The therapeutic effect of NRF2 activator, ezetimibe, in cardiac cachexia.

INTRODUCTION: Heart failure (HF) is caused by functional and structural irregularity leading to impaired ejection or filling capacity of the heart. HF leads to chronic inflammatory conditions in the heart leads to weight loss, anorexia, and muscle atrophy known as cachexia. The present study was carried out to investigate the role of Ezetimibe, an NRF2 activator, in cardiac cachexia and to develop a treatment strategy for cardiac cachexia. METHOD: Balb/c mice of either sex at 6-8 weeks of age were given 2 mg/kg of doxorubicin in 0.9% sodium chloride solution intraperitoneally (i.p.) for the alternate days for the first week and then once a week for the next 4 weeks. After induction of cardiac atrophy, treatment with Ezetimibe (1.5 mg/kg, p.o) was given for the next 4 weeks. RESULT: In the cardiac cachectic animals, a significant decrease in body weight, food, and water intake was observed. Cardiac cachectic animals showed a significant increase in serum glucose, total cholesterol, LDL, triglyceride, VLDL, CK-MB, LDH, and CRP levels. Cardiac atrophic index, heart weight to body weight ratios (HW/BW), right ventricular weight to heart weight ratios (RV/HW), and left ventricular weight to heart weight ratios (LV/HW), were significantly decreased in cardiac cachectic animals. The weights of the skeletal muscles such as EDL, gastrocnemius, soleus, tibialis anterior, and quadriceps muscles, and the weight of adipose tissue such as subcutaneous, visceral, perirenal, and brown adipose tissue were significantly decreased in the cardiac cachectic group relative to the normal group. Treatment with ezetimibe improves body weight, food intake, and water intake. Ezetimibe decreases serum glucose, total cholesterol, LDL, triglyceride, VLDL, CK-MB, LDH and CRP levels. Cardiac atrophic markers such as HW/BW, RV/HW, and LV/HW were improved. The weight of skeletal muscles and adipose tissue was increased after treatment with ezetimibe. CONCLUSION: Our data showed that the NRF2 activator, Ezetimibe produces a beneficial effect on cardiac cachexia in the doxorubicin-induced cardiac cachexia model. Ezetimibe was successful to reduce the levels of inflammatory cytokines, ameliorate the effects on cardiac muscle wasting, lipid levels, fat tissues, and skeletal muscles.

Unravelling the role of cathepsins in cardiovascular diseases.

Lysosomal cathepsins as a regulatory medium have been assessed as potential therapeutic targets for the treatment of various cardiac diseases such as abdominal aortic aneurysm, hypertension, cardiomyopathy, coronary heart disease, atherosclerosis, etc. They are ubiquitous lysosomal proteases with papain-like folded protein structures that are involved in a variety of physiological processes, such as the digestion of proteins, activation of pro-inflammatory molecules, degradation of extracellular matrix components, and maturation of peptide hormones. Cathepsins are classified into three major groups: cysteine cathepsins, aspartic cathepsins, and serine-threonine cathepsins. Each of these groups is further divided into subgroups based on their substrate specificity, structural characteristics, and biochemical properties. Several studies suggest that cathepsins control the degradation of ECM components such as collagen and elastin fibres. These enzymes are highly expressed in macrophages and inflammatory cells, and their upregulation has been demonstrated to be critical in the progression of atherosclerotic lesions. Additionally, increased cathepsin activity has been linked to increased vascular inflammation and oxidative stress, both of which are associated with CVDs. Specifically, the inhibition of cathepsins may reduce the release of pro-apoptotic mediators such as caspase-3 and PARP-1, which are thought to contribute to plaque instability. The potential of cathepsins as biomarkers and therapeutic targets has also been supported by the identification of potential cathepsin inhibitors, which could be used to modulate the activities of cathepsins in a range of diseases. This review shall familiarise the readers with the role of cysteinyl cathepsins and their inhibitors in the pathogenesis of cardiovascular diseases.

Deliberation on debilitating condition of cancer cachexia: Skeletal muscle wasting.

BACKGROUND: Cancer cachexia is a debilitating syndrome associated with marked body loss because of muscular atrophy and fat loss. There are several mechanisms contributing to the pathogenesis of cachexia. The presence of the tumor releases cytokines from inflammatory and immune cells, which play a significant role in activating and deactivating certain pathways associated with protein, carbohydrate, and lipid metabolism. This review focuses on various cascades involving an imbalance between protein synthesis and degradation in the skeletal muscles. OBJECTIVES: This study aimed to elucidate the mechanisms involved in skeletal muscle wasting phenomenon over the last few years. METHODS: This article briefly overviews different pathways responsible for muscle atrophy in cancer cachexia. Studies published up to April 2023 were included. Important findings and study contributions were chosen and compiled using several databases including PubMed, Google Scholar, Science Direct, and ClinicalTrials.gov using relevant keywords. RESULTS: Cancer cachexia is a complex disease involving multiple factors resulting in atrophy of skeletal muscles. Systemic inflammation, altered energy balance and carbohydrate metabolism, altered lipid and protein metabolism, and adipose tissue browning are some of the major culprits in cancer cachexia. Increased protein degradation and decreased protein synthesis lead to muscle atrophy. Changes in signaling pathway like ubiquitin-proteasome, autophagy, mTOR, AMPK, and IGF-1 also lead to muscle wasting. Physical exercise, nutritional supplementation, steroids, myostatin inhibitors, and interventions targeting on inflammation have been investigated to treat cancer cachexia. Some therapy showed positive results in preclinical and clinical settings, although more research on the efficacy and safety of the treatment should be done. CONCLUSION: Muscle atrophy in cancer cachexia is the result of multiple complex mechanisms; as a result, a lot more research has been done to describe the pathophysiology of the disease. Targeted therapy and multimodal interventions can improve clinical outcomes for patients.

Unveiling the Role of the Proton Gateway, Uncoupling Proteins (UCPs), in Cancer Cachexia.

Uncoupling proteins (UCPs) are identified as carriers of proton ions between the mitochondrial inner membrane and the mitochondrial matrix. ATP is mainly generated through oxidative phosphorylation in mitochondria. The proton gradient is generated across the inner mitochondrial membrane and the mitochondrial matrix, which facilitates a smooth transfer of electrons across ETC complexes. Until now, it was thought that the role of UCPs was to break the electron transport chain and thereby inhibit the synthesis of ATP. UCPs allow protons to pass from the inner mitochondrial membrane to the mitochondrial matrix and decrease the proton gradient across the membrane, which results in decreased ATP synthesis and increased production of heat by mitochondria. In recent years, the role of UCPs in other physiological processes has been deciphered. In this review, we first highlighted the different types of UCPs and their precise location across the body. Second, we summarized the role of UCPs in different diseases, mainly metabolic disorders such as obesity and diabetes, cardiovascular complications, cancer, wasting syndrome, neurodegenerative diseases, and kidney complications. Based on our findings, we conclude that UCPs play a major role in maintaining energy homeostasis, mitochondrial functions, ROS production, and apoptosis. Finally, our findings reveal that mitochondrial uncoupling by UCPs may treat many diseases, and extensive clinical studies are required to meet the unmet need of certain diseases.

mRNA-Based Vaccine for COVID-19: They Are New but Not Unknown!

mRNA vaccines take advantage of the mechanism that our cells use to produce proteins. Our cells produce proteins based on the knowledge contained in our DNA; each gene encodes a unique protein. The genetic information is essential, but cells cannot use it until mRNA molecules convert it into instructions for producing specific proteins. mRNA vaccinations provide ready-to-use mRNA instructions for constructing a specific protein. BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) both are newly approved mRNA-based COVID-19 vaccines that have shown excellent protection and efficacy. In total, there are five more mRNA-based vaccine candidates for COVID-19 under different phases of clinical development. This review is specifically focused on mRNA-based vaccines for COVID-19 covering its development, mechanism, and clinical aspects.

Long-acting opioids and cardiovascular diseases: Help or hindrance!

Opioids are widely being used for chronic pain management, cough and diarrhea suppressants, anesthetic agents, and opioid de-addiction therapy. Opioid receptors, present in the central nervous system and peripheral tissues, are documented to regulate several cardiac functions through different signaling pathways. Long-acting opioids (LAO) have been successfully evaluated for their beneficial effects in various cardiovascular diseases viz. myocardial infarction, ischemic reperfusion injuries, atherosclerosis etc. However, on the other hand, several research studies pointed towards the harmful effects of LAOs which are mainly associated with QTc prolongation, torsade de pointes, ventricular arrhythmias, and cardiac arrest. This review shall familiarize readers with the benefits as well as the harmful effects of long-acting opioids in cardiovascular diseases. We have also provided an overview of cardiac opioid receptors, endogenous cardiac opioid peptides, and regulation of cardiovascular functions by central and cardiac opioid receptors.

Beneficial effects of buspirone in endothelin-1 induced stroke cachexia in rats.

Stroke cachexia is associated with prolonged inflammation, muscle loss, poor prognosis, and early death of stroke patients. No particular treatment is available to cure the symptoms or disease. The present study aimed to evaluate the effect of a 5-HT1a agonist, buspirone on stroke cachexia. Wistar rats were injected with endothelin-1 to the bregma region of the brain to induce ischemic stroke followed by induction of cachexia after 4 days. Treatment with buspirone (3 mg/kg p.o) was given for 4 weeks after confirmation of cachexia in animals. Disease control animals exhibited decrease in wire hanging time and increase in foot fault numbers compared to normal animals. Disease control animals also showed weight loss, decrease in food intake, increased serum glucose and lipid profile along with high serum levels of inflammatory cytokines-TNF-α, IL-6 and decrease in weight of skeletal muscle and adipose tissues. Treatment with buspirone improves behavioural parameters along with increases food intake and body weight, decreased inflammatory cytokines IL-6 and TNF-α and serum glucose levels with increase in lipid profile. Buspirone also increased the weight of adipose tissue and maintain the skeletal muscle architecture and function as depicted in histopathological studies. Our study suggests that buspirone produces beneficial role in stroke cachexia by increasing body weight, food intake and adipose tissue depots by activating on 5-HT receptors. Buspirone decreases inflammatory markers in stroke cachexia although mechanism behind it was not fully understood. Buspirone decreases circulating blood glucose by stimulating glucose uptake in skeletal muscle via 5-HT receptors and maintained lipid profile. Buspirone was found to be effective in ameliorating cachectic conditions in stroke.

Repositioning of simvastatin for diabetic colon cancer: role of CDK4 inhibition and apoptosis.

There is increased risk of colon cancer in both men and women having diabetes. The objective of the study was to evaluate the role of simvastatin in colon cancer associated with type 2 diabetes mellitus. Diabetes was induced by administering high fat diet with low dose streptozotocin model. 1,2 dimethylhydrazine (25 mg/kg, sc) was used for colon cancer induction. MTT assay, scratch assay, clonogenic assay and annexin V-FITC assay using flow cytometry were performed on HCT-15 cell line. Simvastatin controlled diabetes and colon cancer in animal models and reduced mRNA expression of CDK4 in colon tissues. In vitro studies revealed that simvastatin showed a decrease in cell viability and produced dose dependent decrease in clone formation. There was decrease in the rate of migration with increase in concentration of simvastatin in scratch assay. Moreover, simvastatin induced apoptosis as depicted from annexin V-FITC assay using flow cytometry as well as that revealed by tunnel assay. Our data suggest that simvastatin exhibits protective role in colon cancer associated with diabetes mellitus and acts possibly via down regulation of CDK4 and induction of apoptosis and hence can be considered for repositioning in diabetic colon cancer.

Evaluation of selected antidiabetics in cardiovascular complications associated with cancer cachexia.

So far, the cardio-protective potential of antidiabetics is proved, but their effect on cardiovascular complications associated with cancer cachexia is not explored until now. Insulin resistance and glucose intolerance along with systemic inflammation are prominent in cachexia but the potential effect of antidiabetic agents especially those belonging to biguanide, DPP4 inhibitors and SGLT2 on the heart are not studied till now. In present study, the effect of metformin, vildagliptin, teneligliptin, dapagliflozin and empagliflozin on cardiovascular complications associated with cancer cachexia by using B16F1 induced metastatic cancer cachexia and urethane-induced cancer cachexia was studied. These antidiabetic agents proved to be beneficial against cachexia-induced atrophy of the heart, preserved ventricular weights, maintained cardiac hypertrophic index, preserved the wasting of cardiac muscles assessed by HE staining, Masson trichrome staining, periodic acid Schiff staining and picro-Sirius red staining. Altered cardiac gene expression was attenuated after treatment with selected antidiabetics, thus preventing cardiac atrophy. Also, antidiabetic agents treatment improved the serum creatinine kinase MB, Sodium potassium ATPase and collagen in the heart. Reduction in blood pressure and heart rate was observed after treatment with antidiabetic agents. Results of our study show that the selected antidiabetics prove to be beneficial in attenuating the cardiac atrophy and helps in regulation of hemodynamic stauts in cancer cachexia-induced cardiovascular complications. Our study provides some direction towards use of selected antidiabetic agents in the management of cardiovascular complications associated with cancer cachexia and the study outcomes can be useful in desiging clinical trials.

New Drug Delivery Systems Developed for Brain Targeting.

The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSF) are two of the most complex and sophisticated concierges that defend the central nervous system (CNS) by numerous mechanisms. While they maintain the neuro-ecological homeostasis through the regulated entry of essential biomolecules, their conservative nature challenges the entry of most of the drugs intended for CNS delivery. Targeted delivery challenges for a diverse spectrum of therapeutic agents/drugs (non-small molecules, small molecules, gene-based therapeutics, protein and peptides, antibodies) are diverse and demand specialized delivery and disease-targeting strategies. This review aims to capture the trends that have shaped the current brain targeting research scenario. This review discusses the physiological, neuropharmacological, and etiological factors that participate in the transportation of various drug delivery cargoes across the BBB/BCSF and influence their therapeutic intracranial concentrations. Recent research works spanning various invasive, minimally invasive, and non-invasive brain- targeting approaches are discussed. While the pre-clinical outcomes from many of these approaches seem promising, further research is warranted to overcome the translational glitches that prevent their clinical use. Non-invasive approaches like intranasal administration, P-glycoprotein (P-gp) inhibition, pro-drugs, and carrier/targeted nanocarrier-aided delivery systems (alone or often in combination) hold positive clinical prospects for brain targeting if explored further in the right direction.

PROTACs: Novel approach for cancer breakdown by breaking proteins.

Ubiquitination defects have been reported in various diseases, including neurodegenerative diseases, metabolic disorders and cancer. Balance between degradation and synthesis of the proteins to treat cancer can be managed by designing a chimeric molecule, known as Proteolysis Targeting Chimeric molecule (Lee, Kim et al. 2021). Proteolysis-targeting chimeras (PROTACs) acts as a tool for conducting therapeutic intervention. It eradicates or reduces the proteins that are responsible for causing diseases. Each PROTAC contains a target warhead, an E3 ligand and a linker. E3 ligases are recruited by these bifunctional molecules, and the Ubiquitin (Ub) Proteasome System (UPS) is used to target the degradation of specific proteins. As compared to inhibition, this degradation offers several advantages in the drug resistance, selectivity, and potency. Thus, numerous small molecule PROTACs are identified so far. In this review, the development of PROTACs, historical milestones, the biological mechanism, advantages and recent progress, and role of PROTAC in prostate cancer, breast cancer, non-hodgkin lymphoma, multiple myeloma, and malignant peripheral nerve sheath tumors are summarized.

Role of NIMA-related kinase 2 in lung cancer: Mechanisms and therapeutic prospects.

The second most common cancer in both males and females is lung cancer. Chemotherapeutic resistance is the main problem associated with the treatment of lung cancer. Radiation therapy and surgery also produce recurrence in lung cancer patients; this shows the need to develop novel agents acting on new targets. A never in mitosis (NIMA)-related kinase 2 (NEK2) is a serine/threonine kinase associated with the family of NIMA-related kinase (NEK). NEK2 plays an important role in the regulating mitotic processes, such as centrosome duplication and separation, kinetochore attachment, spindle assembly checkpoint, and microtubule stabilization. Several in vitro, in vivo, and clinical studies have confirmed the overexpression of NEK2 in various types of cancers including lung cancer. Overexpression of NEK2 in non-small cell lung cancer (NSCLC) cells increased cell proliferation and chromosomal instability. The overexpression of NEK2 results in the activation of its downstream proteins such as ß-catenin, MAD2, Hec1, rootletin, C-Nap1, CDC20, Cep68, and Sgo1. Activation of the Akt, ß-catenin, and Wnt pathways could promote growth and metastasis of lung cancer cells. Such confirmation suggests that NEK2 is a novel target for treating many cancers including lung cancer. The current review provides an idea about functions and regulation of NEK2 and emphasizes about the role of NEK2 in lung cancer by discussing in vitro, in vivo, and clinical studies pertaining to the same.

The burning furnace: Alteration in lipid metabolism in cancer-associated cachexia.

Cancer cachexia can be defined as a complex metabolic syndrome characterized by weight loss, anorexia, and emaciation due to the wasting of adipose tissue and skeletal muscle. In the last decade, much research has been done to decipher the role of lipid metabolism in cancer cachexia. Tumors, as well as host-derived factors, cause major metabolic changes in the body. Metabolic changes lead to higher energy expenditure by the host. To meet the high energy demand, the host utilizes fat depots stored in adipose tissues by a process known as lipolysis. High catabolic and low anabolic response leads to loss of adipose tissue. A significant insight has been made regarding adipose tissue "browning" bestow on thermogenic activities of adipocytes that result in catabolic energy expenditure. Both lipolysis and WAT browning play an important role in exhaustion adipose tissue. The goal of this review is to summarise what is currently known and about altered lipid metabolism and its utilization in cancer cachexia.

Systemic study of selected histone deacetylase inhibitors in cardiac complications associated with cancer cachexia.

Cancer cachexia is mainly characterized by wasting of skeletal muscles and fat and body weight loss, along with severe complications of major organs like liver, heart, brain and bone. There can be diminishing performance of these major organs as cancer cachexia progresses, one such drastic effect on the cardiac system. In the present study, differential effect of histone deacetylase inhibitors (HDACi) on cardiac complications associated with cancer cachexia is studied. Two models were used to induce cancer cachexia: B16F1 induced metastatic cancer cachexia and Lewis lung carcinoma cell - induced cancer cachexia. Potential of Class I HDACi entinostat, Class II HDACi MC1568, and nonspecific HDACi sodium butyrate on cardiac complications were evaluated using the cardiac hypertrophy markers, hemodynamic markers, and cardiac markers along with histopathological evaluation of heart sections by Periodic acid-Schiff staining, Masson's trichrome staining, Picro-sirius red staining, and haematoxylin and eosin staining. Immunohistochemistry evaluation by vimentin and caspase 3 protein expression was evaluated. Entinostat showed promising results by attenuating the cardiac complications, and MC1568 treatment further exacerbated the cardiac complications, while non-conclusive effect were recorded after treatment with sodium butyrate. This study will be helpful in evaluating other HDACi for potential in cardiac complications associated with cancer cachexia.

The Deadly Duo of COVID-19 and Cancer!

As of September 19, 2020, about 30 million people have been infected with the novel corona virus disease 2019 (COVID-19) globally, and the numbers are increasing at an alarming rate. The disease has a tremendous impact on every aspect of life, but one of the biggest, related to human health and medical sciences, is its effect on cancer. Nearly 2% of the total COVID-19 patients prior to May 2020 had cancer, and the statistics are quite frightening as the patient can be referred to as "doubly unfortunate" to suffer from cancer with the added misery of infection with COVID-19. Data regarding the present situation are scarce, so this review will focus on the deadly duo of COVID-19 and cancer. The focus is on molecular links between COVID-19 and cancer as inflammation, immunity, and the role of angiotensin converting enzyme 2 (ACE2). Complications may arise or severity may increase in cancer patients due to restrictions imposed by respective authorities as an effort to control COVID-19. The impact may vary from patient to patient and factors may include a delay in diagnosis, difficulty managing both cancer therapy and COVID-19 at same time, troubles in routine monitoring of cancer patients, and delays in urgent surgical procedures and patient care. The effect of anti-cancer agents on the condition of cancer patients suffering from COVID-19 and whether these anti-cancer agents can be repurposed for effective COVID-19 treatment are discussed. The review will be helpful in the management of deadly duo of COVID-19 and cancer.

Investigation into the role of anti-diabetic agents in cachexia associated with metastatic cancer.

Cancer cachexia (CC) is a syndrome associated with cancer, and the global burden is increasing rapidly. Alteration in carbohydrate, lipid and protein metabolism along with systemic inflammation are characteristics of CC. Until now the available treatment for CC is limited to controlling inflammation and nutrition. Anti-diabetics are widely used agents to treat diabetics, this agent's act by regulating the carbohydrate metabolism, also they are known to have beneficial effects in maintaining protein and lipid balance. Role of anti-diabetics in cancer is being evaluated continuously and biguanides, dipeptidyl peptidase 4 (DPP4) inhibitors and Sodium glucose co-transporter 2 (SGLT2) inhibitors have proven anti-cancer potential. In this study, metastatic B16-F1 cell line induced cancer cachexia model used to evaluate potential of biguanides (metformin), DPP-4 inhibitors (teneligliptin and vildagliptin) and SGLT2 inhibitors (empagliflozin and dapagliflozin) in cancer cachexia. Our results suggest that anti-diabetic agents have potential to decrease rate of proliferation of tumor, restrict body mass markers, decrease inflammation, regulate carbohydrate mechanism and induce skeletal muscle hypertrophy. These findings may be helpful in management of cancer cachexia and increase the quality of life and survival chances of cancer cachexia patient.

Protocatechuic acid attenuates chronic unpredictable mild stress induced-behavioral and biochemical alterations in mice.

Amelioration of oxidative stress via promoting the endogenous antioxidant system and enhancement of monoamines in brain were the important underlying antidepressant mechanism of protocatechuic acid (PCA). The aim of the present study is to explore the potential antidepressant mechanism(s) PCA in chronic unpredictable mild stress (CUMS) mice. Mice were subjected to CUMS protocol for 4 weeks, and administered with PCA (100 and 200 mg/kg) and fluoxetine (20 mg/kg) for 24 days (from day 8th to 31st). Behavioral (sucrose preference, immobility time, exploratory behavior), and biochemical alterations such as serum corticosterone, brain derived neurotrophic factor (BDNF), inflammatory cytokines, tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), and antioxidants parameters were investigated. Experimental findings revealed that CUMS subjected mice exhibited significant impairment in behavioral alterations, such as increased immobility time, impaired preference to the sucrose solution, BDNF levels and, serum corticosterone, cytokines, malondialdehyde (MDA) formation with impaired antioxidants in the hippocampus and cerebral cortex. Administration of PCA to CUMS mice attenuated the immobility time, serum corticosterone, cytokines TNF-α, and IL-6, MDA formation and improved sucrose preference, including restoration of BDNF level. Thus, the present findings demonstrated the antidepressant potential of PCA which is largely achieved probably through maintaining BDNF level, and by modulation of the oxidative stress response, cytokines systems, and antioxidant defense system in mice.

Fabrication and Characterization of Surface Engineered Rifampicin Loaded Lipid Nanoparticulate Systems for the Potential Treatment of Tuberculosis: An In Vitro and In Vivo Evaluation.

The main aim of the present investigation highlights the development of mannose appended rifampicin containing solid lipid nanoparticles (Mn-RIF-SLNs) for the management of pulmonary TB. The developed Mn-RIF-SLNs showed particle size of Mn-RIF-SLNs (479 ± 13 nm) which was found to be greater than that of unconjugated SLNs (456 ± 11 nm), with marginal reduction in percentage entrapment efficiency (79.41 ± 2.42%). The in vitro dissolution studies depicted an initial burst release followed by sustained release profile indicating biphasic release pattern, close-fitting Weibull model having least F-value. The cytotoxicity studies using J774A.1 cell line represented that the developed SLNs were non-toxic and safe as compared to free drug. Fluorescence imaging and flow cytometric (FACS) analysis depicted significant (1.79-folds) intracellular uptake of coumarin-6 (fluorescent marker) loaded Mn-C6-SLNs. The in vivo pharmacokinetic studies in sprague-dawley rats were performed and Mn-RIF-SLNs showed remarkable enhancement in terms of relative bioavailability (~17-folds) as compared to its drug solution via oral administration. The biodistribution studies revealed higher lung accumulation (1.8-folds) of Mn-RIF-SLNs as compared to the Un-RIF-SLNs. In conclusion, the developed Mn-RIF-SLNs could serve as a promising tool for delivering the drug cargo to the site of infection (lungs) in the treatment of TB.