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Advances in the development of mitochondrial pyruvate carrier inhibitors for therapeutic applications
Full text linkThe mitochondrial pyruvate carrier (MPC) is a transmembrane protein complex critical for cellular energy metabolism, enabling the transport of pyruvate from the cytosol into the mitochondria, where it fuels the citric acid cycle. By regulating this essential entry point of carbon into mitochondrial metabolism, MPC is pivotal for maintaining cellular energy balance and metabolic flexibility. Dysregulation of MPC activity has been implicated in several metabolic disorders, including type 2 diabetes, obesity, and cancer, underscoring its potential as a therapeutic target. This review provides an overview of the MPC complex, examining its structural components, regulatory mechanisms, and biological functions. We explore the current understanding of transcriptional, translational, and post-translational modifications that modulate MPC function and highlight the clinical relevance of MPC dysfunction in metabolic and neurodegenerative diseases. Progress in the development of MPC-targeting therapeutics is discussed, with a focus on challenges in designing selective and potent inhibitors. Emphasis is placed on modern approaches for identifying novel inhibitors, particularly virtual screening and computational strategies. This review establishes a foundation for further research into the medicinal chemistry of MPC inhibitors, promoting advances in structure-based drug design to develop therapeutics for metabolic and neurodegenerative diseases
Norovirus co-opts NINJ1 for selective protein secretion
Full text linkPlasma membrane rupture by Ninjurin-1 (NINJ1) executes programmed cell death, releasing large cellular damage-associated molecular patterns (DAMPs). However, the regulation and selectivity of NINJ1-mediated DAMP release remain unexplored. Here, we uncover that murine norovirus (MNoV) strategically co-opts NINJ1 to selectively release the intracellular viral protein NS1, while NINJ1-mediated plasma membrane rupture simultaneously bulk-releases various cellular DAMPs. Host caspase-3 cleaves the precursor NS1/2, leading to NS1 secretion via an unconventional pathway. An unbiased CRISPR screen identifies NINJ1 as an essential factor for NS1 secretion. During infection, NINJ1 is recruited to the viral replication site, where it oligomerizes and forms speckled bodies, directly interacting with NS1. Subsequent mutagenesis studies identify critical amino acid residues of NS1 necessary for its interaction with NINJ1 and selective secretion. Genetic ablation or pharmaceutical inhibition of caspase-3 inhibits oral MNoV infection in mice. This study underscores the co-option of NINJ1 for controlled release of an intracellular viral protein
Cardiotoxicity following thoracic radiotherapy for lung cancer
Full text linkRadiotherapy is the standard of care treatment for unresectable NSCLC, combined with concurrent chemotherapy and adjuvant immunotherapy. Despite technological advances in radiotherapy planning and delivery, the risk of damage to surrounding thoracic tissues remains high. Cardiac problems, including arrhythmia, heart failure and ischaemic events, occur in 20% of patients with lung cancer who undergo radiotherapy. As survival rates improve incrementally for this cohort, minimising the cardiovascular morbidity of RT is increasingly important. Problematically, the reporting of cardiac endpoints has been poor in thoracic radiotherapy clinical trials, and retrospective studies have been limited by the lack of standardisation of nomenclature and endpoints. How baseline cardiovascular profile and cardiac substructure radiation dose distribution impact the risk of cardiotoxicity is incompletely understood. As Thoracic Oncology departments seek to expand the indications for radiotherapy, and as the patient cohort becomes older and more comorbid, there is a pressing need for cardiotoxicity to be comprehensively characterised with sophisticated oncology, physics and cardio-oncology evaluations. This review synthesises the evidence base for cardiotoxicity in conventional radiotherapy, focusing on lung cancer, including current data, unmet clinical needs, and future scientific directions
Null method to estimate the maximal PA at subsaturating concentrations of agonist
Full text linkThe maximal probability of being in an active state (PA,max) is a measure of gating efficacy for a given agonist acting on a given receptor channel. In macroscopic electrophysiological recordings, PA,max is typically estimated by comparing the amplitude of the current response to a saturating concentration of a test agonist to that of a reference agonist with known PA. Here, we describe an approach to estimate the PA,max for low-efficacy agonists at subsaturating concentrations. In this approach, the amplitude of the response to a high-efficacy control agonist applied alone is compared with the amplitude of the response to a control agonist coapplied with the low-efficacy test agonist that binds to the same site(s). If the response to the combination is larger than the response to the control agonist alone, then the PA,max of the test agonist is greater than the PA of the control response. Conversely, if the response to the control agonist is reduced upon exposure to the test agonist, then the PA,max of the test agonist is smaller than the PA of the control response. The exact PA,max of the test agonist can be determined by testing its effect at different concentrations of the control agonist to estimate the PA at which the effect changes direction. The main advantage of this approach lies in the ability to use low, subsaturating concentrations of the test agonist. The model-based predictions are supported by observations from activation of heteromeric and homomeric GABAA receptors by combinations of high- and low-efficacy orthosteric agonists
So Much More
No full textDr. Shourik Dutta is an anesthesiology resident. He shared a poem on the struggle to exist across multiple spaces.
Excerpt:
Because I am so much more than a doctor Because I am so much more than my brown skin But I fear, no one is ready to see That I am so much mor
I Am Forty, I Am Free
No full textDr. Naazia Azhar is a faculty member in the Department of Psychiatry. She shared a story about accepting yourself.
Excerpt:
...All three of us feel relieved, calm, happy. The feeling permeates the room. He has been doing so well for the past month
Tenapanor improves abdominal symptoms irrespective of changes in complete spontaneous bowel movement frequency in adults with irritable bowel syndrome with constipation
Full text linkINTRODUCTION: Tenapanor is a first-in-class, minimally absorbed intestinal sodium/hydrogen exchanger isoform 3 inhibitor approved by the US Food and Drug Administration for adults with irritable bowel syndrome with constipation (IBS-C). Pooled data from the phase 2b (NCT01923428) and phase 3 T3MPO-1 (NCT02621892) and T3MPO-2 (NCT02686138) studies examined the effects of tenapanor on abdominal symptoms independent of tenapanor\u27s effect on complete spontaneous bowel movement (CSBM) frequency in adults with IBS-C.
METHODS: This post hoc analysis was performed for patients with no CSBMs in ≥6 of the first 12 weeks of treatment (no-CSBM subgroup). The three-item abdominal score (AS3; the average of weekly abdominal pain, bloating, and discomfort scores) measured abdominal symptom response in tenapanor versus placebo. The overall change from baseline and response rate (improvement of ≥2 points or a reduction of ≥30%) in AS3 and individual abdominal scores during the 12 weeks were assessed.
RESULTS: In the pooled safety analysis set (N = 1,382), 641 patients were classified as no-CSBM patients and 640 were included in the efficacy analysis. Among the no-CSBM subgroup, tenapanor-treated patients experienced a greater improvement in AS3 in week 12 versus placebo-treated patients (least squares mean change, -1.74 vs. -1.29; p = 0.007), and the AS3 responder rate was higher for tenapanor (40.2% vs. 29.6%; p = 0.008). Similar improvements were displayed across individual abdominal symptom scores. Diarrhea was the most common adverse event in tenapanor-treated patients.
CONCLUSION: Tenapanor was observed to improve abdominal symptoms independent of its effect on bowel symptoms in adults with IBS-C
Non-invasive assessment of vascular damage through pulse wave velocity and superb microvascular imaging in pre-dialysis patients
Full text linkExpression of a single inhibitory member of the Ly49 receptor family is sufficient to license NK cells for effector functions
No full textNatural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of major histocompatibility complex class I (MHC-I) and related molecules. Functionally, these receptor families are involved in the licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s were unable to reject missing-self target cells in vivo, were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. Expression of Ly49A alone on an H-2