The Pathophysiological Associations Between Obesity, NAFLD, and Atherosclerotic Cardiovascular Diseases.

Obesity, non-alcoholic fatty liver disease (NAFLD), and atherosclerotic cardiovascular diseases are common and growing public health concerns. Previous epidemiological studies unfolded the robust correlation between obesity, NAFLD, and atherosclerotic cardiovascular diseases. Obesity is a well-known risk factor for NAFLD, and both of them can markedly increase the odds of atherosclerotic cardiovascular diseases. On the other hand, significant weight loss achieved by lifestyle modification, bariatric surgery, or medications, such as semaglutide, can concomitantly improve NAFLD and atherosclerotic cardiovascular diseases. Therefore, certain pathophysiological links are involved in the development of NAFLD in obesity, and atherosclerotic cardiovascular diseases in obesity and NAFLD. Moreover, recent studies indicated that simultaneously targeting several mechanisms by tirzepatide and retatrutide leads to greater weight loss and markedly improves the complications of metabolic syndrome. These findings remind the importance of a mechanistic viewpoint for breaking the association between obesity, NAFLD, and atherosclerotic cardiovascular diseases. In this review article, we mainly focus on shared pathophysiological mechanisms, including insulin resistance, dyslipidemia, GLP1 signaling, inflammation, oxidative stress, mitochondrial dysfunction, gut dysbiosis, renin-angiotensin-aldosterone system (RAAS) overactivity, and endothelial dysfunction. Most of these pathophysiological alterations are primarily initiated by obesity. The development of NAFLD further exacerbates these molecular and cellular alterations, leading to atherosclerotic cardiovascular disease development or progression as the final manifestation of molecular perturbation. A better insight into these mechanisms makes it feasible to develop new multi-target approaches to simultaneously unhinge the deleterious chain of events linking obesity and NAFLD to atherosclerotic cardiovascular diseases.

Impact of Negative Fluid Balance on Mortality and Outcome of Patients with Confirmed COVID-19.

Purpose: Maintaining the proper fluid balance is a fundamental step in the management of hospitalized patients. The current study evaluated the impact of negative fluid balance on outcomes of patients with confirmed COVID-19. Methods: We considered the negative fluid balance as a higher output fluid compared to the input fluid. The fluid balance was categorized into four groups (group 4: -850 to -500 ml/day; group 3: -499 to -200 ml/day, group 2: -199 to 0 ml/day, and group 1 : 1 to 1000 ml/day) and included ordinally in the model. The outcomes were all-cause mortality, length of hospitalization, and improvement in oxygen saturation. Results: The fluid balance differed significantly among nonsurvivors and survivors (MD: -317.93, 95% CI: -410.21, -225.69, and p < 0.001). After adjusting for potential confounders, there was a significantly lower frequency of mortality in patients with negative fluid balance compared to the controls (aRR: 0.69, 95% CI: 0.57, 0.84, and p < 0.001). Similarly, the length of hospitalization was significantly shorter in the negative fluid balance group in comparison to the control group (aMD: -1.01, 95% CI: -1.74, -0.28, and p=0.006). Conclusion: We determined that the negative fluid balance was associated with favorable outcomes in COVID-19 patients. The negative fluid balance was associated with the reduced mortality rate and length of hospitalization as well as improvement in oxygen saturation. Moreover, the NT-proBNP >781 pg/mL and fluid balance >-430 mL might be the predictors for positive fluid balance and mortality, respectively.

Weight loss breaks the bond between nonalcoholic fatty liver disease and cardiovascular diseases: A clinical and epidemiological perspective.

Nonalcoholic fatty liver disease (NAFLD) is a growing health concern that is closely related to obesity and metabolic syndrome. In particular, NAFLD has been increasingly reported in adolescents and young adults in recent years. Cardiovascular diseases (CVDs) such as cardiac remodeling, heart failure, myocardial infarction, valvular heart diseases, and arrhythmia are more common in patients with NAFLD. CVD are the major cause of mortality in NAFLD. Although NAFLD often affects patients with obesity/overweight, it can also affect subjects with normal body mass index (BMI), known as lean NAFLD, which has a strong correlation with CVD. Obesity imposes a considerably increased risk of NAFLD and CVD. Consistently, weight-lowering approaches that can pronouncedly decrease body weight and maintain it in the long term, such as bariatric surgery and treatment with semaglutide and tirzepatide, have been promising in alleviating both CVD and NAFLD. Interestingly, compared with patients with NAFLD and obesity, a minimal amount of weight loss resolves NAFLD in lean patients. Besides the widespread use of bariatric surgery, the development of new GLP-1 agonists and GLP-1 GIP agonists revolutionized the treatment of obesity in recent years. Here, we discuss the interwoven correlation between obesity, NAFLD, and CVD and the benefits of weight-lowering approaches.

Effect of thymoquinone on pharmacokinetics of 5-fluorouracil in rats and its effect on human cell line in vitro.

Thymoquinone (TQ) is one of the components extracted from Nigella sativa seeds and has antioxidant, anti-inflammatory, and anticancer effects. We evaluated the effect of TQ on 5-fluorouracil (5-FU) pharmacokinetics (PK) in vivo and in vitro on human colorectal cancer cell line. Ten Adult male Wistar rats were assigned to two groups. TQ treated group received intraperitoneal TQ once daily for 14 consecutive days (5 mg/kg). Both groups received intraperitoneal 5-FU (50 mg/kg) on day 15 and blood samples were collected from retro-orbital plexus. The pharmacokinetics parameters were analyzed using high-performance liquid chromatography (HPLC). Moreover, various concentrations of 5-FU, TQ, and combination of 5-FU and TQ were added to the HT-29 cell line and cell viability was measured using 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay. The maximum serum concentration (Cmax), area under the curve (AUC), and time of maximum concentration (Tmax) of 5-FU in TQ treated group were significantly increased approximately by 61, 60, and 24% compared to the control group, respectively. The combination of 5-FU with TQ (0.284 mM) showed a greater inhibitory effect on HT-29 cell growth compared to the alone 5-FU (0.027 and 0.055 mM) administration. TQ increases the AUC, Cmax, and Tmax of 5-FU and has a synergistic effect on the PK of 5-FU. Moreover, low concentration of TQ enhances the inhibitory effects of 5-FU on cell growth in colorectal cancer cell line. This synergistic effect might enhance the anticancer effects of low concentration of 5-FU, leading to drug dose reduction and reduced systemic toxicity of this chemotherapeutic agent.

Effect of Ketorolac on Pharmacokinetics and Pharmacodynamics of 5-Fluorouracil: In Vivo and In Vitro Study.

Background: This study aimed to evaluate the impact of ketorolac on the pharmacokinetics of 5-FU and its effect on the efficacy of 5-fluorouracil (5-FU) on the HT-29 cell line. Methods: Cell culture: the HT-29 cell line was treated with different concentrations of 5-FU, ketorolac, and combination of 5-FU and ketorolac for 24 and 48 hours. The cell viability (%) was calculated by the MTT assay. Animal study: rats were randomly divided into control and pretreatment groups. The control group received physiological saline, whereas the pretreatment group received ketorolac by intraperitoneal (i.p.) injections on a daily basis for 14 days. On the 15th day, both groups received 5-FU (i.p.). Blood samples were collected at different times for HPLC analysis, and 5-FU pharmacokinetic parameters were calculated. Results: At cell culture study, in a certain concentration range, combination therapy showed synergistic effects (<0.05). However, at concentrations above this range, combination therapy showed antagonistic effects on 5-FU efficacy (<0.05). According to the pharmacokinetic analysis, pretreatment with ketorolac resulted in a significant increase in AUC, C max, and T max of 5-FU (<0.05) and a significant decrease in V/F and Cl/F of 5-FU (<0.05). Conclusions: Combination therapy with ketorolac and 5-FU, depending on time and concentration, has a synergistic effect on reducing the viability of cancer cells. Also, ketorolac is able to alter the pharmacokinetics of 5-FU. Since there is a close relationship between pharmacokinetic parameters of 5-FU and its effectiveness/toxicity, it seems that these changes are towards creating a synergistic effect on 5-FU cytotoxicity. These results suggest the need to optimize the dose of these drugs in order to increase clinical efficacy and reduce the toxicity associated with them.

Rare case of aspergillus brain abscess in an immunocompromised patient.

We present a case of aspergillus brain abscess in a 48-year-old woman with a history of kidney transplantation and no underlying central nervous system (CNS) disease. Follow-up of the patient for 4 years shows normal findings. Early diagnosis and aggressive treatment could improve the prognosis of this fatal complication.

The Footprint of Kynurenine Pathway in Cardiovascular Diseases.

Kynurenine pathway is the main route of tryptophan metabolism and produces several metabolites with various biologic properties. It has been uncovered that several cardiovascular diseases are associated with the overactivation of kynurenine pathway and kynurenine and its metabolites have diagnostic and prognostic value in cardiovascular diseases. Furthermore, it was found that several kynurenine metabolites can differently affect cardiovascular health. For instance, preclinical studies have shown that kynurenine, xanthurenic acid and cis-WOOH decrease blood pressure; kynurenine and 3-hydroxyanthranilic acid prevent atherosclerosis; kynurenic acid supplementation and kynurenine 3-monooxygenase (KMO) inhibition improve the outcome of stroke. Indoleamine 2,3-dioxygenase (IDO) overactivity and increased kynurenine levels improve cardiac and vascular transplantation outcomes, whereas exacerbating the outcome of myocardial ischemia, post-ischemic myocardial remodeling, and abdominal aorta aneurysm. IDO inhibition and KMO inhibition are also protective against viral myocarditis. In addition, dysregulation of kynurenine pathway is observed in several conditions such as senescence, depression, diabetes, chronic kidney disease (CKD), cirrhosis, and cancer closely connected to cardiovascular dysfunction. It is worth defining the exact effect of each metabolite of kynurenine pathway on cardiovascular health. This narrative review is the first review that separately discusses the involvement of kynurenine pathway in different cardiovascular diseases and dissects the underlying molecular mechanisms.

Clinically suspected myocarditis in COVID-19 patients: Case series and review of the literature.

This Study describes eleven patients positive for severe acute respiratory syndrome coronavirus 2. In our cases, females and younger patients developed more severe disease. In contrast, improvement in left ventricular ejection fraction and N-terminal prohormone brain natriuretic peptide within the first week of treatment contributed to promising outcomes.

Target Sestrin2 to Rescue the Damaged Organ: Mechanistic Insight into Its Function.

Sestrin2 is a stress-inducible metabolic regulator and a conserved antioxidant protein which has been implicated in the pathogenesis of several diseases. Sestrin2 can protect against atherosclerosis, heart failure, hypertension, myocardial infarction, stroke, spinal cord injury neurodegeneration, nonalcoholic fatty liver disease (NAFLD), liver fibrosis, acute kidney injury (AKI), chronic kidney disease (CKD), and pulmonary inflammation. Oxidative stress and cellular damage signals can alter the expression of Sestrin2 to compensate for organ damage. Different stress signals such as those mediated by P53, Nrf2/ARE, HIF-1α, NF-κB, JNK/c-Jun, and TGF-ß/Smad signaling pathways can induce Sestrin2 expression. Subsequently, Sestrin2 activates Nrf2 and AMPK. Furthermore, Sestrin2 is a major negative regulator of mTORC1. Sestrin2 indirectly regulates the expression of several genes and reprograms intracellular signaling pathways to attenuate oxidative stress and modulate a large number of cellular events such as protein synthesis, cell energy homeostasis, mitochondrial biogenesis, autophagy, mitophagy, endoplasmic reticulum (ER) stress, apoptosis, fibrogenesis, and lipogenesis. Sestrin2 vigorously enhances M2 macrophage polarization, attenuates inflammation, and prevents cell death. These alterations in molecular and cellular levels improve the clinical presentation of several diseases. This review will shed light on the beneficial effects of Sestrin2 on several diseases with an emphasis on underlying pathophysiological effects.

Immune checkpoint inhibitors and cardiotoxicity: possible mechanisms, manifestations, diagnosis and management.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a new class of anticancer drugs that enhance the immune system function and activate T cells against cancerous cells. Although cardiac complications are not common, they could be accompanied with high morbidity and mortality. AREAS COVERED: Regarding the importance of cardiac complications and their subsequent burden on individuals and the healthcare system, this review attempts to discuss the mechanism, diagnosis, and management of myocarditis, besides recapitulating the possible mechanism of other cardiac adverse events. Moreover, we briefly discuss the concurrent administration of other chemotherapeutic agents. EXPERT OPINION: Due to insufficient knowledge concerning the physiopathology of immune-related adverse events (irAEs) and their potential further complications, cardiovascular complications in particular and in the context of this paper's focus, cooperation of oncologists, immunologists, and cardiologists is necessary for the management of patients. Experimental approaches such as using corticosteroids are becoming a part of guidelines for managing cardiac irAEs. However, a unique algorithm for diagnosis and management is necessary, especially in myocarditis cases. Furthermore, more studies are required to resolve current challenges, including prevention of myocarditis, concurrent administration of other chemotherapeutic agents, and re-introducing patients with ICIs.

Effect of Hydroxychloroquine and Azithromycin on QT Interval Prolongation and Other Cardiac Arrhythmias in COVID-19 Confirmed Patients.

BACKGROUND: Hydroxychloroquine with or without azithromycin was one of the common therapies at the beginning of the COVID-19 pandemic. They can prolong QT interval, cause torsade de pointes, and lead to sudden cardiac death. We aimed to assess QT interval prolongation and its risk factors in patients who received hydroxychloroquine with or without azithromycin. METHODS: This study was a retrospective cohort study. One hundred seventy-two confirmed COVID-19 patients were included in this study, hospitalized at Babol University of Medical Sciences hospitals between March 5, 2020, and April 3, 2020. Patients were divided into two groups: hydroxychloroquine alone and hydroxychloroquine with azithromycin. Electrocardiograms were used for outcome assessment. RESULTS: 83.1% of patients received hydroxychloroquine plus azithromycin vs. 16.9% of patients who received only hydroxychloroquine. The mean age of patients was 59.2 ± 15.4.The mean of posttreatment QTc interval in the monotherapy group was shorter than the mean of posttreatment QTc interval in the combination therapy group, but it had no significant statistical difference (462.5 ± 43.1 milliseconds vs. 464.3 ± 59.1 milliseconds; p = 0.488). Generally, 22.1% of patients had a prolonged QTc interval after treatment. Male gender, or baseline QTc ≥ 450 milliseconds, or high-risk Tisdale score increased the likelihood of prolonged QTc interval. Due to QTc prolongation, fourteen patients did not continue therapy after four days. CONCLUSIONS: Hospitalized patients treated by hydroxychloroquine with or without azithromycin had no significant difference in prolongation of QT interval and outcome. The numbers of patients with prolonged QT intervals in this study emphasize careful cardiac monitoring during therapy, especially in high-risk patients.

A brief review of the latest pharmacological treatments of COVID-19.

New Coronavirus which is called 2019-nCoV (2019-Novel-Coronavirus) or SARS-Cov-2 (Severe Acute respiratory Syndrome-Coronavirus 2) causes deadly pneumonia that first appeared in December 2019 in Wuhan city in China. This virus spreads all over the world quickly and made several problems for the community and healthcare system. Several drugs have been tried to manage COVID-19; however, our knowledge of this virus is not complete. At any rate, effective treatment or vaccine for this disease has not been discovered yet. Furthermore, to achieve this goal, more studies are needed on the structure of the virus and its pathogenesis mechanism. In this article, we summarized several articles suggesting treatments of COVID-19.