Leroy Pakkiri - Academia.edu (original) (raw)

Papers by Leroy Pakkiri

medRxiv (Cold Spring Harbor Laboratory), May 14, 2024

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Circulation, Nov 11, 2016

Research Square (Research Square), Apr 4, 2024

Statins are a first line treatment for reducing cardiovascular risk, however the individual clini... more Statins are a first line treatment for reducing cardiovascular risk, however the individual clinical benefit of statins remains highly variable. To understand the clinical impact of individual statin metabolites on long-term clinical outcomes, we conducted a 5-year, multicentre, prospective, observational trial of 1362 cardiology patients across two independent healthcare systems in Singapore. In addition to genotyping, subjects were also phenotyped based on mass spectrometry quantification of all known plasma statin metabolites, sampled at two time points in late elimination phase. The atorvastatin lactone metabolite (ATVLAC) ≥3.9ng/mL 13 hours post-dose predicted Major Adverse Cardiovascular Events (MACE) (HR=2.45) and all-cause mortality (HR=3.18), independently of drug dose and achieved LDL. UGT1A, a lactoneproducing gene, associated with ATVLAC at genome-wide significance, independently predicted MACE (HR=1.40). Simvastatin Lactone (SMVLAC) also associated with MACE and UGT1A, suggesting a class effect. Among 51 co-prescribed non-statin drugs, omeprazole (a UGT inducer) was the strongest predictor of plasma ATVLAC (1.41-fold) and MACE (HR=1.46). These results suggest the statin lactone metabolite is a determinant of differential outcomes in statin takers and omeprazole co-prescription is a novel, potential risk factor. Genotyping the enzymatic source of statin lactone, UGT1A, may play a role in pharmacogenetic risk prediction.

bioRxiv (Cold Spring Harbor Laboratory), Oct 6, 2023

Despite anti-tuberculous treatment (ATT), central nervous system tuberculosis (CNS-TB) still caus... more Despite anti-tuberculous treatment (ATT), central nervous system tuberculosis (CNS-TB) still cause permanent neurological deficits and death. To identify prognostic factors, we profiled a prospective cohort of tuberculous meningitis (TBM) and non-TBM patients. We determined significantly increased cerebrospinal fluid (CSF) matrix metalloproteinases (MMPs) and neutrophil extracellular traps (NETs) are up-regulated in TBM patients with neuroradiological abnormalities and poor outcomes. To dissect mechanisms, we created a CNS-TB murine model which show neutrophil-rich necrotizing pyogranulomas with MMP-9 and NETs colocalizing, resembling human CNS-TB. Spatial transcriptomic analysis of both human and murine CNS-TB demonstrates a highly-inflamed and neutrophil-rich microenvironment of inflammatory immune responses, extracellular matrix degradation and angiogenesis within CNS-TB granulomas. Murine CNS-TB treated with ATT and MMP inhibitors SB-3CT or doxycycline show significantly suppressed NETs with improved survival. MMP inhibition arms show attenuated inflammation and well-formed blood vessels within granulomas. Adjunctive doxycycline is highly promising to improve CNS-TB outcomes and survival.

The Journal of Allergy and Clinical Immunology, Dec 1, 2022

Metabolites, Mar 29, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Journal of orthopaedic translation, Jul 1, 2022

Frontiers in Physiology, Jan 9, 2019

While dietary or supplementary antioxidants are thought to inhibit or delay oxidation of biologic... more While dietary or supplementary antioxidants are thought to inhibit or delay oxidation of biological molecules, their utility in vivo has been marred by equivocal evidence. Consumption of polyphenol rich foods has been thought to alleviate postprandial oxidative stress and/or improve endothelial function. Although, previous studies suggested the utility of allantoin as a biomarker of oxidative stress, controlled dose response studies with dietary antioxidants to test this in humans have been limited. We therefore investigated the effects of 2 doses of polyphenol rich curry consumption on postprandial plasma concentrations of allantoin, allantoin to uric acid ratio, F2isoprostanes using liquid chromatography-tandem mass spectrometry (LCMS-MS) and measured endothelial function using peripheral arterial tonometry (endoPAT). In a randomized controlled crossover trial in 17 non-smoking, healthy, Chinese men, aged 23.7 ± 2.4 years and BMI 23.1 ± 2.3 kg/m 2 , the volunteers consumed 3 test meals in a random order, consisting of either non-curry Dose 0 Control (D0C, 0 g spices), or Dose 1 Curry (D1C, 6 g spices) or Dose 2 Curry (D2C, 12 g spices), after overnight fast. There were significant reductions in postprandial allantoin concentrations (p < 0.001) and allantoin to uric acid ratio (p < 0.001) at 2 h and 3 h following test meal consumption, indicating improvements in postprandial redox balance with increasing curry doses, although there were no differences between treatments on F2isoprostane concentrations or on RHI (measured at 2 h only). Allantoin may have a utility as a biomarker of redox balance, in an acute setting. The study was registered at www.clinicaltrials.gov (Identifier No. NCT02599272).

Metabolites

Eating late in the day is associated with circadian desynchrony, resulting in dysregulated metabo... more Eating late in the day is associated with circadian desynchrony, resulting in dysregulated metabolism and increased cardiometabolic disease risk. However, the underlying mechanisms remain unclear. Using targeted metabolomics of postprandial plasma samples from a secondary analysis of a randomised 2 × 2 crossover study in 36 healthy older Chinese adults, we have compared postprandial metabolic responses between high (HI) glycemic index (GI) or low-GI (LO) meals, consumed either at breakfast (BR) or at dinner (DI). 29 out of 234 plasma metabolites exhibited significant differences (p < 0.05) in postprandial AUC between BR and DI sessions, whereas only five metabolites were significantly different between HI and LO sessions. There were no significant interactions between intake timing and meal GI. Lower glutamine: glutamate ratio, lower lysine and higher trimethyllysine (TML) levels were found during DI compared with BR, along with greater postprandial reductions (δAUC) in creatine ...

Frontiers in Medicine, Nov 25, 2022

and Drum CL (2022) Deep phenotyping of oxidative stress in emergency room patients reveals homoar... more and Drum CL (2022) Deep phenotyping of oxidative stress in emergency room patients reveals homoarginine as a novel predictor of sepsis severity, length of hospital stay, and length of intensive care unit stay.

Journal of Orthopaedic Translation

Journal of Allergy and Clinical Immunology

Clinical and Translational Science, 2021

N‐acetylcysteine (NAC) is an antidote to prevent acetaminophen (paracetamol‐APAP)‐induced acute l... more N‐acetylcysteine (NAC) is an antidote to prevent acetaminophen (paracetamol‐APAP)‐induced acute liver injury (ALI). The 3‐bag licensed 20.25 h standard regimen, and a 12 h modified regimen, are used to treat APAP overdose. This study evaluated the redox thiol response and APAP metabolites, in patients with a single APAP overdose treated with either the 20.25 h standard or 12 h modified regimen. We used liquid chromatography tandem mass spectrometry to quantify clinically important oxidative stress biomarkers and APAP metabolites in plasma samples from 45 patients who participated in a randomized controlled trial (SNAP trial). We investigated the time course response of plasma metabolites at predose, 12 h, and 20.25 h post‐start of NAC infusion. The results showed that the 12 h modified regimen resulted in a significant elevation of plasma NAC and cysteine concentrations at 12 h post‐infusion. We found no significant alteration in the metabolism of APAP, mitochondrial, amino acids, a...

Acetaminophen (APAP) overdose is a leading cause of untreatable liver failure. In the mouse model... more Acetaminophen (APAP) overdose is a leading cause of untreatable liver failure. In the mouse model of APAP-induced liver injury (AILI), the administration of recombinant human interleukin 11 (rhIL11) is protective. Here we show that the beneficial effect of rhIL11 in the mouse is due to its unexpected and paradoxical inhibition of endogenous mouse IL11 activity. Contrary to the accepted paradigm IL11 is a potent hepatotoxin across species, which is secreted from damaged hepatocytes to drive an autocrine loop of NOX4 and JNK-dependent apoptosis. Mice with hepatocyte-specific Il11 expression spontaneously develop liver failure whereas those with Il11ra1 deletion are remarkably protected from AILI. Neutralizing anti-IL11R antibodies administered to moribund mice 10 hours following a lethal APAP overdose results in 90% survival that is associated with very large liver regeneration. Our data overturn a misconception, identify a new disease mechanism and suggest IL11 as a therapeutic targe...

Frontiers in Physiology, 2019

bioRxiv (Cold Spring Harbor Laboratory), Mar 13, 2024

5 Zhang, H. et al. Lifelong in vivo cell-lineage tracing shows that no oogenesis originates from ... more 5 Zhang, H. et al. Lifelong in vivo cell-lineage tracing shows that no oogenesis originates from putative germline stem cells in adult mice.

Based on recent analytical and enzymological studies, a topological model for the role of a-D-man... more Based on recent analytical and enzymological studies, a topological model for the role of a-D-mannosyl-(1!3)-a-D-mannosyl-(1!3)-diacylglycerol (Man2-DAG) as a lipid anchor precursor and mannosylphosphorylundecaprenol (Man-P-Und) as a mannosyl donor in the assembly of a membrane-associated lipomannan (LM) in Micrococcus luteus has been proposed. In this study, a [3H]mannose-suicide selection procedure has been used to identify temperature-sensitive (ts) mutants defective in LM assembly. Two micro-coccal mutants with abnormal levels of Man2-DAG and LM at the nonpermissive temperature (37C), mms1 and mms2, have been isolated and characterized. In vivo and in vitro biochemical assays indicate that mms1 cells have a defect in the mannosyltransferase catalyzing the conversion of Man-DAG to Man2-DAG, and mms2 has a temperature-sensitive defect in the synthesis of Man-P-Und. Becausemms1 cells are depleted of endogenous Man2-DAG, membranes from this mutant efficiently converted purified, exo...