Tubular CPT1A deletion minimally affects aging and chronic kidney injury.

Kidney tubules use fatty acid oxidation (FAO) to support their high energetic requirements. Carnitine palmitoyltransferase 1A (CPT1A) is the rate-limiting enzyme for FAO, and it is necessary to transport long-chain fatty acids into mitochondria. To define the role of tubular CPT1A in aging and injury, we generated mice with tubule-specific deletion of Cpt1a (Cpt1aCKO mice), and the mice were either aged for 2 years or injured by aristolochic acid or unilateral ureteral obstruction. Surprisingly, Cpt1aCKO mice had no significant differences in kidney function or fibrosis compared with wild-type mice after aging or chronic injury. Primary tubule cells from aged Cpt1aCKO mice had a modest decrease in palmitate oxidation but retained the ability to metabolize long-chain fatty acids. Very-long-chain fatty acids, exclusively oxidized by peroxisomes, were reduced in kidneys lacking tubular CPT1A, consistent with increased peroxisomal activity. Single-nuclear RNA-Seq showed significantly increased expression of peroxisomal FAO enzymes in proximal tubules of mice lacking tubular CPT1A. These data suggest that peroxisomal FAO may compensate in the absence of CPT1A, and future genetic studies are needed to confirm the role of peroxisomal ß-oxidation when mitochondrial FAO is impaired.

Interruption of perivascular and perirenal adipose tissue thromboinflammation rescues prediabetic cardioautonomic and renovascular deterioration.

The cardiovascular and renovascular complications of metabolic deterioration are associated with localized adipose tissue dysfunction. We have previously demonstrated that metabolic impairment delineated the heightened vulnerability of both the perivascular (PVAT) and perirenal adipose tissue (PRAT) depots to hypoxia and inflammation, predisposing to cardioautonomic, vascular and renal deterioration. Interventions either addressing underlying metabolic disturbances or halting adipose tissue dysfunction rescued the observed pathological and functional manifestations. Several lines of evidence implicate adipose tissue thromboinflammation, which entails the activation of the proinflammatory properties of the blood clotting cascade, in the pathogenesis of metabolic and cardiovascular diseases. Despite offering valuable tools to interrupt the thromboinflammatory cycle, there exists a significant knowledge gap regarding the potential pleiotropic effects of anticoagulant drugs on adipose inflammation and cardiovascular function. As such, a systemic investigation of the consequences of PVAT and PRAT thromboinflammation and its interruption in the context of metabolic disease has not been attempted. Here, using an established prediabetic rat model, we demonstrate that metabolic disturbances are associated with PVAT and PRAT thromboinflammation in addition to cardioautonomic, vascular and renal functional decline. Administration of rivaroxaban, a FXa inhibitor, reduced PVAT and PRAT thromboinflammation and ameliorated the cardioautonomic, vascular and renal deterioration associated with prediabetes. Our present work outlines the involvement of PVAT and PRAT thromboinflammation during early metabolic derangement and offers novel perspectives into targeting adipose tissue thrombo-inflammatory pathways for the management its complications in future translational efforts.

Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue.

The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.

An objective evaluation of fundamental pharmacogenomics knowledge among pharmacists and pharmacy students.

Introduction: Possessing a correct and comprehensive foundation on the science of pharmacogenomics (PGx) is an important prerequisite for pharmacists to successfully apply pharmacogenomic testing to patient care. While some work has addressed general PGx knowledge among pharmacists, little research has specifically focused on PGx foundational knowledge. This study examines the level of foundational knowledge of PGx and interest in learning about PGx among community pharmacists and first-year pharmacy students at Beirut Arab University (BAU), Beirut, Lebanon. Methods: A cross-sectional survey was self-administered to community pharmacists within a random sample of community pharmacies in Beirut, Lebanon, and to first-year BAU pharmacy students. The knowledge component of the instrument consisted of 25 items, each worth one point, addressing fundamental PGx information. The validity and internal consistency of the designed instrument were tested among the study population. Correlation analysis was carried out between aggregate knowledge and key variables for participating pharmacists. Results: Of 150 approached pharmacists, 137 (91 %) participated and of 132 pharmacy students, 131 (99 %) participated. The average knowledge score for community pharmacists was 15 (Standard Deviation = 4) out of a possible total of 25 with the total number of correct answers ranging from 8 to 24 out of 25 questions. The average score for pharmacy students was 17 (Standard Deviation = 5) out of a possible total of 25 with the total number of correct answers ranging from 5 to 24. Pharmacists' age and years of practice were associated with a lower aggregate knowledge score (r = -0.20; p < 0.05 and r = -0.21; p < 0.05), respectively. Pharmacists' interest in learning about PGx varied whereas 62 % were either interested or very interested in learning about PGx. Students' interest, however, was higher with 70 % being either interested or very interested. Specific PGx topics of interest to participants were highlighted. Conclusion: This study identified areas where PGx foundational knowledge was acceptable and others where significant opportunities for improvement exist. These results add to the rapidly expanding field of pharmacogenomics education and practice in relation to pharmacy. In particular, these findings have significant implications for planning pharmacogenomics-related educational activities targeting current and future pharmacists.

Perirenal Adipose Tissue Inflammation: Novel Insights Linking Metabolic Dysfunction to Renal Diseases.

A healthy adipose tissue (AT) is indispensable to human wellbeing. Among other roles, it contributes to energy homeostasis and provides insulation for internal organs. Adipocytes were previously thought to be a passive store of excess calories, however this view evolved to include an endocrine role. Adipose tissue was shown to synthesize and secrete adipokines that are pertinent to glucose and lipid homeostasis, as well as inflammation. Importantly, the obesity-induced adipose tissue expansion stimulates a plethora of signals capable of triggering an inflammatory response. These inflammatory manifestations of obese AT have been linked to insulin resistance, metabolic syndrome, and type 2 diabetes, and proposed to evoke obesity-induced comorbidities including cardiovascular diseases (CVDs). A growing body of evidence suggests that metabolic disorders, characterized by AT inflammation and accumulation around organs may eventually induce organ dysfunction through a direct local mechanism. Interestingly, perirenal adipose tissue (PRAT), surrounding the kidney, influences renal function and metabolism. In this regard, PRAT emerged as an independent risk factor for chronic kidney disease (CKD) and is even correlated with CVD. Here, we review the available evidence on the impact of PRAT alteration in different metabolic states on the renal and cardiovascular function. We present a broad overview of novel insights linking cardiovascular derangements and CKD with a focus on metabolic disorders affecting PRAT. We also argue that the confluence among these pathways may open several perspectives for future pharmacological therapies against CKD and CVD possibly by modulating PRAT immunometabolism.

Molecular and Biological Mechanisms Underlying Gender Differences in COVID-19 Severity and Mortality.

Globally, over two million people have perished due to the recent pandemic caused by SARS-CoV-2. The available epidemiological global data for SARS-CoV-2 portrays a higher rate of severity and mortality in males. Analyzing gender differences in the host mechanisms involved in SARS-CoV-2 infection and progression may offer insight into the more detrimental disease prognosis and clinical outcome in males. Therefore, we outline sexual dimorphisms which exist in particular host factors and elaborate on how they may contribute to the pronounced severity in male COVID-19 patients. This includes disparities detected in comorbidities, the ACE2 receptor, renin-angiotensin system (RAS), signaling molecules involved in SARS-CoV-2 replication, proteases which prime viral S protein, the immune response, and behavioral considerations. Moreover, we discuss sexual disparities associated with other viruses and a possible gender-dependent response to SARS-CoV-2 vaccines. By specifically highlighting these immune-endocrine processes as well as behavioral factors that differentially exist between the genders, we aim to offer a better understanding in the variations of SARS-CoV-2 pathogenicity.

The pleiotropic effects of antithrombotic drugs in the metabolic-cardiovascular-neurodegenerative disease continuum: impact beyond reduced clotting.

Antithrombotic drugs are widely used for primary and secondary prevention, as well as treatment of many cardiovascular disorders. Over the past few decades, major advances in the pharmacology of these agents have been made with the introduction of new drug classes as novel therapeutic options. Accumulating evidence indicates that the beneficial outcomes of some of these antithrombotic agents are not solely related to their ability to reduce thrombosis. Here, we review the evidence supporting established and potential pleiotropic effects of four novel classes of antithrombotic drugs, adenosine diphosphate (ADP) P2Y12-receptor antagonists, Glycoprotein IIb/IIIa receptor Inhibitors, and Direct Oral Anticoagulants (DOACs), which include Direct Factor Xa (FXa) and Direct Thrombin Inhibitors. Specifically, we discuss the molecular evidence supporting such pleiotropic effects in the context of cardiovascular disease (CVD) including endothelial dysfunction (ED), atherosclerosis, cardiac injury, stroke, and arrhythmia. Importantly, we highlight the role of DOACs in mitigating metabolic dysfunction-associated cardiovascular derangements. We also postulate that DOACs modulate perivascular adipose tissue inflammation and thus, may reverse cardiovascular dysfunction early in the course of the metabolic syndrome. In this regard, we argue that some antithrombotic agents can reverse the neurovascular damage in Alzheimer's and Parkinson's brain and following traumatic brain injury (TBI). Overall, we attempt to provide an up-to-date comprehensive review of the less-recognized, beneficial molecular aspects of antithrombotic therapy beyond reduced thrombus formation. We also make a solid argument for the need of further mechanistic analysis of the pleiotropic effects of antithrombotic drugs in the future.

Peri-renal adipose inflammation contributes to renal dysfunction in a non-obese prediabetic rat model: Role of anti-diabetic drugs.

Diabetic nephropathy is a major health challenge with considerable economic burden and significant impact on patients' quality of life. Despite recent advances in diabetic patient care, current clinical practice guidelines fall short of halting the progression of diabetic nephropathy to end-stage renal disease. Moreover, prior literature reported manifestations of renal dysfunction in early stages of metabolic impairment prior to the development of hyperglycemia indicating the involvement of alternative pathological mechanisms apart from those typically triggered by high blood glucose. Here, we extend our prior research work implicating localized inflammation in specific adipose depots in initiating cardiovascular dysfunction in early stages of metabolic impairment. Non-obese prediabetic rats showed elevated glomerular filtration rates and mild proteinuria in absence of hyperglycemia, hypertension, and signs of systemic inflammation. Isolated perfused kidneys from these rats showed impaired renovascular endothelial feedback in response to vasopressors and increased flow. While endothelium dependent dilation remained functional, renovascular relaxation in prediabetic rats was not mediated by nitric oxide and prostaglandins as in control tissues, but rather an upregulation of the function of epoxy eicosatrienoic acids was observed. This was coupled with signs of peri-renal adipose tissue (PRAT) inflammation and renal structural damage. A two-week treatment with non-hypoglycemic doses of metformin or pioglitazone, shown previously to ameliorate adipose inflammation, not only reversed PRAT inflammation in prediabetic rats, but also reversed the observed functional, renovascular, and structural renal abnormalities. The present results suggest that peri-renal adipose inflammation triggers renal dysfunction early in the course of metabolic disease.

Dysregulation of Angiotensin Converting Enzyme 2 Expression and Function in Comorbid Disease Conditions Possibly Contributes to Coronavirus Infectious Disease 2019 Complication Severity.

ACE2 has emerged as a double agent in the COVID-19 ordeal, as it is both physiologically protective and virally conducive. The identification of ACE2 in as many as 72 tissues suggests that extrapulmonary invasion and damage is likely, which indeed has already been demonstrated by cardiovascular and gastrointestinal symptoms. On the other hand, identifying ACE2 dysregulation in patients with comorbidities may offer insight as to why COVID-19 symptoms are often more severe in these individuals. This may be attributed to a pre-existing proinflammatory state that is further propelled with the cytokine storm induced by SARS-CoV-2 infection or the loss of functional ACE2 expression as a result of viral internalization. Here, we aim to characterize the distribution and role of ACE2 in various organs to highlight the scope of damage that may arise upon SARS-CoV-2 invasion. Furthermore, by examining the disruption of ACE2 in several comorbid diseases, we offer insight into potential causes of increased severity of COVID-19 symptoms in certain individuals. SIGNIFICANCE STATEMENT: Cell surface expression of ACE2 determines the tissue susceptibility for coronavirus infectious disease 2019 infection. Comorbid disease conditions altering ACE2 expression could increase the patient's vulnerability for the disease and its complications, either directly, through modulation of viral infection, or indirectly, through alteration of inflammatory status.

Adipose Tissue Immunomodulation: A Novel Therapeutic Approach in Cardiovascular and Metabolic Diseases.

Adipose tissue is a critical regulator of systemic metabolism and bodily homeostasis as it secretes a myriad of adipokines, including inflammatory and anti-inflammatory cytokines. As the main storage pool of lipids, subcutaneous and visceral adipose tissues undergo marked hypertrophy and hyperplasia in response to nutritional excess leading to hypoxia, adipokine dysregulation, and subsequent low-grade inflammation that is characterized by increased infiltration and activation of innate and adaptive immune cells. The specific localization, physiology, susceptibility to inflammation and the heterogeneity of the inflammatory cell population of each adipose depot are unique and thus dictate the possible complications of adipose tissue chronic inflammation. Several lines of evidence link visceral and particularly perivascular, pericardial, and perirenal adipose tissue inflammation to the development of metabolic syndrome, insulin resistance, type 2 diabetes and cardiovascular diseases. In addition to the implication of the immune system in the regulation of adipose tissue function, adipose tissue immune components are pivotal in detrimental or otherwise favorable adipose tissue remodeling and thermogenesis. Adipose tissue resident and infiltrating immune cells undergo metabolic and morphological adaptation based on the systemic energy status and thus a better comprehension of the metabolic regulation of immune cells in adipose tissues is pivotal to address complications of chronic adipose tissue inflammation. In this review, we discuss the role of adipose innate and adaptive immune cells across various physiological and pathophysiological states that pertain to the development or progression of cardiovascular diseases associated with metabolic disorders. Understanding such mechanisms allows for the exploitation of the adipose tissue-immune system crosstalk, exploring how the adipose immune system might be targeted as a strategy to treat cardiovascular derangements associated with metabolic dysfunctions.

Molecular Insights Into SARS COV-2 Interaction With Cardiovascular Disease: Role of RAAS and MAPK Signaling.

In December 2019, reports of viral pneumonia came out of Wuhan city in Hubei province in China. In early 2020, the causative agent was identified as a novel coronavirus (CoV) sharing some sequence similarity with SARS-CoV that caused the severe acute respiratory syndrome outbreak in 2002. The new virus, named SARS-CoV-2, is highly contagious and spread rapidly across the globe causing a pandemic of what became known as coronavirus infectious disease 2019 (COVID-19). Early observations indicated that cardiovascular disease (CVD) patients are at higher risk of progression to severe respiratory manifestations of COVID-19 including acute respiratory distress syndrome. Moreover, further observations demonstrated that SARS-CoV-2 infection can induce de novo cardiac and vascular damage in previously healthy individuals. Here, we offer an overview of the proposed molecular pathways shared by the pathogenesis of CVD and SARS-CoV infections in order to provide a mechanistic framework for the observed interrelation. We examine the crosstalk between the renin-angiotensin-aldosterone system and mitogen activated kinase pathways that potentially links cardiovascular predisposition and/or outcome to SARS-CoV-2 infection. Finally, we summarize the possible effect of currently available drugs with known cardiovascular benefit on these pathways and speculate on their potential utility in mitigating cardiovascular risk and morbidity in COVID-19 patients.

Molecular basis of the counteraction by calcium channel blockers of cyclosporine nephrotoxicity.

Nephrotoxicity is a serious side effect for the immunosuppressant drug cyclosporine A(CSA). In this study, we tested the hypothesis that administration of calcium channel blockers such as verapamil or nifedipine ameliorates renal CSA-induced renal dysfunction. Furthermore, our study investigates the roles of inflammatory, oxidative, and fibrotic pathways in CSA-induced renal dysfunction. Six groups of male rats ( n = 6/group) were used and received one of the following treatments for seven consecutive days: vehicle (Cremophor EL ip), CSA (25 mg·kg-1·day-1 ip), verapamil (2 mg·kg-1·day-1 ip), nifedipine (3 mg·kg-1·day-1 ip), CSA in the presence or absence of either verapamil, or nifedipine. Biochemical and histomorphometric analyses showed that rats treated with CSA exhibited clear signs of nephrotoxicity that included 1) proteinuria and elevations in serum creatinine and blood urea nitrogen, 2) mesangial expansion, 3) increases in glomerular and tubular type IV collagen expression, and 4) increases in the glomerulosclerosis and tubulointerstitial fibrosis indices. Although the single administration of nifedipine or verapamil had no significant effect on renal pathology, or its biochemical and physiological function, the concurrent use of either calcium channel blockers significantly and equipotently ameliorated the biochemical, morphological, and functional derangements caused by CSA. More importantly, we report that the oxidative (reactive oxygen species production, NADPH-oxidase activity, and dual oxidase 1/2 levels), fibrotic (transforming growth factor-ß1 expression), and inflammatory (NF-κB expression) manifestations of renal toxicity induced by CSA were significantly reversed upon administration of nifedipine or verapamil. Together, these results highlight the efficacy of calcium channel-blocking agents in attenuating CSA-induced nephrotoxicity and predisposing biochemical and molecular machineries.

CYP4A/CYP2C modulation of the interaction of calcium channel blockers with cyclosporine on EDHF-mediated renal vasodilations in rats.

The endothelium-derived hyperpolarizing factor (EDHF) serves as a back-up mechanism that compensates for reduced nitric oxide (NO)/prostanoids bioavailability. Here we investigated whether (i) under conditions of vascular endothelium dysfunction, the immunosuppressant drug cyclosporine (CSA) upregulates EDHF-dependent renal vasodilations through altering CYP4A/CYP2C signaling, and (ii) calcium channel blockers modulate the CSA/EDHF/CYP interaction. Rats were treated with CSA, verapamil, nifedipine, or their combinations for 7days. Blood pressure (BP) was measured by tail-cuff plethysmography. Kidneys were then isolated, perfused with physiological solution containing L-NAME (NOS inhibitor) and diclofenac (cyclooxygenase inhibitor, DIC), and preconstricted with phenylephrine. CSA (25mgkg-1day-1 for 7days) increased BP and augmented carbachol renal vasodilations. The co-treatment with verapamil (2mgkg-1day-1) or nifedipine (3mgkg-1day-1) abolished CSA hypertension and conversely affected carbachol vasodilations (increases vs. decreases). Infusion of MSPPOH (epoxyeicosatrienoic acids, EETs, inhibitor) reduced carbachol vasodilations in kidneys of all rat groups, suggesting the importance of EETs in these responses. By contrast, 20-Hydroxyeicosatetraenoic Acid (20-HETE) inhibition by HET0016 increased carbachol vasodilations in control rats, an effect that disappeared by CSA treatment, and reappeared in rats treated with CSA/verapamil or CSA/nifedipine. Renal protein expression of CYP2C and CYP4A as well as their vasoactive products (EETs/20-HETE) were increased in CSA-treated rats. Whereas the CYP2C/EETs effects of CSA were abolished by verapamil and intensified by nifedipine, the CYP4A/20-HETE effects were reduced by either CCB. Overall, nifedipine and verapamil blunts CSA hypertension but variably affected concomitantly enhanced EDHF-dependent renal vasodilations and alterations in CYP2C/CYP4A signaling.