewed 122 patients with rectal cancer whose serum CEA levels were measured on the preoperative day and postoperative days 7 and 30. Patients with preoperative CEA levels <5.0 ng/ml were excluded. An exponential trend line was drawn using the three CEA values. Patients were categorized into three groups based on R(2) values calculated through trend line, which indicates the correlation coefficient between exponential graph and measured CEA values: exponential decrease group (group 1: 0.9 < R(2) < or = 1.0), nearly exponential decrease group (group 2: 0.5 < R(2) < or = 0.9), and randomized clearance group (group 3: 0.5 < or = R(2)). We then analyzed the CEA clearance pattern as a prognostic indicator. RESULTS: With a median follow-up of 57 months, the 5-year overall survival was 62.3% vs. 48.1% vs. 25% and the 5-year disease-free survival was 58.6% vs. 52.7% vs. 25% among groups 1, 2, and 3 (P = 0.014, P = 0.027, respectively) in patients with stage III rectal cancer. For those with stage II rectal cancer, the 5-year overall survival rate of group 1 was significantly better than groups 2 and 3 (88.8% vs. 74.1%, respectively, P = 0.021). CONCLUSIONS: the postoperative pattern of CEA clearance is a useful prognostic determinant in patients with rectal cancer. Patients with a randomized pattern of CEA clearance after tumor resection should be regarded as having the possibility of a persistent CEA source and may require consideration of intensive follow-up or adjuvant therapy.ope

Cystamine induces AIF-mediated apoptosis through glutathione depletion

AbstractCystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting γ-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death

Orientia tsutsugamushi and Comparative Analysis within the Rickettsiales Order

Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular bacterium that belongs to the order of Rickettsiales. Recently, we have reported that O. tsutsugamushi has a unique genomic structure, consisting of highly repetitive sequences, and suggested that it may provide valuable insight into the evolution of intracellular bacteria. Here, we have used genomic information to construct the major metabolic pathways of O. tsutsugamushi and performed a comparative analysis of the metabolic genes and pathways of O. tsutsugamushi with other members of the Rickettsiales order. While O. tsutsugamushi has the largest genome among the members of this order, mainly due to the presence of repeated sequences, its metabolic pathways have been highly streamlined. Overall, the metabolic pathways of O. tsutsugamushi were similar to Rickettsia but there were notable differences in several pathways including carbohydrate metabolism, the TCA cycle, and the synthesis of cell wall components as well as in the transport systems. Our results will provide a useful guide to the postgenomic analysis of O. tsutsugamushi and lead to a better understanding of the virulence and physiology of this intracellular pathogen

Imaging Findings of Castleman's Disease Localized in the Axilla: A Case Report

Castleman's disease is a rare benign lymphoproliferative disorder of uncertain origin which most commonly involves the mediastinum but rarely affects the axilla. We report a case of localized Castleman's disease involving the axillary lymph node. Mammography revealed a well-defined, homogeneously dense ovoid mass, 3 cm in size, in the left axilla, while gray-scale ultrasonography (US) demonstrated a well-defined, uniformly hypoechoic ovoid mass with good through transmission. Peripheral hypervascularity was observed at power Dopper US, and early rapid homogeneous enhancement at contrast-enhanced dynamic CT

Assessment of Cellular Uptake Efficiency According to Multiple Inhibitors of Fe3O4-Au Core-Shell Nanoparticles: Possibility to Control Specific Endocytosis in Colorectal Cancer Cells

Abstract Magnetite (Fe3O4)-gold (Au) core-shell nanoparticles (NPs) have unique magnetic and optical properties. When combined with biological moieties, these NPs can offer new strategies for biomedical applications, such as drug delivery and cancer targeting. Here, we present an effective method for the controllable cellular uptake of magnetic core-shell NP systems combined with biological moieties. Vimentin, which is the structural protein, has been biochemically confirmed to affect phagocytosis potently. In addition, vimentin affects exogenic materials internalization into cells even though under multiple inhibitions of biological moieties. In this study, we demonstrate the cellular internalization performance of Fe3O4-Au core-shell NPs with surface modification using a combination of biological moieties. The photofluorescence of vimentin-tagged NPs remained unaffected under multiple inhibition tests, indicating that the NPs were minimally influenced by nystatin, dynasore, cytochalasin D, and even the Muc1 antibody (Ab). Consequently, this result indicates that the Muc1 Ab can target specific molecules and can control specific endocytosis. Besides, we show the possibility of controlling specific endocytosis in colorectal cancer cells