Healynichols2067

Low response to glucocorticoid (GC) predicts therapeutic failure in acute T lymphoblastic leukemia (T-ALL). The efficient and safe strategies are still required for the treatment of relapsed T-ALL. Our previous study revealed that tetrandrine induces apoptosis in human T lymphoblastoid leukemia cells possibly via activation of NF-κB. GCs are recognized as typical NF-κB inhibitors and are used for the treatment of T-ALL patients. In the present study, we examined whether methylprednisolone (MP) potentiates the cytotoxic effect of tetrandrine (TET) via NF-κB regulation by using human T lymphoblastoid leukemia MOLT-4 cells. WST-8 assay data showed that nM grade of MP increased cytotoxicity of TET against MOLT-4 cells in vitro. This effect seemed to be related to the potentiation of TET action by MP to induce apoptosis. Meanwhile, the combination also impeded the transition of cell cycle from G0/G1 phase to S phase. However, the regulation effect of this combination on cell cycle had no relationship with cyclin signaling pathway, since the drug-combination did not influence on the expression of cyclin A2/B1/D1 in MOLT-4 cells. On the other hand, the combination significantly inhibited the phosphorylation of NF-κB (p less then 0.01). DNA inhibitor These results suggest that nM grade of MP potentiates the cytotoxic effect of TET possibly via regulation of NF-κB activation and "G0/G1 to S" phase transition in human T lymphoblastoid leukemia MOLT-4 cells. Combination of TET and MP may provide a new therapeutic strategy for relapsed T-ALL.Postsynaptic Density Protein-95 (PSD-95) is a major scaffolding protein in the excitatory synapses in the brain and a critical regulator of synaptic maturation for NMDA and AMPA receptors. PSD-95 deficiency has been linked to cognitive and learning deficits implicated in neurodevelopmental disorders such as autism and schizophrenia. Previous studies have shown that PSD-95 deficiency causes a significant reduction in the excitatory response in the hippocampus. However, little is known about whether PSD-95 deficiency will affect gamma-aminobutyric acid (GABA)ergic inhibitory synapses. Using a PSD-95 transgenic mouse model (PSD-95+/-), we studied how PSD-95 deficiency affects GABAA receptor expression and function in the medial prefrontal cortex (mPFC) during adolescence. Our results showed a significant increase in the GABAA receptor subunit α1. Correspondingly, there are increases in the frequency and amplitude in spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons in the mPFC of PSD-95+/- mice, along with a significant increase in evoked IPSCs, leading to a dramatic shift in the excitatory-to-inhibitory balance in PSD-95 deficient mice. Furthermore, PSD-95 deficiency promotes inhibitory synapse function via upregulation and trafficking of NLGN2 and reduced GSK3β activity through tyr-216 phosphorylation. Our study provides novel insights on the effects of GABAergic transmission in the mPFC due to PSD-95 deficiency and its potential link with cognitive and learning deficits associated with neuropsychiatric disorders.The core (capsid) protein of hepatitis B virus (HBV) is the building block of nucleocapsids where viral DNA reverse transcriptional replication takes place and mediates virus-host cell interaction important for the persistence of HBV infection. The pleiotropic role of core protein (Cp) in HBV replication makes it an attractive target for antiviral therapies of chronic hepatitis B, a disease that affects more than 257 million people worldwide without a cure. Recent clinical studies indicate that core protein allosteric modulators (CpAMs) have a great promise as a key component of hepatitis B curative therapies. Particularly, it has been demonstrated that modulation of Cp dimer-dimer interactions by several chemical series of CpAMs not only inhibit nucleocapsid assembly and viral DNA replication, but also induce the disassembly of double-stranded DNA-containing nucleocapsids to prevent the synthesis of cccDNA. Moreover, the different chemotypes of CpAMs modulate Cp assembly by interaction with distinct amino acid residues at the HAP pocket between Cp dimer-dimer interfaces, which results in the assembly of Cp dimers into either non-capsid Cp polymers (type I CpAMs) or empty capsids with distinct physical property (type II CpAMs). The different CpAMs also differentially modulate Cp metabolism and subcellular distribution, which may impact cccDNA metabolism and host antiviral immune responses, the critical factors for the cure of chronic HBV infection. This review article highlights the recent research progress on the structure and function of core protein in HBV replication cycle, the mode of action of CpAMs, as well as the current status and perspectives on the discovery and development of core protein-targeting antivirals. This article forms part of a symposium in Antiviral Research on "Wide-ranging immune and direct-acting antiviral approaches to curing HBV and HDV infections."The nuclear factor erythroid 2 related factor 2 (Nrf2) pathway upregulates key cellular defenses. Clinical trials are utilizing pharmacologic Nrf2 inducers such as bardoxolone methyl to treat chronic kidney disease, but Nrf2 activation has been linked to a paradoxical increase in; proteinuria. To understand this effect, we examined genetically engineered mice with elevated Nrf2 signaling due to reduced expression of the Nrf2 inhibitor, Kelch-like ECH-associated protein-1 (Keap1). These Keap1FA/FA mice lacked baseline proteinuria but exhibited increased; proteinuria in experimental models evoked by adriamycin, angiotensin II, or protein overload. After injury, Keap1FA/FA mice had increased glomerulosclerosis, nephrin disruption and shedding, podocyte injury, foot process effacement, and interstitial fibrosis. Keap1FA/FA mice also had higher daytime blood pressures and lower heart rates measured by radiotelemetry. Conversely, Nrf2 knockout mice were protected from proteinuria. We also examined the pharmacologic Nrf2 inducer CDDO-Im. Compared to angiotensin II alone, the combination of angiotensin II and CDDO-Im significantly increased proteinuria, a phenomenon not observed in Nrf2 knockout mice. This effect was not accompanied by additional increases in blood pressure. Finally, Nrf2 was found to be upregulated in the glomeruli of patients with focal segmental glomerulosclerosis, diabetic nephropathy, fibrillary glomerulonephritis, and membranous nephropathy. Thus, our studies demonstrate that Nrf2 induction in mice may exacerbate proteinuria in chronic kidney disease.Immunotactoid glomerulopathy (ITG) is a rare form of glomerulonephritis for which our understanding is limited to case reports and small case series. Herein we describe the clinical, pathologic, and outcome characteristics of 73 patients with ITG who typically presented with proteinuria, hematuria, and renal insufficiency. Hematologic disorders were present in 66% of patients, including lymphoma in 41% (mainly chronic lymphocytic leukemia/small lymphocytic lymphoma), monoclonal gammopathy in 20%, and multiple myeloma in 6%. Light microscopy revealed endocapillary proliferative (35%), membranoproliferative (29%) and membranous (29%) patterns of glomerular involvement. Electron microscopy revealed characteristic microtubular deposits with a diameter of 14-60 nm, hollow cores, frequent parallel alignment, and a predominant distribution outside of the lamina densa of the glomerular basement membrane. Importantly, immunofluorescence revealed IgG-dominant staining which was light chain and IgG subclass restricted in 67% of cases, indicating monoclonal composition. This finding was used to distinguish monoclonal and polyclonal variants of ITG. As compared to polyclonal, monoclonal ITG had a higher incidence of lymphoma (53% vs.11%), multiple myeloma (8% vs. 0), and monoclonal gammopathy (22% vs. 16%). Monoclonal ITG was more commonly treated with clone-directed therapy, which was associated with more frequent remission and less frequent end stage kidney disease. link2 Thus, a third of ITG cases are polyclonal but a quarter of these cases are associated with hematologic conditions, underscoring the need for hematologic evaluation in all patients with ITG. Hence, based on these distinctions, ITG should be subclassified into monoclonal and polyclonal variants. Prognosis of ITG is good if the underlying hematologic condition is treated.During embryonic development in bilaterally symmetric organisms, correct midline crossing is important for the proper formation of functional neural circuits. The aberrant development of neural circuits can result in multiple neurodevelopmental disorders, including horizontal gaze palsy, congenital mirror movement disorder, and autism spectrum disorder. Thus, understanding the molecular mechanisms that regulate proper axon guidance at the midline can provide insights into the pathology of neurological disorders. The signaling mechanisms that regulate midline crossing have been extensively studied in the Drosophila ventral nerve cord and the mouse embryonic spinal cord. In this review, we discuss these axon guidance mechanisms, highlighting the most recent advances in the understanding of how commissural axons switch their responsiveness from attractants to repellents during midline crossing.The community lockdown measures implemented in the United States from late March to late May of 2020 resulted in a significant reduction in the community transmission of the COVID-19 pandemic throughout the country. link3 However, a number of US states are currently experiencing an alarming post-lockdown resurgence of the pandemic, triggering fears for a devastating second pandemic wave. We designed a mathematical model for addressing the key question of whether or not the universal use of face masks can halt such resurgence (and possibly avert a second wave, without having to undergo another cycle of major community lockdown) in the states of Arizona, Florida, New York and the entire US. Model calibration, using cumulative mortality data for the four jurisdictions during their respective pre-lockdown and lockdown periods, show that pre-symptomatic and asymptomatically-infectious individuals are, by far, the main drivers of the COVID-19 pandemic in each of the jurisdictions. The implication of this result is that d strategy. Finally, it is shown that the universal use of face masks in public, with at least moderate level of compliance, could halt the post-lockdown resurgence of COVID-19, in addition to averting the potential for (and severity of) a second wave of the pandemic in each of the four jurisdictions.Mitochondrial dysfunction and stem cell exhaustion are among the nine separate hallmarks of aging. Emerging evidence however suggests that mitochondrial activity can have a profound influence on the self-renewal and function of stem cells, thus mechanistically linking mitochondrial function and stem cell decline. In this review, we discuss how accumulation of mtDNA mutations or alterations in mitochondrial dynamics, turnover, and signaling can modulate age-dependent stem cell function. Finally, we also describe how mitochondrial substrate utilization influences stem and progenitor activity. Together, this growing body of evidence suggests that modulation of mitochondrial activity might provide a strategy to slow or reverse age-dependent stem cell decline, and potentially, slow or reverse human aging.