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.

Roles of ARF tumour suppressor protein in lung cancer: time to hit the nail on the head!

Owing to its poor prognosis, the World Health Organization (WHO) lists lung cancer on top of the list when it comes to growing mortality rates and incidence. Usually, there are two types of lung cancer, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), which also includes adenocarcinoma, squamous cell carcinoma and large cell carcinomas. ARF, also known in humans as p14ARF and in the mouse as p19ARF, is a nucleolar protein and a member of INK4, a family of cyclin-independent kinase inhibitors (CKI). These genes are clustered on chromosome number 9p21 within the locus of CDKN2A. NSCLC has reported the role of p14ARF as a potential target. p14ARF has a basic mechanism to inhibit mouse double minute 2 protein that exhibits inhibitory action on p53, a phosphoprotein tumour suppressor, thus playing a role in various tumour-related activities such as growth inhibition, DNA damage, autophagy, apoptosis, cell cycle arrest and others. Extensive cancer research is ongoing and updated reports regarding the role of ARF in lung cancer are available. This article summarizes the available lung cancer ARF data, its molecular mechanisms and its associated signalling pathways. Attempts have been made to show how p14ARF functions in different types of lung cancer providing a thought to look upon ARF as a new target for treating the debilitating condition of lung cancer.

Keeping abreast about ashwagandha in breast cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Ashwagandha has been used as an ayurvedic medicine in the form of 'Rasayana' (as a tonic) even before 3000 BCE in India. As per Ayurveda, it has long been used traditionally for the treatment of inflammation, weakness, impotence, pulmonary tuberculosis. This plant is also beneficial in lumbago and leucorrhea in the female. In the recent past, Withania has shown its anti-cancerous activity in various experimental models. In addition, Withania also possesses many other properties such as anti-oxidant, anti-stress, adaptogenic, and regenerative which will eventually be beneficial and safe in treating cancer patients. AIM OF THE STUDY: This review aims to provide experimental evidence along with a deeper insight into molecular mechanisms of Ashwagandha (Withania somnifera (L.) Dunal) through which it acts as a chemotherapeutic agent against different types of breast cancer. MATERIALS AND METHODS: Literature searches with the help of electronic online databases (Elsevier, Google Scholar, Scopus, Springer Link, ScienceDirect, ResearchGate, PubMed) were carried out. The timeline for collection of data for the review article was from 2000 to 2019. The plant name was validated from The Plant List (2013). Version 1.1. Published on http://www.theplantlist.org/(accessed 21st March 2020). RESULTS: Various forms of Withania somnifera were used and several in vitro, in vivo, and clinical studies were reported by researchers. They found ashwagandha to exhibit anti-apoptotic, anti-metastatic, anti-invasive and anti-inflammatory properties and gave the evidence that ashwagandha has a capability for averting and treating breast cancer. CONCLUSION: Various in vitro and in vivo studies suggested Ashwagandha may possess a potential for treating breast cancer, especially ER/PR positive breast cancer and triple-negative breast cancer. A clinical trial has also been conducted in the past that suggested its potential in refining quality of life in breast cancer patients. Studies directed towards molecular pathways have helped in unravelling the key mechanisms of ashwagandha. Future research should be directed towards translational studies involving breast cancer patients. These will reinforce the ancient power of our Ayurvedic medicine.