Interplay between JAK/STAT pathway and non-coding RNAs in different cancers.

Progress in the identification of core multi-protein modules within JAK/STAT pathway has enabled researchers to develop a better understanding of the linchpin role of deregulated signaling cascade in carcinogenesis and metastasis. More excitingly, complex interplay between JAK/STAT pathway and non-coding RNAs has been shown to reprogramme the outcome of signaling cascade and modulate immunological responses within tumor microenvironment. Wealth of information has comprehensively illustrated that most of this complexity regulates the re-shaping of the immunological responses. Increasingly sophisticated mechanistic insights have illuminated fundamental role of STAT-signaling in polarization of macrophages to M2 phenotype that promotes disease aggressiveness. Overall, JAK/STAT signaling drives different stages of cancer ranging from cancer metastasis to the reshaping of the tumor microenvironment. JAK/STAT signaling has also been found to play role in the regulation of infiltration and activity of natural killer cells and CD4/CD8 cells by PD-L1/PD-1 signaling. In this review, we have attempted to set spotlight on regulation of JAK/STAT pathway by microRNAs, long non-coding RNAs and circular RNAs in primary tumors and metastasizing tumors. Therefore, existing knowledge gaps need to be addressed to propel this fledgling field of research to the forefront and bring lncRNAs and circRNAs to the frontline of clinical practice. Leveraging the growing momentum will enable interdisciplinary researchers to gain transition from segmented view to a fairly detailed conceptual continuum.

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.

Nanotechnology-based cancer chemoprevention in glioblastoma.

Brain tumours are heterogeneous and are classified comprehensively into molecular subtypes based on genetic alterations. Glioblastoma rapid progression, drug resistance, and recurrence have been scientifically linked to several factors, including its rapid growth rate, loss of apoptosis, pro-survival signalling, molecular heterogeneities and hallmark features to infiltrate vital brain structures. Because of the growing demand for design and development of delivery systems to overcome the existing limitations with the current therapeutic strategies, researchers are exploiting multifaceted aspects of nanotechnology to improve delivery of the drug payload. Firstly, nanotechnology procedures can improve the drug delivery methods with the help of nanoparticles (NPs) based nanovectors that can efficiently cross blood-brain barrier. Secondly, NPs also improve the cellular uptake of the drug as they can efficiently bind with the cell surface. Thirdly, NPs make the delivery of siRNAs and peptides possible, which can suppress the resistance of glioblastoma against TMZ or other chemo-preventive drugs. Fourthly, the use of metal NPs increases the efficiency of scanning or magnetic resonance imaging (MRI) procedures as they can produce contrasts in it. Lastly, NPs make it possible to use highly targeted co-administered strategies like chemoprevention and near infrared (NIR) or radiotherapy (RT). Hence, nanotechnology offers several promising solutions against glioblastoma by countering it on many fronts.

Role of Ubiquitination and Epigenetics in the Regulation of AhR Signaling in Carcinogenesis and Metastasis: "Albatross around the Neck" or "Blessing in Disguise".

The molecular mechanisms and signal transduction cascades evoked by the activation of aryl hydrocarbon receptor (AhR) are becoming increasingly understandable. AhR is a ligand-activated transcriptional factor that integrates environmental, dietary and metabolic cues for the pleiotropic regulation of a wide variety of mechanisms. AhR mediates transcriptional programming in a ligand-specific, context-specific and cell-type-specific manner. Pioneering cutting-edge research works have provided fascinating new insights into the mechanistic role of AhR-driven downstream signaling in a wide variety of cancers. AhR ligands derived from food, environmental contaminants and intestinal microbiota strategically activated AhR signaling and regulated multiple stages of cancer. Although AhR has classically been viewed and characterized as a ligand-regulated transcriptional factor, its role as a ubiquitin ligase is fascinating. Accordingly, recent evidence has paradigmatically shifted our understanding and urged researchers to drill down deep into these novel and clinically valuable facets of AhR biology. Our rapidly increasing realization related to AhR-mediated regulation of the ubiquitination and proteasomal degradation of different proteins has started to scratch the surface of intriguing mechanisms. Furthermore, AhR and epigenome dynamics have shown previously unprecedented complexity during multiple stages of cancer progression. AhR not only transcriptionally regulated epigenetic-associated molecules, but also worked with epigenetic-modifying enzymes during cancer progression. In this review, we have summarized the findings obtained not only from cell-culture studies, but also from animal models. Different clinical trials are currently being conducted using AhR inhibitors and PD-1 inhibitors (Pembrolizumab and nivolumab), which confirm the linchpin role of AhR-related mechanistic details in cancer progression. Therefore, further studies are required to develop a better comprehension of the many-sided and "diametrically opposed" roles of AhR in the regulation of carcinogenesis and metastatic spread of cancer cells to the secondary organs.

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.

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.

Regulation of Ferroptosis by Non-Coding RNAs: Mechanistic Insights.

The discovery of ferroptosis has paradigmatically shifted our about different types of cell death. The wealth of information gathered over decades of pioneering research has empowered researchers to develop a better comprehension of the versatile regulators of ferroptosis. In this comprehensive review, we have attempted to put a spotlight on the indispensable involvement of non-coding RNAs in the regulation of ferroptosis. We have analyzed the functional role of microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs in the regulation of ferroptosis and how inhibition of ferroptosis promotes carcinogenesis and metastasis. SIGNIFICANCE STATEMENT: The manuscript provides a systematic mechanistic and conceptual comprehension of the recently emerging dynamics of non-coding RNAs and ferroptosis. We also analyze how this interplay shapes the complex process of carcinogenesis and metastasis.

Suppressive effects of bioactive herbal polysaccharides against different cancers: From mechanisms to translational advancements.

BACKGROUND: Fueled by rapidly evolving comprehension of multifaceted nature of cancers, recently emerging preclinical and clinical data have supported researchers in the resolution of knowledge gaps to deepen the understanding of the molecular mechanisms. The extra-ordinary and bewildering chemical diversity encompassed by biologically active natural products continues to be of relevance to drug discovery. Accumulating evidence has spurred a remarkable evolution of concepts related to pharmacological target of oncogenic signaling pathways by polysaccharides in different cancers. PURPOSE: The objective of the current review is to provide new insights into study progress on anticancer effects of bioactive herbal polysaccharides. METHODS: PubMed, Scopus, Web of Science, Embase, and other databases were searched for articles related to anticancer effects of polysaccharides. Searches were conducted to locate relevant publications published up to October 2022. RESULTS: Polysaccharides have been reported to pleiotropically modulate TGF/SMAD, BMP/SMAD, TLR4, mTOR, CXCR4 and VEGF/VEGFR cascades. We have also summarized how different polysaccharides regulated apoptosis and non-coding RNAs. Additionally, this mini-review describes increasingly sophisticated understanding related to polysaccharides mediated tumor suppressive and anti-metastatic effects in tumor-bearing mice. We have also provided an overview of the clinical trials related to chemopreventive role of polysaccharides. CONCLUSION: Genomic and proteomic findings from these studies will facilitate 'next-generation' clinical initiatives in the prevention/inhibition of cancer.

Regulation of Cell Signaling Pathways and Non-Coding RNAs by Baicalein in Different Cancers.

Landmark discoveries in molecular oncology have provided a wide-angle overview of the heterogenous and therapeutically challenging nature of cancer. The power of modern 'omics' technologies has enabled researchers to deeply and comprehensively characterize molecular mechanisms underlying cellular functions. Interestingly, high-throughput technologies have opened new horizons for the design and scientific fool-proof evaluation of the pharmacological properties of targeted chemical compounds to tactfully control the activities of the oncogenic protein networks. Groundbreaking discoveries have galvanized the expansion of the repertoire of available pharmacopoeia to therapeutically target a myriad of deregulated oncogenic pathways. Natural product research has undergone substantial broadening, and many of the drugs which constitute the backbone of modern pharmaceuticals have been derived from the natural cornucopia. Baicalein has gradually gained attention because of its unique ability to target different oncogenic signal transduction cascades in various cancers. We have partitioned this review into different sub-sections to provide a broader snapshot of the oncogenic pathways regulated by baicalein. In this review, we summarize baicalein-mediated targeting of WNT/ß-catenin, AKT/mTOR, JAK/STAT, MAPK, and NOTCH pathways. We also critically analyze how baicalein regulates non-coding RNAs (microRNAs and long non-coding RNAs) in different cancers. Finally, we conceptually interpret baicalein-mediated inhibition of primary and secondary growths in xenografted mice.

Regulation of RASSF by non-coding RNAs in different cancers: RASSFs as masterminds of their own destiny as tumor suppressors and oncogenes.

Ras-association domain family (RASSF) proteins are tumor suppressors and have gained phenomenal limelight because of their mechanistic role in the prevention/inhibition of carcinogenesis and metastasis. Decades of research have demystified wide ranging activities of RASSF molecules in multiple stages of cancers. Although major fraction of RASSF molecules has tumor suppressive roles, yet there is parallel existence of proof-of-concept about moonlighting activities of RASSF proteins as oncogenes. RASSF proteins tactfully rewire signaling cascades for prevention of cancer and metastasis but circumstantial evidence also illuminates oncogenic role of different RASSF proteins in different cancers. In this review we have attempted to provide readers an overview of the complex interplay between non-coding RNAs and RASSF proteins and how these versatile regulators shape the landscape of carcinogenesis and metastasis.

Occupational burn-out, fatigue and stress in professional rescuers: a cross-sectional study in Kazakhstan.

OBJECTIVES: To find predictors of burn-out in a cohort of rescuers. DESIGN: Cross-sectional study. SETTING: Republican Rescue Squad (N=105) and Republican Mudslide Rescue Service under the Ministry of Emergency Situations (N=480) in Almaty, Kazakhstan. PARTICIPANTS: In total, we included 268 (80% men, median age 38 (IQR 22) years) rescuers from both organisations. PRIMARY AND SECONDARY OUTCOME MEASURES: We offered a questionnaire to rescuers, which included Maslach Burnout Inventory, quantifying emotional exhaustion (EX), cynicism (CY) and professional efficacy (PE) along with fatigue, stress and health-related quality of life (HRQL) tools. RESULTS: Lower scores of HRQL (Physical Component Score (PCS) beta -0.04 (95% CI -0.06 to -0.02); Mental Component Score beta -0.03 (95% CI -0.05 to -0.01)), higher fatigue (Fatigue Severity Scale (FSS) score beta 0.03 (95% CI 0.03 to 0.04)) and stress (Perceived Stress Score-10 beta 0.04 (95% CI 0.02 to 0.06)) independently predicted greater EX. Lower PCS (beta -0.03 (95% CI -0.06 to -0.01)) and FSS (beta 0.02 (95% CI 0.01 to 0.03)) could predict more CY burn-out. In addition to stress, higher education (beta 0.86 (95% CI 0.40 to 1.32)) was positively associated with lower burn-out severity in PE domain. CONCLUSIONS: Fatigue, stress and HRQL were associated with burn-out in rescuers. Addressing these predictors may help guide further interventions to reduce occupational burn-out.

Knowledge and experience of Kazakhstan athletes in anti-doping and the impact of past educational intervention.

BACKGROUND: Although Kazakhstan National Anti-Doping Organization (KazNADO) exists since 2013, but little is yet known about anti-doping (AD) knowledge of Kazakhstan athletes. The aim of this study was to assess the AD education knowledge level and experience among Kazakhstan athletes, as well as the impact of any past AD educational program on them. METHODS: Altogether, 590 athletes (the median was age 17 years (interquartile range 8)), representing various sports, participated in the web-based study and completed the questionnaire, which consisted of socio-demographic part and ALPHA test. We assessed the association of any past AD education and experience with anti-doping knowledge using adjusted regression models. RESULTS: A total of 54.6% participants underwent doping control and 82,7% of athletes received AD education at least once. More than 300 participants (50.8%) provided correct answers for 10 questions. Age and years in sports (competition duration) were significantly associated with the ALPHA scores of athletes. Athletes who received AD education more than once in the past had significantly higher ALPHA scores than non-AD educated athletes in most questions. CONCLUSION: AD education was associated with AD knowledge. Further research is needed to identify the adherence to anti-doping knowledge.

Quality of life in children with cochlear implants in Kazakhstan.

BACKGROUND: Although cochlear implantation (CI) has been performed in Kazakhstan since 2007 little is known about quality of life of patients after CI. The aim of this study was to assess the health-related quality of life (HRQoL) of Kazakhstani children after CI. METHODS: Altogether, 53 families with a child using a cochlear implant for at least 1 year participated in the study between July 20, 2019 and February 20, 2020 at the Audiological Сenter of Almaty, Kazakhstan. The parents/caregivers completed the "Children with Cochlear Implants: Parental Perspectives (CCIPP)" questionnaire. RESULTS: 'Well-being and happiness' subdomain of the HRQoL yielded the highest ratings. 'Communication', 'general functioning', 'self-reliance', and 'supporting the child' subdomains each achieved significant (p < 0.01) associations with all HRQoL subdomains. There were positive correlations between language used by the parent who completed the questionnaire (Kazakh or Russian) and three HRQoL subdomains, including 'well-being and happiness', 'supporting the child' and 'social relations'. CONCLUSION: Parents/caregivers reported high quality of life in all HRQoL subdomains. Further research in this area with more detailed socio-demographic and medical history data is required to identify quality of life predictors in children after cochlear implantation.

Cerebral ischemia reperfusion injury: from public health perspectives to mechanisms.

Cerebral ischemia/reperfusion injury has emerged as an intricate mechanism. However, identification of wide-ranging mechanisms which mechanistically regulate reperfusion injuries have significantly improved our understanding. Recent advancements in our knowledge about the molecular consequences of ischemia and reperfusion might be advantageous in the development of innovative therapeutic strategies for the treatment of patients with ischemia and reperfusionassociated organ dysfunction and tissue inflammation. Some of the extensively studied mechanisms of reperfusion injury consist of oxidative stress, mitochondrial mechanisms, infiltration of leukocytes, activation/aggregation of the platelets, complement activation, and disruption of the blood-brain-barrier (BBB), which eventually results in the brain oedema or haemorrhagic transformations. In this review, we have attempted to provide a review of the protein networks involved in the regulation of cerebral ischemia reperfusion injury and how different natural products have shown potential in the amelioration of reperfusion induced injuries.

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.

Testosterone and occupational burnout in professional male firefighters.

BACKGROUND: Very little is known about the biologic predictors of the occupational burnout in firefighters. The aim of this study was to characterize testosterone profile of active firefighters and quantify its association with three domains of the occupational burnout. METHODS: We enrolled 100 firefighters (median age 28 (interquartile range (IQR) 9.8) years with 5 (IQR 9) years in service) of three fire departments in Almaty, Kazakhstan. Demographics, smoking status, health-related quality of life (HRQL) and burnout scores of Maslach Burnout Inventory were assessed using a questionnaire, while total blood testosterone was measured in venous blood. Logistic regression models were used to quantify the association of blood testosterone with each burnout domain in the adjusted for confounders models. RESULTS: The median blood testosterone level was 14 (IQR 3.5) nmol/l and was only predicted by age (beta - 0.14, p < 0.01, 79% power). There were no differences in blood testosterone levels between occupational groups (Group 1 (firefighters), 14.6 (IQR 3.4); Group 2 (fire truck drivers), 14.7 (IQR 5.6); Group 3 (shift commanders, division heads, department managers and engineers), 14 (IQR 4.1) nmol/l, Kruskal-Wallis p = 0.32) or departments. Testosterone could not predict EX or CY, but had a negative association with PE score reflecting more burnout (odds ratio 1.18 (95% confidence interval 1.01;1.38)), adjusted for age, mental component of HRQL and education. CONCLUSIONS: Firefighters with higher testosterone may develop burnout in PE earlier, and this should be considered for proper work placement within the rescue system.

Underlying causes of cerebral palsy: public health perspectives.

Cerebral palsy (CP) is a neurological pathology that is characterized by a combination of signs and symptoms that occur in neurodegenerative or metabolic disorder during the first few years of life. It is a complex pathology orchestrated by a plethora of different causes. The current diagnostic regimen for CP involves brain magnetic resonance imaging (MRI), and antenatal and perinatal insult. Despite advances in the field of genetics and molecular biology, the evaluating the underlying causes of this severe pathology are still bleak. In this review we have attempted to provide a landscape of the underlying mechanisms of cerebral palsy. We have partitioned this review broadly into genetic and proteomic-based studies, which have enriched our understanding about the pathogenesis of CP.

Bacterial resistance in the intensive care unit of developing countries: Report from a tertiary hospital in Kazakhstan.

OBJECTIVES: The aim of this study was to describe the patterns of antimicrobial resistance (AMR) of bacterial isolates causing hospital-acquired infections (HAIs) in the intensive care unit (ICU) of a tertiary hospital in Kazakhstan. METHODS: This was a retrospective analysis of AMR in the ICU of the National Research Center for Oncology and Transplantation (Astana, Kazakhstan) during the year 2015. RESULTS: During the study period, 546 patients were admitted to the ICU, of whom 135 (24.7%) developed at least one HAI. Most HAIs caused by Gram-positive bacteria were due to Enterococcus faecalis, which were resistant to aminoglycosides in >70% cases. Gram-negative bacteria were isolated in ca. 50% of cases, thus representing the greatest burden of HAIs. Very high resistance rates to ceftriaxone, cefotaxime and cefuroxime were observed. Moreover, Pseudomonas aeruginosa and Acinetobacter baumannii were resistant to carbapenems in <20% and in ca. 45% of cases, respectively. CONCLUSION: This study demonstrates the urgent need to implement more rational use of antimicrobials in Kazakhstan, which can be done only by establishing a proactive surveillance system along with an appropriate infection control programme.