Bufalin-Mediated Regulation of Cell Signaling Pathways in Different Cancers: Spotlight on JAK/STAT, Wnt/ß-Catenin, mTOR, TRAIL/TRAIL-R, and Non-Coding RNAs.

The renaissance of research into natural products has unequivocally and paradigmatically shifted our knowledge about the significant role of natural products in cancer chemoprevention. Bufalin is a pharmacologically active molecule isolated from the skin of the toad Bufo gargarizans or Bufo melanostictus. Bufalin has characteristically unique properties to regulate multiple molecular targets and can be used to harness multi-targeted therapeutic regimes against different cancers. There is burgeoning evidence related to functional roles of signaling cascades in carcinogenesis and metastasis. Bufalin has been reported to regulate pleiotropically a myriad of signal transduction cascades in various cancers. Importantly, bufalin mechanistically regulated JAK/STAT, Wnt/ß-Catenin, mTOR, TRAIL/TRAIL-R, EGFR, and c-MET pathways. Furthermore, bufalin-mediated modulation of non-coding RNAs in different cancers has also started to gain tremendous momentum. Similarly, bufalin-mediated targeting of tumor microenvironments and tumor macrophages is an area of exciting research and we have only started to scratch the surface of the complicated nature of molecular oncology. Cell culture studies and animal models provide proof-of-concept for the impetus role of bufalin in the inhibition of carcinogenesis and metastasis. Bufalin-related clinical studies are insufficient and interdisciplinary researchers require detailed analysis of the existing knowledge gaps.

Multifunctional Roles of Betulinic Acid in Cancer Chemoprevention: Spotlight on JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and Non-Coding RNAs in the Inhibition of Carcinogenesis and Metastasis.

The pursual of novel anticancer molecules from natural sources has gained worthwhile appreciation, and a significant fraction of conceptual knowledge has revolutionized our understanding about heterogeneous nature of cancer. Betulinic acid has fascinated interdisciplinary researchers due to its tremendous pharmacological properties. Ground-breaking discoveries have unraveled previously unprecedented empirical proof-of-concept about momentous chemopreventive role of betulinic acid against carcinogenesis and metastasis. Deregulation of cell signaling pathways has been reported to play a linchpin role in cancer progression and colonization of metastatically competent cancer cells to the distant organs for the development of secondary tumors. Importantly, betulinic acid has demonstrated unique properties to mechanistically modulate oncogenic transduction cascades. In this mini-review, we have attempted to provide a sophisticated compendium of regulatory role of betulinic acid in cancer chemoprevention. We have partitioned this multi-component review into different sections in which we summarized landmark research-works which highlighted betulinic acid mediated regulation of JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and ubiquitination pathways in the inhibition of cancer. In parallel, betulinic acid mediated regulation of signaling cascades and non-coding RNAs will be critically analyzed in cell culture and animal model studies. Better comprehension of the pharmaceutical features of betulinic acid and mapping of the existing knowledge gaps will be valuable in the translatability of preclinical studies into rationally designed clinical trials.

Role of TRP channels in carcinogenesis and metastasis: Pathophysiology and regulation by non-coding RNAs.

In 2021, David Julius and Ardem Patapoutian received Nobel Prize in Physiology or Medicine for their ground-breaking discoveries in the functional characterization of receptors for temperature and touch. Transient receptor potential (TRP) channels have captivated tremendous appreciation as promising drug targets over the past few years because of central involvement in different cancers. Based on the insights gleaned from decades of high-quality research, basic and clinical scientists have unveiled how Transient receptor potential channels regulated cancer onset and progression. Pioneering studies have sparked renewed interest and researchers have started to scratch the surface of mechanistic role of these channels in wide variety of cancers. In this review we have attempted to provide a summary of most recent updates and advancements made in the biology of these channels in context of cancers. We have partitioned this review into different subsections on the basis of emerging evidence about characteristically distinct role of TRPV (TRPV1, TRPV5), TRPM (TRPM3, TRPM7) and TRPC in cancers. Regulation of TRP channels by non-coding RNAs is also a very exciting area of research which will be helpful in developing a sharper understanding of the multi-step aspects of cancers.

TRAIL-mediated signaling in bladder cancer: realization of clinical efficacy of TRAIL-based therapeutics in medical oncology.

Bladder cancer is a therapeutically challenging disease and wealth of knowledge has enabled researchers to develop a clear understanding of mechanisms which underlie carcinogenesis and metastasis. Excitingly, research over decades has unveiled wide-ranging mechanisms which serve as central engine in progression of bladder cancer. Loss of apoptosis, drug resistance, and pro-survival signaling are some of the highly studied cellular mechanisms. Therefore, restoration of apoptosis in resistant cancers is a valuable and attractive strategy. Discovery of TRAIL-mediated signaling cascade is an intriguing facet of molecular oncology. In this review, we have provided an overview of the translational and foundational advancements in dissecting the genomic and proteomic cartography of TRAIL signaling exclusively in the context of bladder cancer. We have also summarized how different natural products sensitized drug-resistant bladder cancer cells to TRAIL-mediated apoptosis. Interestingly, different death receptors that activate agonistic antibodies have been tested in various phases of clinical trials against different cancers. Certain clues of scientific evidence have provided encouraging results about efficacy of these agonistic antibodies (lexatumumab and mapatumumab) against bladder cancer cell lines. Therefore, multipronged approaches consisting of natural products, chemotherapeutics, and agonistic antibodies will realistically and mechanistically provide proof-of-concept for the translational potential of these combinatorial strategies in well-designed clinical trials.

Health-Related Quality of Life in Patients with Chronic Hepatitis B: A Meta-Analysis of Observational Studies.

Background: Chronic hepatitis B virus (CHB) infection is one of the most common liver infections worldwide. Approximately 240 million patients are diagnosed with CHB. The objective of this meta-analysis was to identify the effect of CHB on the affected patients' health-related quality of life and compare with the control group. Methods: A comprehensive search was conducted through PubMed, Medline, ProQuest, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, and Web of Science databases up to Jul 2022. Results: Five primary observational studies using SF-36 and WHOQOL surveys with 1135 participants (646 with CHB and 489 healthy individuals) included in the meta-analysis. We evaluated the scores of physical and mental component summaries. HRQoL was comparable in both groups. The disease's impact appears to slightly affect the mental component summary than the physical component summary. Conclusion: The HRQoL in CHB patients is mainly reflected in the impairment of the mental aspect. It is vital to focus on optimally managing care, family and social support, stress management.

Features of the Development of a Mobile Application for Cardiac Patients.

Background: An important global public health problem in many economically developed countries, in particular in Kazakhstan, is the leading cause of morbidity and mortality from cardiovascular disease (CVD), both in urban and rural areas. Objective: This study aims to develop the design of a mobile application for smartphones for cardiac patients, taking into account the specifics of outpatient care. Methods: This methodological study includes identified educational and prevention content for CVD patients to develop an education and monitoring tool using a smartphone app. The application was developed according to the stages of analysis, design, development, implementation and evaluation, which is a systematic training model of design. The levels of satisfaction with the developed application for smartphones among 65 outpatients with CVD were assessed using a questionnaire during their visit to a medical organization. Results: The «My Heart¼ smartphone app was developed based on a review of the literature related to educating patients with CVD, consulting specialists, monitoring and searching for medical smartphone applications that are already available. The content of education and registration includes three main sections, containing basic questions on registration and monitoring of the condition, materials on education and prevention of CVD, such as a daily questionnaire and nutritional advice. After modification based on expert feedback, the application was finally developed and evaluated by patients who reported being satisfied with the usefulness of the application. Conclusions: This application is developed as a research tool to further conduct a study in CVD patients. Current evaluation was a pilot testing wherein this application showed promising results.

Cost-effectiveness of Oral Protease Inhibitors Co-administration versus Pegylated Interferon-Α2b and Ribavirin Only for the Patients with Hepatitis C Genotype 1 in Kazakhstan Health Care Settings.

BACKGROUND: The triple therapy including peginterferon, ribavirin and protease inhibitors was more effective compared to the combination of only peginterferon and ribavirin. This study aimed to assess the cost-effectiveness of triple treatment in either treatment-naïve and treatment-experienced patients in Kazakhstan. METHODS: A Markov model was created to assess long-term clinical advantages and the cost-effectiveness of the triple therapy from Kazakhstan payer perspective. Health state transition probabilities, pharmaceutical and other costs (according to the price in 2015), and utility rate were acquired from the published studies and publicly available sources. All used costs and benefits were discounted at 5% per year. RESULTS: Despite treatment background, the patients, receiving boceprevir and telaprevir, were estimated to experience less serious liver-disease complications, more life-years, and more QALYs compared to the patients having standard of care. For treatment-experienced group, boceprevir and telaprevir were dominant, with more QALYs. For all the groups of patients, incremental costs per QALY gained were between USD14995 and USD18075. The total average cost of boceprevir is slightly more costly than a standard duration of treatment with telaprevir, and so is the average cost per SVR. Extensive sensitivity analyses verified robust model results. CONCLUSION: The inclusion of protease inhibitors to standard management for the therapy of patients with genotype 1 chronic HCV infection in Kazakhstan is predicted to be cost-effective using a typically applied willingness to pay threshold of USD37805 (3 times GDP per capita).