Publications by authors named "Mukesh K Jain"

161 Publications

Efficacy and Safety of Orally Administered Acotiamide Extended-Release Tablets Among Functional Dyspepsia-Postprandial Distress Syndrome Patients: A Randomized, Double-Blind, Multicenter Study.

Cureus 2021 Apr 8;13(4):e14361. Epub 2021 Apr 8.

Clinical Development and Medical Affairs, Hetero Labs Limited, Hyderabad, IND.

Background: Acotiamide, is the world's first-in-class, prokinetic drug and world's first approved treatment for postprandial distress syndrome (PDS) symptoms of functional dyspepsia (FD). An extended-release (ER) formulation of this drug product, developed first-time in the world has been evaluated in phase 3, a comparative trial to explore the efficacy and safety in patients with FD-PDS.

Methods: In this study, 219 patients with FD-PDS aged 18-65 years were randomized (1:1) to receive either acotiamide ER 300 mg once daily or acotiamide 100 mg three times daily for four weeks. The primary efficacy endpoint was responder rates for the overall treatment effect (OTE) at end of week 4. Secondary efficacy endpoints included OTE at each week, elimination rate of postprandial fullness, upper abdominal bloating and early satiation, improvement of individual symptom scores, and quality of life (QoL). The safety endpoints included assessments of treatment-emergent adverse events (TEAEs).

Results: The responder rate for OTE at the end of the four week period, in acotiamide ER 300 mg OD versus acotiamide 100 mg TID group was 92.66% and 94.39% (97.5% CI -8.3,4.8), respectively, in per-protocol (PP) population and 92.66% and 92.73% (97.5% CI -7.0,6.8), respectively, in intent to treat (ITT) population. All other secondary efficacy endpoints, including QoL, were significantly improved with acotiamide ER 300 mg. Both the formulations of acotiamide significantly improved symptom severity and eliminated meal-related symptoms in patients with FD. Adverse events were reported by 7.9% of patients in acotiamide ER 300 mg and 9.2% in acotiamide 100 mg patients; the most common adverse event reported was a headache.

Conclusions: The efficacy and safety of acotiamide ER 300 mg once daily were observed to be comparable to acotiamide immediate release 100 mg thrice daily. A significant improvement in QoL over a four-week treatment period in FD-PDS patients was observed.
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http://dx.doi.org/10.7759/cureus.14361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098008PMC
April 2021

Reducing acetylated tau is neuroprotective in brain injury.

Cell 2021 Apr 10. Epub 2021 Apr 10.

Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH, USA.

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.
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http://dx.doi.org/10.1016/j.cell.2021.03.032DOI Listing
April 2021

Safeguarding the Vasculature: Redundant Transcriptional Machinery Ensures Endothelial Protection.

Arterioscler Thromb Vasc Biol 2021 03 24;41(3):1124-1126. Epub 2021 Feb 24.

Department of Medicine, Case Cardiovascular Research Institute (D.R.S., M.K.J.), Case Western Reserve University, Cleveland, OH.

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http://dx.doi.org/10.1161/ATVBAHA.120.315868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927772PMC
March 2021

Muscle Krüppel-like factor 15 regulates lipid flux and systemic metabolic homeostasis.

J Clin Invest 2021 Feb;131(4)

Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.

Skeletal muscle is a major determinant of systemic metabolic homeostasis that plays a critical role in glucose metabolism and insulin sensitivity. By contrast, despite being a major user of fatty acids, and evidence that muscular disorders can lead to abnormal lipid deposition (e.g., nonalcoholic fatty liver disease in myopathies), our understanding of skeletal muscle regulation of systemic lipid homeostasis is not well understood. Here we show that skeletal muscle Krüppel-like factor 15 (KLF15) coordinates pathways central to systemic lipid homeostasis under basal conditions and in response to nutrient overload. Mice with skeletal muscle-specific KLF15 deletion demonstrated (a) reduced expression of key targets involved in lipid uptake, mitochondrial transport, and utilization, (b) elevated circulating lipids, (c) insulin resistance/glucose intolerance, and (d) increased lipid deposition in white adipose tissue and liver. Strikingly, a diet rich in short-chain fatty acids bypassed these defects in lipid flux and ameliorated aspects of metabolic dysregulation. Together, these findings establish skeletal muscle control of lipid flux as critical to systemic lipid homeostasis and metabolic health.
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http://dx.doi.org/10.1172/JCI139496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880311PMC
February 2021

Clinico-radiological Profile of Posterior Reversible Encephalopathy Syndrome and Its Associated Risk Factors in PICU: A Single-center Experience from a Tertiary Care Hospital in Bhubaneswar, Odisha.

Indian J Crit Care Med 2020 Dec;24(12):1223-1229

Department of Radio Diagnosis, Sum Ultimate Medicare, Bhubaneswar, Odisha, India.

Objective: Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiographic entity of heterogeneous etiologies having similar clinical and neuroimaging features. Pediatric data are sparse, making early diagnosis challenging, which needs a high index of suspicion. So, we conducted this study to evaluate clinico-radiological features, associated risk factors, etiology, and outcome in children.

Materials And Methods: This is a retrospective case series of patients, diagnosed as having PRES and followed up at a tertiary care hospital in Eastern India between September 2016 and December 2019.

Results: Among 16 patients with a median age of 9.5 years [interquartile range (IQR) 8-13.75] and a male preponderance (75%), common underlying diseases were post-streptococcal glomerulonephritis (56.3%) and renovascular hypertension (12.5%). Acute elevation of blood pressure was found in all patients ( = 16). The neurological symptom was seizure (87.5%), mental changes (68.75%), headache (43.8%), vomiting (31.3%), and visual disturbances (31.3%). The most common triggering factor was hypertension (100%), use of mycophenolate mofetil and prednisolone (12.5%), and hemodialysis (12.5%). Anemia was present in 15 (93.4%) patients at the time of admission. All showed abnormal neuroimaging with 55% having atypical involvement. The most common site was the parietal-occipital cortex (88%), frontal and temporal lobe (44% cases each), and the cerebellum (13%). Clinical recovery was followed by a radiological resolution in all survived except in one, who developed visual impairment.

Conclusion: Posterior reversible encephalopathy syndrome should be considered in the differential diagnosis of patients who present with acute neurological disturbances and underlying diseases such as renal disorders, vasculitis, malignancy, and use of immunosuppressant accompanied by hypertension. Early diagnosis and treatment of comorbid conditions are of paramount importance for the early reversal of the syndrome.

How To Cite This Article: Behera CK, Jain MK, Mishra R, Jena PK, Dash SK, Sahoo RK. Clinico-radiological Profile of Posterior Reversible Encephalopathy Syndrome and Its Associated Risk Factors in PICU: A Single-center Experience from a Tertiary Care Hospital in Bhubaneswar, Odisha. Indian J Crit Care Med 2020;24(12):1223-1229.
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http://dx.doi.org/10.5005/jp-journals-10071-23680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775924PMC
December 2020

Exposure to Air Pollution Disrupts Circadian Rhythm through Alterations in Chromatin Dynamics.

iScience 2020 Nov 24;23(11):101728. Epub 2020 Oct 24.

Cardiovascular Research Institute, Department of Medicine, University Hospitals/Case Western Reserve University, Cleveland, OH, USA.

Particulate matter ≤2.5μm (PM) air pollution is a leading environmental risk factor contributing disproportionately to the global burden of non-communicable disease. We compared impact of chronic exposure to PM alone, or with light at night exposure (LL) on metabolism. PM induced peripheral insulin resistance, circadian rhythm (CR) dysfunction, and metabolic and brown adipose tissue (BAT) dysfunction, akin to LL (with no additive interaction between PM and LL). Transcriptomic analysis of liver and BAT revealed widespread but unique alterations in CR genes, with evidence for differentially accessible promoters and enhancers of CR genes in response to PM by ATAC-seq. The histone deacetylases 2, 3, and 4 were downregulated with PM exposure, with increased promoter occupancy by the histone acetyltransferase p300 as evidenced by ChIP-seq. These findings suggest a previously unrecognized role of PM in promoting CR disruption and metabolic dysfunction through epigenetic regulation of circadian targets.
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http://dx.doi.org/10.1016/j.isci.2020.101728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672280PMC
November 2020

Myeloid Krüppel-like factor 2 is a critical regulator of metabolic inflammation.

Nat Commun 2020 11 18;11(1):5872. Epub 2020 Nov 18.

Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

Substantial evidence implicates crosstalk between metabolic tissues and the immune system in the inception and progression of obesity. However, molecular regulators that orchestrate metaflammation both centrally and peripherally remains incompletely understood. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as an essential regulator of obesity and its sequelae. In mice and humans, consumption of a fatty diet downregulates myeloid KLF2 levels. Under basal conditions, myeloid-specific KLF2 knockout mice (K2KO) exhibit increased feeding and weight gain. High-fat diet (HFD) feeding further exacerbates the K2KO metabolic disease phenotype. Mechanistically, loss of myeloid KLF2 increases metaflammation in peripheral and central tissues. A combination of pair-feeding, bone marrow-transplant, and microglial ablation implicate central and peripheral contributions to K2KO-induced metabolic dysfunction observed. Finally, overexpression of myeloid KLF2 protects mice from HFD-induced obesity and insulin resistance. Together, these data establish myeloid KLF2 as a nodal regulator of central and peripheral metabolic inflammation in homeostasis and disease.
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http://dx.doi.org/10.1038/s41467-020-19760-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674440PMC
November 2020

Molecular link between circadian clocks and cardiac function: a network of core clock, slave clock, and effectors.

Curr Opin Pharmacol 2020 Nov 12;57:28-40. Epub 2020 Nov 12.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

The circadian rhythm has a strong influence on both cardiac physiology and disease in humans. Preclinical studies primarily using tissue-specific transgenic mouse models have contributed to our understanding of the molecular mechanism of the circadian clock in the cardiovascular system. The core clock driven by CLOCK:BMAL1 complex functions as a universal timing machinery that primarily sets the pace in all mammalian cell types. In one specific cell or tissue type, core clock may control a secondary transcriptional oscillator, conceptualized as slave clock, which confers the oscillatory expression of tissue-specific effectors. Here, we discuss a core clock-slave clock-effectors network, which links the molecular clock to cardiac function.
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http://dx.doi.org/10.1016/j.coph.2020.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113333PMC
November 2020

P7C3-A20 treatment one year after TBI in mice repairs the blood-brain barrier, arrests chronic neurodegeneration, and restores cognition.

Proc Natl Acad Sci U S A 2020 11 21;117(44):27667-27675. Epub 2020 Oct 21.

Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106;

Chronic neurodegeneration in survivors of traumatic brain injury (TBI) is a major cause of morbidity, with no effective therapies to mitigate this progressive and debilitating form of nerve cell death. Here, we report that pharmacologic restoration of the blood-brain barrier (BBB), 12 mo after murine TBI, is associated with arrested axonal neurodegeneration and cognitive recovery, benefits that persisted for months after treatment cessation. Recovery was achieved by 30 d of once-daily administration of P7C3-A20, a compound that stabilizes cellular energy levels. Four months after P7C3-A20, electron microscopy revealed full repair of TBI-induced breaks in cortical and hippocampal BBB endothelium. Immunohistochemical staining identified additional benefits of P7C3-A20, including restoration of normal BBB endothelium length, increased brain capillary pericyte density, increased expression of BBB tight junction proteins, reduced brain infiltration of immunoglobulin, and attenuated neuroinflammation. These changes were accompanied by cessation of TBI-induced chronic axonal degeneration. Specificity for P7C3-A20 action on the endothelium was confirmed by protection of cultured human brain microvascular endothelial cells from hydrogen peroxide-induced cell death, as well as preservation of BBB integrity in mice after exposure to toxic levels of lipopolysaccharide. P7C3-A20 also protected mice from BBB degradation after acute TBI. Collectively, our results provide insights into the pathophysiologic mechanisms behind chronic neurodegeneration after TBI, along with a putative treatment strategy. Because TBI increases the risks of other forms of neurodegeneration involving BBB deterioration (e.g., Alzheimer's disease, Parkinson's disease, vascular dementia, chronic traumatic encephalopathy), P7C3-A20 may have widespread clinical utility in the setting of neurodegenerative conditions.
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http://dx.doi.org/10.1073/pnas.2010430117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959512PMC
November 2020

A Rare Case of Podophyllin Poisoning: Early Intervention is Lifesaving.

Indian J Crit Care Med 2020 Jun;24(6):477-479

Department of Pediatrics, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India.

Accidental poisoning in children is very common, making up 10.9% of all unintentional injuries worldwide. Africa has the highest incidence of fatal poisonings worldwide, at 4 per 100,000. Poisoning with podophyllin is rare, with most cases documented around the 1970s to 1980s. Podophyllin is a resin mixture obtained from the dried Rhizome and roots of (North America) and (India). Podophyllotoxin is the most toxic chemical present in the podophyllin, which is lipid soluble; so crosses the cell membrane easily and inhibits mitotic spindle formation. Both topical application and oral consumption can cause podophyllin poisoning. Neurotoxicity is the most serious effect along with bone marrow depression, gastrointestinal irritation, and hepatic and renal dysfunction. Management of podophyllin toxicity is mainly symptomatic, and no specific antidote exists. We report a case of a 2-year-old-year girl with accidental podophyllin poisoning, who presented with neurotoxicity followed by multiorgan dysfunction and then succumbed. Education of parents and healthcare workers on home safety still remains the mainstay of prevention. Jain MK, Patnaik S, Rup AR, Gaurav A. A Rare Case of Podophyllin Poisoning: Early Intervention is Lifesaving. Indian J Crit Care Med 2020;24(6):477-479.
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http://dx.doi.org/10.5005/jp-journals-10071-23448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435106PMC
June 2020

Metabolic effects of air pollution exposure and reversibility.

J Clin Invest 2020 11;130(11):6034-6040

Department of Environmental Health and Engineering and.

Air pollution involving particulate matter smaller than 2.5 μm in size (PM2.5) is the world's leading environmental risk factor contributing to mortality through cardiometabolic pathways. In this study, we modeled early life exposure using chow-fed C57BL/6J male mice that were exposed to real-world inhaled, concentrated PM2.5 (~10 times ambient levels/~60-120 μg/m3) or filtered air over a 14-week period. We investigated the effects of PM2.5 on phenotype, the transcriptome, and chromatin accessibility and compared these with the effects of a prototypical high-fat diet (HFD) as well as cessation of exposure on phenotype reversibility. Exposure to PM2.5 impaired glucose and insulin tolerance and reduced energy expenditure and 18FDG-PET uptake in brown adipose tissue. Multiple differentially expressed gene clusters in pathways involving metabolism and circadian rhythm were noted in insulin-responsive tissues. Although the magnitude of transcriptional change detected with PM2.5 exposure was lower than that observed with a HFD, the degree of alteration in chromatin accessibility after PM2.5 exposure was significant. The novel chromatin remodeler SMARCA5 (SWI/SNF complex) was regulated in response to PM2.5 exposure, the cessation of which was associated with a reversal of insulin resistance and restoration of chromatin accessibility and nucleosome positioning near transcription start sites, as well as a reversal of exposure-induced changes in the transcriptome, including SMARCA5. These changes indicate pliable epigenetic control mechanisms following cessation of exposure.
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http://dx.doi.org/10.1172/JCI137315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598058PMC
November 2020

Celiac Disease and Portal Hypertension: A Causal Association or Just a Coincidence?

J Clin Exp Hepatol 2020 Jul-Aug;10(4):290-295. Epub 2019 Nov 22.

Department of Gastroenterology, SMS Medical College and Hospital, Jaipur, India.

Introduction: Celiac disease (CD) has been linked to portal hypertension (PHT) of varied etiology, but the causality association has never been proved. We aim to study the prevalence of CD in patients of PHT of different etiology.

Methods: A prospective observational study was conducted from June 2017 to December 2018 involving all the cases of PHT of varied etiology. Consecutive patients of PHT with chronic liver disease (CLD) of defined etiology like ethanol, viral hepatitis (B or C), Budd-Chiari syndrome (BCS), autoimmune-related cirrhosis, and cryptogenic CLD (cCLD) (group A) and those with noncirrhotic PHT (NCPHT), which included noncirrhotic portal fibrosis (NCPF) and extrahepatic portal vein obstruction (EHPVO) (group B), were screened for CD by IgA anti-tTG antibody followed by duodenal biopsy in serology-positive patients.

Results: Out of a total of 464 patients, group A constituted 382 patients, CLD related to ethanol (155), cCLD (147), hepatitis B (42), hepatitis C (21), autoimmune (10), and BCS (7), whereas 82 patients were in group B with NCPF (64) and EHPVO (18). Total 29 patients were diagnosed with CD in both groups, 17 in group A (4.5%) and 12 in group B (14.6%). In group A, 13 patients with cCLD, two with HBV-related CLD, one with BCS, and one with autoimmune-related CLD were concomitantly diagnosed as CD. In group B, CD was diagnosed in 12 patients of NCPF (11) and EHPVO (1). Liver histology showed chronic hepatitis in two patients and was normal in three patients.

Conclusion: CD is common in PHT of different etiology, especially in cCLD, NCPH and autoimmune hepatitis; however, the etiological basis for this association is still to be defined. The likelihood of CD is higher in liver disease than the general population, and these patients should be screened for CD.
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http://dx.doi.org/10.1016/j.jceh.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335706PMC
November 2019

Kruppel-Like Factor 15 Regulates the Circadian Susceptibility to Ischemia Reperfusion Injury in the Heart.

Circulation 2020 04 27;141(17):1427-1429. Epub 2020 Apr 27.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX (L.L., H.L., C.-L.T., L.Z.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197441PMC
April 2020

Saving the Endangered Physician-Scientist - A Plan for Accelerating Medical Breakthroughs.

N Engl J Med 2019 Aug;381(5):399-402

From the Harrington Discovery Institute and the Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, and the Case Cardiovascular Research Institute, Case Western Reserve University, Cleveland (M.K.J.); the Howard Hughes Medical Institute and the Departments of Pediatrics and Genetics, University of Michigan, Ann Arbor (V.G.C.); the Department of Medicine and the Institute for Immunity, Transplantation, and Infection (P.J.U.), and the Department of Molecular and Cellular Physiology (B.K.K.), Stanford University School of Medicine, Stanford, CA; Frazier Healthcare Partners, Seattle (T.Y.); and the Howard Hughes Medical Institute and the Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC (R.L.).

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http://dx.doi.org/10.1056/NEJMp1904482DOI Listing
August 2019

KLF4 in Macrophages Attenuates TNF-Mediated Kidney Injury and Fibrosis.

J Am Soc Nephrol 2019 10 23;30(10):1925-1938. Epub 2019 Jul 23.

Division of Nephrology,

Background: Polarized macrophage populations can orchestrate both inflammation of the kidney and tissue repair during CKD. Proinflammatory M1 macrophages initiate kidney injury, but mechanisms through which persistent M1-dependent kidney damage culminates in fibrosis require elucidation. Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor that suppresses inflammatory signals, is an essential regulator of macrophage polarization in adipose tissues, but the effect of myeloid KLF4 on CKD progression is unknown.

Methods: We used conditional mutant mice lacking KLF4 or TNF (KLF4's downstream effector) selectively in myeloid cells to investigate macrophage KLF4's role in modulating CKD progression in two models of CKD that feature robust macrophage accumulation, nephrotoxic serum nephritis, and unilateral ureteral obstruction.

Results: In these murine CKD models, KLF4 deficiency in macrophages infiltrating the kidney augmented their M1 polarization and exacerbated glomerular matrix deposition and tubular epithelial damage. During the induced injury in these models, macrophage-specific KLF4 deletion also exacerbated kidney fibrosis, with increased levels of collagen 1 and -smooth muscle actin in the injured kidney. CD11bLy6C myeloid cells isolated from injured kidneys expressed higher levels of TNF mRNA versus wild-type controls. In turn, mice bearing macrophage-specific deletion of TNF exhibited decreased glomerular and tubular damage and attenuated kidney fibrosis in the models. Moreover, treatment with the TNF receptor-1 inhibitor R-7050 during nephrotoxic serum nephritis reduced damage, fibrosis, and necroptosis in wild-type mice and mice with KLF4-deficient macrophages, and abrogated the differences between the two groups in these parameters.

Conclusions: These data indicate that macrophage KLF4 ameliorates CKD by mitigating TNF-dependent injury and fibrosis.
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http://dx.doi.org/10.1681/ASN.2019020111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779357PMC
October 2019

Taking KLF9 to "Cort" for crimes against metabolism.

J Clin Invest 2019 04 29;129(6):2178-2180. Epub 2019 Apr 29.

Case Cardiovascular Research Institute and University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.

Glucocorticoids (GCs) are essential for proper glycemic control, but in excess, can lead to hyperglycemia and diabetes. In this issue of the JCI, Cui et al. elucidate a mechanism by which GCs regulate gluconeogenesis utilizing the transcription factor Krüppel-like factor 9 (KLF9) in physiology and disease settings. They report that KLF9 is a GC-inducible factor that ultimately increases the transcription of proliferator-activated receptor γ coactivator 1 α (PGC1α), resulting in gluconeogenesis. Given the high incidence of GC-induced diabetes, identification of this signaling axis provides, not only critical scientific insight, but also a foundation for preventative therapies for patients receiving chronic GC treatment.
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http://dx.doi.org/10.1172/JCI128481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546472PMC
April 2019

KLF15 regulates endobiotic and xenobiotic metabolism.

Nat Metab 2019 04 8;1(4):422-430. Epub 2019 Apr 8.

Case Cardiovascular Research Institute Case Western Reserve University, Harrington Heart and Vascular Institute University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

Hepatic metabolism and elimination of endobiotics (for example, steroids, bile acids) and xenobiotics (for example, drugs, toxins) is essential for health. While the enzymatic (termed phase I-II) and transport machinery (termed phase III) controlling endobiotic and xenobiotic metabolism (EXM) is known, understanding of molecular nodal points that coordinate EXM function in physiology and disease remains incomplete. Here we show that the transcription factor Kruppel-like factor 15 (KLF15) regulates all three phases of the EXM system by direct and indirect pathways. Unbiased transcriptomic analyses coupled with validation studies in cells, human tissues, and animals, support direct transcriptional control of the EXM machinery by KLF15. Liver-specific deficiency of KLF15 (Li-KO) results in altered expression of numerous phase I-III targets, and renders animals resistant to the pathologic effects of bile acid and acetaminophen toxicity. Furthermore, Li-KO mice demonstrate enhanced degradation and elimination of endogenous steroid hormones, such as testosterone and glucocorticoid, resulting in reduced male fertility and blood glucose levels, respectively. Viral reconstitution of hepatic KLF15 expression in Li-KO mice reverses these phenotypes. Our observations identify a previously unappreciated transcriptional pathway regulating metabolism and elimination of endobiotics and xenobiotics.
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http://dx.doi.org/10.1038/s42255-019-0054-7DOI Listing
April 2019

ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects.

Nat Commun 2019 03 26;10(1):1371. Epub 2019 Mar 26.

Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.

Mitochondrial fragmentation and bioenergetic failure manifest in Huntington's disease (HD), a fatal neurodegenerative disease. The factors that couple mitochondrial fusion/fission with bioenergetics and their impacts on neurodegeneration however remain poorly understood. Our proteomic analysis identifies mitochondrial protein ATAD3A as an interactor of mitochondrial fission GTPase, Drp1, in HD. Here we show that, in HD, ATAD3A dimerization due to deacetylation at K135 residue is required for Drp1-mediated mitochondrial fragmentation. Disturbance of ATAD3A steady state impairs mtDNA maintenance by disrupting TFAM/mtDNA binding. Blocking Drp1/ATAD3A interaction with a peptide, DA1, abolishes ATAD3A oligomerization, suppresses mitochondrial fragmentation and mtDNA lesion, and reduces bioenergetic deficits and cell death in HD mouse- and patient-derived cells. DA1 treatment reduces behavioral and neuropathological phenotypes in HD transgenic mice. Our findings demonstrate that ATAD3A plays a key role in neurodegeneration by linking Drp1-induced mitochondrial fragmentation to defective mtDNA maintenance, suggesting that DA1 might be useful for developing HD therapeutics.
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http://dx.doi.org/10.1038/s41467-019-09291-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435701PMC
March 2019

Regulation of MicroRNA Machinery and Development by Interspecies S-Nitrosylation.

Cell 2019 02;176(5):1014-1025.e12

Institute for Transformative Molecular Medicine and Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA. Electronic address:

Bioactive molecules can pass between microbiota and host to influence host cellular functions. However, general principles of interspecies communication have not been discovered. We show here in C. elegans that nitric oxide derived from resident bacteria promotes widespread S-nitrosylation of the host proteome. We further show that microbiota-dependent S-nitrosylation of C. elegans Argonaute protein (ALG-1)-at a site conserved and S-nitrosylated in mammalian Argonaute 2 (AGO2)-alters its function in controlling gene expression via microRNAs. By selectively eliminating nitric oxide generation by the microbiota or S-nitrosylation in ALG-1, we reveal unforeseen effects on host development. Thus, the microbiota can shape the post-translational landscape of the host proteome to regulate microRNA activity, gene expression, and host development. Our findings suggest a general mechanism by which the microbiota may control host cellular functions, as well as a new role for gasotransmitters.
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http://dx.doi.org/10.1016/j.cell.2019.01.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559381PMC
February 2019

Induction of Krüppel-like factor 2 reduces K/BxN serum-induced arthritis.

J Cell Mol Med 2019 02 3;23(2):1386-1395. Epub 2018 Dec 3.

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas.

Krüppel-like factor 2 (KLF2) critically regulates activation and function of monocyte, which plays important pathogenic role in progressive joint destruction in rheumatoid arthritis (RA). It is yet to be established the molecular basis of KLF2-mediated regulation of monocytes in RA pathogenesis. Herein, we show that a class of compound, HDAC inhibitors (HDACi) induced KLF2 expression in monocytes both in vitro and in vivo. KLF2 level was also elevated in tissues, such as bone marrow, spleen and thymus in mice after infusion of HDACi. Importantly, HDACi significantly reduced osteoclastic differentiation of monocytes with the up-regulation of KLF2 and concomitant down-regulation of matrixmetalloproteinases both in the expression level as well as in the protein level. In addition, HDACi reduced K/BxN serum-induced arthritic inflammation and joint destruction in mice in a dose-dependent manner. Finally, co-immunoprecipitation and overexpression studies confirmed that KLF2 directly interacts with HDAC4 molecule in cells. These findings provide mechanistic evidence of KLF2-mediated regulation of K/BxN serum-induced arthritic inflammation.
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http://dx.doi.org/10.1111/jcmm.14041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349180PMC
February 2019

An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1.

Blood 2019 02 1;133(7):743-753. Epub 2018 Dec 1.

Department of Medicine, Columbia University Medical Center, New York, NY.

Tissue-type plasminogen activator (tPA) is a major mediator of fibrinolysis and, thereby, prevents excessive coagulation without compromising hemostasis. Studies on tPA regulation have focused on its acute local release by vascular cells in response to injury or other stimuli. However, very little is known about sources, regulation, and fibrinolytic function of noninjury-induced systemic plasma tPA. We explore the role and regulation of hepatocyte-derived tPA as a source of basal plasma tPA activity and as a contributor to fibrinolysis after vascular injury. We show that hepatocyte tPA is downregulated by a pathway in which the corepressor DACH1 represses ATF6, which is an inducer of the tPA gene Hepatocyte-DACH1-knockout mice show increases in liver , circulating tPA, fibrinolytic activity, bleeding time, and time to thrombosis, which are reversed by silencing hepatocyte Conversely, hepatocyte-ATF6-knockout mice show decreases in these parameters. The inverse correlation between DACH1 and / is conserved in human liver. These findings reveal a regulated pathway in hepatocytes that contributes to basal circulating levels of tPA and to fibrinolysis after vascular injury.
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http://dx.doi.org/10.1182/blood-2018-07-864843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376283PMC
February 2019

The Krüppel-Like Factors and Control of Energy Homeostasis.

Endocr Rev 2019 02;40(1):137-152

Case Cardiovascular Research Institute, Case Western Reserve University, Cleveland, Ohio.

Nutrient handling by higher organisms is a complex process that is regulated at the transcriptional level. Studies over the past 15 years have highlighted the critical importance of a family of transcriptional regulators termed the Krüppel-like factors (KLFs) in metabolism. Within an organ, distinct KLFs direct networks of metabolic gene targets to achieve specialized functions. This regulation is often orchestrated in concert with recruitment of tissue-specific transcriptional regulators, particularly members of the nuclear receptor family. Upon nutrient entry into the intestine, gut, and liver, KLFs control a range of functions from bile synthesis to intestinal stem cell maintenance to effect nutrient acquisition. Subsequently, coordinated KLF activity across multiple organs distributes nutrients to sites of storage or liberates them for use in response to changes in nutrient status. Finally, in energy-consuming organs like cardiac and skeletal muscle, KLFs tune local metabolic programs to precisely match substrate uptake, flux, and use, particularly via mitochondrial function, with energetic demand; this is achieved in part via circulating mediators, including glucocorticoids and insulin. Here, we summarize current understanding of KLFs in regulation of nutrient absorption, interorgan circulation, and tissue-specific use.
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http://dx.doi.org/10.1210/er.2018-00151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334632PMC
February 2019

Aryl Hydrocarbon Receptor Nuclear Translocator in Vascular Smooth Muscle Cells Is Required for Optimal Peripheral Perfusion Recovery.

J Am Heart Assoc 2018 06 1;7(11). Epub 2018 Jun 1.

Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH

Background: Limb ischemia resulting from peripheral vascular disease is a common cause of morbidity. Vessel occlusion limits blood flow, creating a hypoxic environment that damages distal tissue, requiring therapeutic revascularization. Hypoxia-inducible factors (HIFs) are key transcriptional regulators of hypoxic vascular responses, including angiogenesis and arteriogenesis. Despite vascular smooth muscle cells' (VSMCs') importance in vessel integrity, little is known about their functional responses to hypoxia in peripheral vascular disease. This study investigated the role of VSMC HIF in mediating peripheral ischemic responses.

Methods And Results: We used mice with smooth muscle-specific deletion of aryl hydrocarbon receptor nuclear translocator (ARNT, HIF-1β), required for HIF transcriptional activity, in a femoral artery ligation model of peripheral vascular disease. mice exhibit impaired perfusion recovery despite normal collateral vessel dilation and angiogenic capillary responses. Decreased blood flow manifests in extensive tissue damage and hypoxia in ligated limbs of mice. Furthermore, loss of aryl hydrocarbon receptor nuclear translocator changes the proliferation, migration, and transcriptional profile of cultured VSMCs. mice display disrupted VSMC morphologic features and wrapping around arterioles and increased vascular permeability linked to decreased local blood flow.

Conclusions: Our data demonstrate that traditional vascular remodeling responses are insufficient to provide robust peripheral tissue reperfusion in mice. In all, this study highlights HIF responses to hypoxia in arteriole VSMCs critical for the phenotypic and functional stability of vessels that aid in the recovery of blood flow in ischemic peripheral tissues.
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http://dx.doi.org/10.1161/JAHA.118.009205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015385PMC
June 2018

Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge.

Sci Rep 2018 05 29;8(1):8251. Epub 2018 May 29.

Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.

Brown adipose tissue (BAT) is a specialized thermogenic organ in mammals. The ability of BAT mitochondria to generate heat in response to cold-challenge to maintain core body temperature is essential for organismal survival. While cold activated BAT mitochondrial biogenesis is recognized as critical for thermogenic adaptation, the contribution of mitochondrial quality control to this process remains unclear. Here, we show mitophagy is required for brown adipocyte mitochondrial homeostasis during thermogenic adaptation. Mitophagy is significantly increased in BAT from cold-challenged mice (4 °C) and in β-agonist treated brown adipocytes. Blockade of mitophagy compromises brown adipocytes mitochondrial oxidative phosphorylation (OX-PHOS) capacity, as well as BAT mitochondrial integrity. Mechanistically, cold-challenge induction of BAT mitophagy is UCP1-dependent. Furthermore, our results indicate that mitophagy coordinates with mitochondrial biogenesis, maintaining activated BAT mitochondrial homeostasis. Collectively, our in vivo and in vitro findings identify mitophagy as critical for brown adipocyte mitochondrial homeostasis during cold adaptation.
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http://dx.doi.org/10.1038/s41598-018-26394-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974273PMC
May 2018

Interventions Targeting Glucocorticoid-Krüppel-like Factor 15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in Spinal Muscular Atrophy Mice.

EBioMedicine 2018 May 4;31:226-242. Epub 2018 May 4.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. Electronic address:

The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn;SMN2 and Smn mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone), genetic (muscle-specific Klf15 overexpression) and dietary (BCAA supplementation) interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling.
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http://dx.doi.org/10.1016/j.ebiom.2018.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013932PMC
May 2018

S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence.

Mol Cell 2018 05;70(3):473-487.e6

Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA. Electronic address:

Most G protein-coupled receptors (GPCRs) signal through both heterotrimeric G proteins and β-arrestins (βarr1 and βarr2). Although synthetic ligands can elicit biased signaling by G protein- vis-à-vis βarr-mediated transduction, endogenous mechanisms for biasing signaling remain elusive. Here we report that S-nitrosylation of a novel site within βarr1/2 provides a general mechanism to bias ligand-induced signaling through GPCRs by selectively inhibiting βarr-mediated transduction. Concomitantly, S-nitrosylation endows cytosolic βarrs with receptor-independent function. Enhanced βarr S-nitrosylation characterizes inflammation and aging as well as human and murine heart failure. In genetically engineered mice lacking βarr2-Cys253 S-nitrosylation, heart failure is exacerbated in association with greatly compromised β-adrenergic chronotropy and inotropy, reflecting βarr-biased transduction and β-adrenergic receptor downregulation. Thus, S-nitrosylation regulates βarr function and, thereby, biases transduction through GPCRs, demonstrating a novel role for nitric oxide in cellular signaling with potentially broad implications for patho/physiological GPCR function, including a previously unrecognized role in heart failure.
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http://dx.doi.org/10.1016/j.molcel.2018.03.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940012PMC
May 2018

Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy.

Proc Natl Acad Sci U S A 2018 05 30;115(20):E4661-E4669. Epub 2018 Apr 30.

Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106;

Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart's adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure.
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http://dx.doi.org/10.1073/pnas.1720065115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960298PMC
May 2018

Krüppel-Like Factors in Vascular Inflammation: Mechanistic Insights and Therapeutic Potential.

Front Cardiovasc Med 2018 5;5. Epub 2018 Feb 5.

Case Cardiovascular Research Institute, Case Western Reserve University, Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.

The role of inflammation in vascular disease is well recognized, involving dysregulation of both circulating immune cells as well as the cells of the vessel wall itself. Unrestrained vascular inflammation leads to pathological remodeling that eventually contributes to atherothrombotic disease and its associated sequelae (e.g., myocardial/cerebral infarction, embolism, and critical limb ischemia). Signaling events during vascular inflammation orchestrate widespread transcriptional programs that affect the functions of vascular and circulating inflammatory cells. The Krüppel-like factors (KLFs) are a family of transcription factors central in regulating vascular biology in states of homeostasis and disease. Given their abundance and diversity of function in cells associated with vascular inflammation, understanding the transcriptional networks regulated by KLFs will further our understanding of the pathogenesis underlying several pervasive health concerns (e.g., atherosclerosis, stroke, etc.) and consequently inform the treatment of cardiovascular disease. Within this review, we will discuss the role of KLFs in coordinating protective and deleterious responses during vascular inflammation, while addressing the potential targeting of these critical transcription factors in future therapies.
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http://dx.doi.org/10.3389/fcvm.2018.00006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807683PMC
February 2018

Aging and the Krüppel-like factors.

Trends Cell Mol Biol 2017 ;12:1-15

Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

The mammalian Krüppel-like factors (KLFs) are a family of zinc-finger containing transcription factors with diverse patterns of expression and a wide array of cellular functions. While their roles in mammalian physiology are well known, there is a growing appreciation for their roles in modulating the fundamental progression of aging. Here we review the current knowledge of Krüppel-like factors with a focus on their roles in processes regulating aging and age-associated diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798252PMC
January 2017

Kruppel-like factor 15 is required for the cardiac adaptive response to fasting.

PLoS One 2018 6;13(2):e0192376. Epub 2018 Feb 6.

Case Cardiovascular Research Institute and Harrington Heart & Vascular Institute, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, OH, United States of America.

Cardiac metabolism is highly adaptive in response to changes in substrate availability, as occur during fasting. This metabolic flexibility is essential to the maintenance of contractile function and is under the control of a group of select transcriptional regulators, notably the nuclear receptor family of factors member PPARα. However, the diversity of physiologic and pathologic states through which the heart must sustain function suggests the possible existence of additional transcriptional regulators that play a role in matching cardiac metabolism to energetic demand. Here we show that cardiac KLF15 is required for the normal cardiac response to fasting. Specifically, we find that cardiac function is impaired upon fasting in systemic and cardiac specific Klf15-null mice. Further, cardiac specific Klf15-null mice display a fasting-dependent accumulation of long chain acylcarnitine species along with a decrease in expression of the carnitine translocase Slc25a20. Treatment with a diet high in short chain fatty acids relieves the KLF15-dependent long chain acylcarnitine accumulation and impaired cardiac function in response to fasting. Our observations establish KLF15 as a critical mediator of the cardiac adaptive response to fasting through its regulation of myocardial lipid utilization.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192376PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800603PMC
April 2018