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.

Sodium orthovanadate exhibits anti-angiogenic, antiapoptotic and blood glucose-lowering effect on colon cancer associated with diabetes.

BACKGROUND: The presence of type 2 diabetes mellitus increases the risk of developing the colon cancer. The main objective of this study was to determine the role of sodium orthovanadate (SOV) in colon cancer associated with diabetes mellitus by targeting the competitive inhibition of PTP1B. METHODS: For in vivo study, high fat diet with low dose streptozotocin model was used for inducing the diabetes mellitus. Colon cancer was induced by injecting 1,2-dimethylhydrazine (25 mg/kg, sc) twice a week. TNM staging and immunohistochemistry (IHC) was carried out for colon cancer tissues. In vitro studies like MTT assay, clonogenic assay, rhodamine-123 dye assay and annexin V-FITC assay using flow cytometry were performed on HCT-116 cell line. CAM assay was performed to examine the anti-angiogenic effect of the drug. RESULTS: Sodium orthovanadate reduces the blood glucose level and tumor parameters in the animals. In vitro studies revealed that SOV decreased cell proliferation dose dependently. In addition, SOV induced apoptosis as depicted from rhodamine-123 dye assay and annexin V-FITC assay using flow cytometry as well as p53 IHC staining. SOV showed reduced angiogenesis effect on eggs which was depicted from CAM assay and also from CD34 and E-cadherin IHC staining. CONCLUSIONS: Our data suggest that SOV exhibits protective role in colon cancer associated with diabetes mellitus. SOV exhibits anti-proliferative, anti-angiogenic and apoptotic inducing effects hence can be considered for therapeutic switching in diabetic colon cancer.

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.

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.

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.

Surface-modified nanoparticles of docetaxel for chemotherapy of lung cancer: An intravenous to oral switch.

Despite being potent, the marketed formulations of Docetaxel (DX) are associated with numerous side effects and are meant for intravenous administration. Advanced pharmaceutical nanotechnology has a significant potential to facilitate the 'intravenous (i.v) to oral switch'. The present research work deals with the development of an orally administrable, folate-receptor-targeted Nanostructured lipid carriers (NLCs) of DX (FA-DX-NLCs) for facilitating oral chemotherapy of lung cancer while overcoming the bioavailability and toxicity issues. The nanoformulation prepared to employ high-pressure homogenization and lyophilization, was evaluated and statistically analyzed for various in-vitro and in-vivo formulation characteristics. The lyophilized nanoparticles were observed to be spherical with a particle size of 183.4 ± 2.13 (D90), Pdi of 0.358 ± 0.03, % EE of 82.41 ± 2.44, % DL of 4.41 ± 0.54 and a zeta potential of -3.3 ± 0.7 mv. The increased oral in-vivo bioavailability of DX was evident from the plasma-concentration area under the time curve (AUC0-t), which was âˆ¼ 27-fold greater for FA-DX-NLCs as compared to DX suspension. The orally administered FA-DX-NLCs exhibited excellent antitumor efficacy in a pre-clinical model of lung carcinoma. Tumor staging, histopathology, and immunostaining of the tumors suggested greater anti-proliferative, apoptotic, anti-metastatic, and anti-angiogenic potential as compared to DX-suspension. The pre-clinical toxicity studies affirmed the excellent safety and bio-compatibility of FA-DX-NLCs. The research work presents immense translational potential for switching the DX-based chemotherapy for lung cancer from 'hospital to home.'

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.

Solanum nigrum L. in COVID-19 and post-COVID complications: a propitious candidate.

COVID-19 is caused by severe acute respiratory syndrome coronavirus-2, SARS-CoV-2. COVID-19 has changed the world scenario and caused mortality around the globe. Patients who recovered from COVID-19 have shown neurological, psychological, renal, cardiovascular, pulmonary, and hematological complications. In some patients, complications lasted more than 6 months. However, significantly less attention has been given to post-COVID complications. Currently available drugs are used to tackle the complications, but new interventions must address the problem. Phytochemicals from natural sources have been evaluated in recent times to cure or alleviate COVID-19 symptoms. An edible plant, Solanum nigrum, could be therapeutic in treating COVID-19 as the AYUSH ministry of India prescribes it during the pandemic. S. nigrum demonstrates anti-inflammatory, immunomodulatory, and antiviral action to treat the SARS-CoV-2 infection and its post-complications. Different parts of the plant represent a reduction in proinflammatory cytokines and prevent multi-organ failure by protecting various organs (liver, kidney, heart, neuro, and lung). The review proposes the possible role of the plant S. nigrum in managing the symptoms of COVID-19 and its post-COVID complications based on in silico docking and pharmacological studies. Further systematic and experimental studies are required to validate our hypothesis.

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.

Cardiac Complications: The Understudied Aspect of Cancer Cachexia.

The global burden of cancer cachexia is increasing along with drastic increase in cancer patients. Cancer itself leads to cachexia, and cachexia development is associated with events like altered hemodynamics, and reduced functional capacity of the heart among others which lead to failure of the heart and are called cardiovascular complications associated with cancer cachexia. In some patients, the anti-cancer therapy also leads to this cardiovascular complications. So, in this review, an attempt is made to understand the mechanisms, pathophysiology of cardiovascular events in cachectic patients. Important processes which cause cardiovascular complications include alterations in the structure of the heart, loss of cardiac mass and functioning, cardiac fibrosis and cardiac remodeling, apoptosis, cardiac muscle atrophy, and mitochondrial alterations. Previously, the available treatment options were limited to nutraceuticals and physical exercise. Recently, studies with some prospective agents that can improve cardiac health have been reported, but whether their action is effective in cardiovascular complications associated with cancer cachexia is not known or are under trial.

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.