In this narrative review, we present a comprehensive assessment on the putative roles of long non-coding RNAs (lncRNAs) in intermittent hypoxia (IH) and sleep apnea. Collectively, the evidence from cell culture, animal, and clinical research studies points to the functional involvement of lncRNAs in the pathogenesis, diagnosis, and potential treatment strategies for this highly prevalent disorder. Further research is clearly warranted to uncover the mechanistic pathways and to exploit the therapeutic potential of lncRNAs, thereby improving the management and outcomes of patients suffering from sleep apnea.

Low tissue oxygenation, termed hypoxia, is a characteristic of solid tumors with negative consequences. Tumor-associated macrophages (TAMs) accumulate in hypoxic tumor regions and correlate with worse outcomes in cancer patients across several tumor types. Thus, the molecular mechanism in which macrophages respond to low oxygen tension has been increasingly investigated in the last decade. Hypoxia stabilizes a group of hypoxia-inducible transcription factors (HIFs) reported to drive transcriptional programs involved in cell survival, metabolism, and angiogenesis. Though both tumor macrophage HIF-1α and HIF-2α correlate with unfavorable tumor microenvironments, most research focuses on HIF-1α as the master regulator of hypoxia signaling, because HIF-1α expression was originally identified in several cancer types and correlates with worse outcome in cancer patients. The relative contribution of each HIFα subunit to cell phenotypes is poorly understood especially in TAMs. Once thought to have overlapping roles, recent investigation of macrophage HIF-2α has demonstrated a diverse function from HIF-1α. Little work has been published on the differential role of hypoxia-dependent macrophage HIF-2α when compared to HIF-1α in the context of tumor biology. This review highlights cellular HIF-2α functions and emphasizes the gap in research investigating oxygen-dependent functions of tumor macrophage HIF-2α.

Since the introduction of Haemophilus influenzae (Hi) serotype b (Hib) vaccination, reports of increasing incidence rates of non-Hib serotypes have emerged. A systematic review was performed to investigate whether the Hi serotype f (Hif) incidence rate has increased globally and to describe its associated disease burden. In the post-Hib vaccine era, evidence shows that the incidence rate of Hif infection is increasing worldwide. In total 94 studies including 2 701 patients reported Hif infections. The estimated pooled incidence rate of Hif infection was 0.15/100 000 population per year (range: 0.05-0.40/100 000), with a median case fatality ratio of 14.3 %. Invasive infections most frequently presented as pneumonia (45 %), septicaemia (34 %) and meningitis (20 %). Of 191 Hif isolates, 87 % were ampicillin-susceptible. Multi-locus sequence typing revealed that Hif were relatively clonal, with the majority belonging to clonal complex 124. Hif causes invasive infections of significant variance in both severity and presentation. Globally, the Hif population shows little genetic variability and currently appears to possess low resistance to antimicrobials.

Von Hippel-Lindau disease is an autosomal dominant disorder characterised by renal cell carcinomas, pancreatic neuroendocrine tumours, central nervous system hemangioblastomas, retinoblastomas, and tumours of the reproductive tract. This disease results from loss of function mutations in the tumour suppressor gene known as the Von Hippel-Lindau gene, located on chromosome 3. Loss of function mutation in the Von Hippel-Lindau gene results in the accumulation of a protein known as a hypoxia-inducible factor, which promotes cellular proliferation and angiogenesis, leading to cancer. Belzutifan inhibits the hypoxia-inducible factor by binding to the Per-ARNT -Sim-B binding pocket on the hypoxia-inducible factor -2α, inhibiting cellular proliferation and angiogenesis. In our thorough literature review, we identified 37 relevant articles. Belzutifan showed clinically meaningful response rates for both Von Hippel-Lindau disease-associated renal cell carcinomas and non-renal cell cancers. The pharmacokinetic profile of belzutifan was much better than its congener molecules due to the optimisation of its dihalide groups from germinal to vicinal. The pharmacodynamic effect of belzutifan was confirmed by its ability to decrease serum erythropoietin, which is a direct result of hypoxia-inducible factor- 2α inhibition. The significant side effects observed were anaemia, hypoxia, fatigue, hypertension, visual impairment and weight gain. Multiple clinical trials are currently underway to determine the role of beluztifan as part of combination regimens in treating Von Hippel-Lindau diseaseassociated malignancies.

In 2019, the scientists who discovered how cells sense and adapt to oxygen availability were awarded the Nobel Prize. This elegant sensing pathway is conserved throughout evolution, and it underpins the physiology and pathology that we, as clinicians in anaesthesia and critical care, encounter on a daily basis. The purpose of this review is to bring hypoxia-inducible factor, and the oxygen-sensing pathway as a whole, to the wider clinical community. We describe how this unifying mechanism was discovered, and how it orchestrates diverse changes such as erythropoiesis, ventilatory acclimatisation, pulmonary vascular remodelling and altered metabolism. We explore the lessons learnt from genetic disorders of oxygen sensing, and the wider implications in evolution of all animal species, including our own. Finally, we explain how this pathway is relevant to our clinical practice, and how it is being manipulated in new treatments for conditions such as cancer, anaemia and pulmonary hypertension.

Fibroblast growth factor 23 (FGF23) plays an important role in the development of chronic kidney disease-mineral bone disorder (CKD-MBD). Abnormally elevated levels of 1,25-dihydroxyvitamin D cause osteocytes to secrete FGF23, which subsequently induces phosphaturia. Recent studies have reported that iron deficiency, erythropoietin (EPO) and hypoxia regulate the pathways responsible for FGF23 production. However, the molecular mechanisms underlying the interactions between FGF23 and anemia-related factors are not yet fully understood. The present review discusses the associations between FGF23, iron, EPO and hypoxia-inducible factors (HIFs), and their impact on FGF23 bioactivity, focusing on recent studies. Collectively, these findings propose interactions between FGF23 gene expression and anemia-related factors, including iron deficiency, EPO and HIFs. Taken together, these results suggest that FGF23 bioactivity is closely associated with the occurrence of CKD-related anemia and CKD-MBD.

We reviewed the research into the mechanisms of growth of triple negative breast cancer (TNBC) based on laboratory pre-clinical studies that have shaped understanding of the disease over the past decade. In response to these findings, we propose an approach to potentially prevent cancer metabolic adaptation and recurrence. This paper collates pre-clinical results, first to determine the tumor\'s mechanisms of growth and then to source natural substances that could potentially suppress those mechanisms. The results from in vivo and in vitro studies of TNBC were combined first to select 10 primary mechanisms (Hypoxia-inducible factor 1α, Hedgehog, MAPK, MTAP, NF-κ B, Notch, P13K, STAT3, and Wnt signaling pathways plus p53 and POL2A gene expression) that promote TNBC growth, and second to propose a treatment array of 21 natural compounds that suppress laboratory models of TNBC via these mechanisms. We included BRCA mutations in the review process, but only pathways with the most preclinical studies utilizing natural products were included. Then we outlined potential biomarkers to assess the changes in the micro-environment and monitor biochemical pathway suppression. This suppression-centric aim targets these mechanisms of growth with the goal of potentially halting tumor growth and preventing cancer cell metabolic adaptation. We chose TNBC to demonstrate this 5-step strategy of supplementary therapy, which may be replicated for other tumor types.

To maintain normal cellular and physiological function, sufficient oxygen is required. Recently, evidence has suggested that hypoxia, either pathological or environmental, may influence bone health. It appears that bone cells are distinctly responsive to hypoxic stimuli; for better or worse, this is still yet to be elucidated. Hypoxia has been shown to offer potentially therapeutic effects for bone by inducing an osteogenic-angiogenic response, although, others have noted excessive osteoclastic bone resorption instead. Much evidence suggests that the hypoxic-inducible pathway is integral in mediating the changes in bone metabolism. Furthermore, many factors associated with hypoxia including changes in energy metabolism, acid-base balance and the increased generation of reactive oxygen species, are known to influence bone metabolism. This review aims to examine some of the putative mechanisms responsible for hypoxic-induced alterations of bone metabolism, with regard to osteoclasts and osteoblasts, both positive and negative.

Human carbonic anhydrases (CA, EC 4.2.1.1) IX and XII are tumor-associated proteins, being part of the molecular machinery that tumor cells build as adaptive responses to hypoxia and acidic conditions characteristic of the \'glycolytic shift\' of many tumors. A wealth of research depicts CA IX and CA XII as biomarkers and therapeutic targets for various cancer types.
The review presents an overview of the role of CA IX and CA XII in hypoxic tumors physio-pathology as well as the principal molecular, structural, and catalytic features of both isozymes. The review then covers the patent literature of medically relevant inhibitors of the tumor-associated CAs produced during the period 2008-2018.
A variety of approaches and design strategies were reported which afford CA IX/XII-specific inhibitors and avoid the compromising effects of isoforms-promiscuous compounds. Access to the crystal structures of human CAs isoforms have improved structure-based drug design campaigns related to zinc-binder chemotypes. Nevertheless, great potential still resides in non-classical CAIs that exhibit alternative binding mechanisms able to further distinguish the various active sites architecture. CA IX inhibitors hybrids/conjugates are increasingly emerging in the field as promising therapeutic tools to combine CA inhibition to the anticancer effects of other moieties or antitumor drugs.

Over the past decade, our understanding of the biology and pathophysiology of renal cell carcinoma (RCC) has improved significantly. Insight into the disease process has helped us in developing newer therapeutic approaches toward RCC. In this article, we review the various genetic and immune-related mechanisms involved in the pathogenesis and development of this cancer and how that knowledge is being used to develop therapeutic targeted drugs for the treatment of RCC. The main emphasis of this review article is on the most common genetic alterations found in clear cell RCC and how various drugs are currently targeting such pathways. This article also looks at the role of the immune system in allowing the growth of RCC and how the immune system can be manipulated to reactivate cytotoxic immunity against RCC.