Despite using a myriad of methods to combat the spread of COVID-19, the healthcare systems (especially the intensive care units) have been overwhelmed, showing an outpaced capacity of available beds and ventilators. Choosing the right criteria to allocate the scarce ICU seems very challenging, being necessary a rapid, uncomplicated and universally accepted tool for patients’ triage regarding access to lifesaving resources; one such criterion, which generates intense debates, is age. Under certain circumstances, it might seem appropriate to choose to treat a young over an old patient. The main advantage of this approach is the potential for long-term survival, implying an equal right to reach an advanced age. Many authors have given moral reasons to support it, mainly based on utilitarian ethics or on distributive justice. However, there are numerous counterarguments to this approach, which we will summarize in this article. We will show that age should never be used as a unique criterion for withholding/not initiating life-saving procedures, even in pandemics or cases in which healthcare resources are extremely scarce. This approach is based on fundamental Codes of Ethics, such as the WMA Code of Ethics or the Oath of Hippocrates and all physicians treating patients should obey them.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been spreading around the world at an exponential pace, leading to millions of individuals developing the associated disease called COVID-19. Due to the novel nature and the lack of immunity within humans, there has been a collective global effort to find effective treatments against the virus. This has led the scientific community to repurpose Food and Drug Administration (FDA) approved drugs with known safety profiles. Of the many possible drugs, vitamin C has been on the shortlist of possible interventions due to its beneficial role as an immune booster and inherent antioxidant properties. Within this manuscript, a detailed discussion regarding the intracellular function and inherent properties of vitamin C is conducted. It also provides a comprehensive review of published research pertaining to the differences in expression of the vitamin C transporter under several pathophysiologic conditions. Finally, we review recently published research investigating the efficacy of vitamin C administration in treating viral infection and life-threatening conditions. Overall, this manuscript aims to present existing information regarding the extent to which vitamin C can be an effective treatment for COVID-19 and possible explanations as to why it may work in some individuals but not in others.

The COVID-19 pandemic that swept the world at the beginning of 2020 is still raging. It is well established that in addition to respiratory symptoms, COVID-19 can also have neurological manifestations that may result from direct or indirect neurological damage. But are these neurological manifestations coincidental or causal? From a neurological perspective, these symptoms could be the result of neurological damage following SARS-CoV-2 infection, or they could be coincidental, from causes such as secondary systemic complications or side effects of drug treatment. The aim of this review is to raise clinician’s awareness to the development of neurological impairment in SARS-CoV-2 infected patients in the current normative prevention and control.

An ever-increasing ageing population has elevated Alzheimer’s disease to be one of the biggest challenges in modern medicine. Alzheimer’s disease is highly complex, and we are still no closer to understanding the causes, let alone an effective treatment. The lack of good experimental models and lack of critical understanding has led to high failure rates of clinical trials with high associated costs, as well as difficulties in implementing treatments. The multifaceted nature of this disease highlights the need for an interdisciplinary approach to address these concerns. In this essay, we suggest how collaborative work can be useful in addressing some of the above issues. We then propose that international organisations and publishers need to support interdisciplinary research by creating platforms, lobbying funders, and pushing for interdisciplinary publications. We further highlight some of the issues involved in implementing these suggestions and argue that willpower of the research community, together with a re-evaluation of evaluation metrics and incentive systems, are needed in order to foster interdisciplinary research. Overall, we emphasise the need for interdisciplinary research in Alzheimer’s disease and suggest that international societies should play a huge role in this endeavour.

COVID-19 is prevalent in the elderly. Old individuals are more likely to develop pneumonia and respiratory failure due to alveolar damage, suggesting that lung senescence may increase the susceptibility to SARS-CoV-2 infection and replication. Considering that human coronavirus (HCoVs; SARS-CoV-2 and SARS-CoV) require host cellular factors for infection and replication, we analyzed Genotype-Tissue Expression (GTEx) data to test whether lung aging is associated with transcriptional changes in human protein-coding genes that potentially interact with these viruses. We found decreased expression of the gene tribbles homolog 3 (TRIB3) during aging in male individuals, and its protein was predicted to interact with HCoVs nucleocapsid protein and RNA-dependent RNA polymerase. Using publicly available lung single-cell data, we found TRIB3 expressed mainly in alveolar epithelial cells that express SARS-CoV-2 receptor ACE2. Functional enrichment analysis of age-related genes, in common with SARS-CoV-induced perturbations, revealed genes associated with the mitotic cell cycle and surfactant metabolism. Given that TRIB3 was previously reported to decrease virus infection and replication, the decreased expression of TRIB3 in aged lungs may help explain why older male patients are related to more severe cases of the COVID-19. Thus, drugs that stimulate TRIB3 expression should be evaluated as a potential therapy for the disease.

Transcranial focused ultrasound stimulation (tFUS) regulates neural activity in different brain regions in humans and animals. However, the role of ultrasound stimulation in modulating neural activity and promoting neurorehabilitation in the ischemic brain is largely unknown. In the present study, we explored the effect of tFUS on neurological rehabilitation and the underlying mechanism. Adult male ICR mice (n=42) underwent transient middle cerebral artery occlusion. One week after brain ischemia, low frequency (0.5 MHz) tFUS was applied to stimulate the ischemic hemisphere of mice for 7 consecutive days (10 minutes daily). Brain infarct volume, neurobehavioral tests, microglia activation, IL-10 and IL-10R levels were further assessed for up to 14 days. We found that the brain infarct volume was significantly reduced in the tFUS treated mice compared to that in the non-treated mice (p<0.05). Similarly, neurological severity scores, elevated body swing test, and corner test improved in the tFUS treated mice (p<0.05). We also demonstrated that tFUS resulted in increased M2 microglia in the ischemic brain region. The expression of IL-10R and IL-10 levels were also substantially upregulated (p<0.05). We concluded that tFUS served as a unique technique to promote neurorehabilitation after brain ischemia by promoting microglia polarization and further regulating IL-10 signaling in the ischemic brain.

Aging and obesity-related conditions seem to worsen the effect of Coronavirus Disease 2019 (COVID-19). This study assessed the possible roles of metabolic/obesity phenotypes and vitamin D status in increasing the greater severity of COVID-19. We studied 353,299 UK Biobank participants from England with a mean age of 67.7 years. Metabolic/obesity phenotypes were defined as a combination of metabolic components (hypertension, high cholesterol, and diabetes) and obesity. Multivariate logistic regression analysis was performed to test whether the addition of metabolic disorders and vitamin D insufficiency increased obesity associations with COVID-19 hospitalization, confirmed COVID-19, and severe COVID-19. Metabolically unhealthy obesity (MUHO) represented 12.3% of the total analytic samples, and 21.5%, 18.5%, and 19.8% of the included subpopulations with COVID-19 hospitalization, confirmed COVID-19, and severe COVID-19, respectively. Vitamin D insufficiency phenotypes represented 53.5% of the total analytic samples, and 59.5%, 61.7%, and 61.5% of the included subpopulations with COVID-19 hospitalization, confirmed COVID-19, and severe COVID-19, respectively. In multivariate logistic regression, MUHO and vitamin D insufficiency and their combination were significantly associated with COVID-19 illness severity (odds ratio [OR] for COVID-19 hospitalization = 2.33, 95% confidence interval [CI], 2.02-2.70; OR for confirmed COVID-19 = 2.06, 95% CI, 1.58-2.70; OR for severe COVID-19 = 2.06, 95% CI, 1.47-2.87). Elderly men were prone to have a higher risk of COVID-19 than women. Our findings showed that MUHO and vitamin D insufficiency are associated with a significantly increased risk of COVID-19 severity, especially for adults 65 years and older. Susceptible individuals should be aware of their conditions and avoid contact with new coronavirus.

Chemokine (C-C motif) receptor 5 (CCR5) is expressed not only in the immune cells but also in cerebral cells such as neurons, glia, and vascular cells. Stroke triggers high expression of CCR5 in the brain. However, the role of CCR5 in stroke remains unclear. In this study, using bone marrow chimeras we have determined the involvement of brain-derived or bone marrow-derived CCR5 in neuroprotection and brain repair after experimental stroke. CCR5^-/- mice that received either wild-type (WT) or CCR5^-/- bone marrow transplantation showed larger infarction sizes than the WT mice that received either WT or CCR5^-/- bone marrow transplantation in both the acute (48h) and subacute (2 months) phases after cerebral cortical ischemia, suggesting that the lack of CCR5 in the brain leads to severe brain damage after stroke. However, the lack of CCR5 in the bone marrow-derived cells did not affect infarction size. The impairments of somatosensory-motor function and motor coordination were exacerbated in the mice lacking CCR5 in the brain. At 2 months post-stroke, increased degenerative neurons, decreased dendrites and synapses, decreased Iba1⁺ microglia/ macrophages, reduced myelination and CNPase⁺ oligodendrocytes in the peri-infarct cortex were observed in the mice lacking CCR5 in the brain. These pathological changes are significantly correlated with the increased infarction size and exacerbated neurological deficits. These data suggest that brain-derived CCR5 plays a key role in neuroprotection and brain repair in the subacute phase of stroke. This study reveals a novel role of CCR5 in stroke, which sheds new light on post-stroke pathomechanism.

Among cerebral venous thrombosis (CVT) patients, those with venous infarction have more severe clinical presentations and worse outcomes. Identifying biomarkers associated with venous infarction in CVT may help understand the pathogenesis and provide potentially useful therapeutic markers. Fifty-two CVT patients were prospectively recruited and divided into three groups: acute/subacute CVT with venous infarction (ASVI, n=30), without venous infarction (ASOVI, n=13), and chronic CVT (n=9). Blood brain barrier (BBB) permeability-related proteins, including claudin-5, occludin, matrix metalloproteinase-9, glial fibrillary acidic protein, and S100B, and inflammation-related factor high-sensitivity C-reactive protein (hs-CRP), were tested in serum and/or cerebrospinal fluid upon admission. We compared these biomarkers between the three groups and investigated their associations with venous infarction and clinical symptom severity in acute/subacute CVT patients on admission using the NIH Stroke Scale (NIHSS). Serum hs-CRP was significantly higher in acute/subacute CVT patients than chronic CVT patients. For acute/subacute CVT patients, levels were significantly higher in the ASVI group than the ASOVI group for serum claudin-5 (medians 2.80 vs. 2.50 mg/I, respectively, P = 0.039) and hs-CRP (medians 17.25 vs. 2.27 mg/l, respectively, P = 0.003). Both these biomarkers, analyzed as categorical or continuous variables, were also significantly associated with venous infarction in acute/subacute CVT patients after logistic regression analysis. Additionally, hs-CRP was positively correlated with the NIHSS (r = 0.710, P < 0.001) on admission in acute/subacute CVT patients. In CVT patients, venous infarction was associated with BBB disruption and potentially inflammation. Hs-CRP might serve as a biomarker reflecting the clinical severity of CVT in the acute/subacute stages.

Mesenchymal stem cells (MSCs) have beneficial effects on wound healing. MSCs function through direct cell-cell communication or indirectly through paracrine secretion of exosomes. Here, we found that MSC-derived exosomes had pro-wound healing effects via promotion of angiogenesis; however, this promoting effect was significantly reduced when senescence was induced in parental MSCs by hydrogen peroxide (H₂O₂). Further experiments showed that decreased miR-146a expression in exosomes derived from senescent MSCs (s-exo) contributed to these findings. In vitro, the pro-angiogenic effect of s-exo on tube formation in human umbilical vein endothelial cells was significantly reduced compared with that of exosomes derived from control MSCs (c-exo). In vivo, higher tube numbers and longer tube lengths were observed in the c-exo group compared with the s-exo group. Using microarray analysis, we found that miR-146a level in s-exo was lower than that in c-exo. Knockdown of miR-146a in c-exo decreased its capacity to promote angiogenesis, and overexpression of miR-146a in s-exo partially rescued its impaired pro-angiogenic capacity, thereby confirming that downregulation of miR-146a contributed to the reduced pro-wound healing capacity of s-exo. Our study is the first to demonstrate that cell senescence induced by H₂O₂ alters the pro-angiogenic ability of exosomes by modulating the expression of exosomal miRNAs, especially miR-146a, thus providing new insights into the correlation between parental cell state and exosome content and function.

Vascular remodeling is an initial step in the development of hypertension. Limb remote ischemic conditioning (LRIC) is a physiological treatment that induces endogenous protective effect during acute ischemic injury. However, the impact of long-term LRIC on hypertension, a chronic disease, is unknown. In this study, we aimed to investigate the LRIC effect on blood pressure and vascular remodeling in spontaneously hypertensive rat (SHR) model and patients with prehypertension and early-stage hypertension. LRIC of rats was performed once a day for 6-weeks. Blood pressure, vascular remodeling (cross-sectional area, extracellular deposition, and smooth muscle cell area), inflammation (inflammatory factors, and inflammatory cells) were compared among normotensive Wistar-Kyoto rats (WKY), WKY RIC group, SHR control group, and SHR RIC. Long-term LRCI treatment (twice a day for 4-weeks) was performed on patients with prehypertension or early-stage hypertension. Blood pressure and pulse wave velocity (PWV) were analyzed before and after LRIC treatment. LRIC treatment decreased blood pressure in SHR (n = 9-10). LRIC ameliorated vascular remodeling by decreasing cross-sectional area, suppressing deposition of the extracellular matrix, and hypertrophy of smooth muscle cell in conduit artery and small resistance artery (n = 7). LRIC decreased proinflammatory factors while increasing the anti-inflammatory factors in the circulation (n = 5). LRIC decreased circulating monocyte and natural killer T-cell levels (n = 5). Furthermore, LRIC treatment decreased blood pressure and improved vascular stiffness in patients (n = 20). In conclusion, long term LRIC could decrease blood pressure and ameliorate vascular remodeling via inflammation regulation. LRIC could be a preventive treatment for people with blood pressure elevation or prehypertension.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and a major cause of death among elderly individuals. The etiology of AD involves a combination of genetic, environmental, and lifestyle factors. A number of epigenetic alterations in AD have recently been reported; for example, studies have found an increase in histone acetylation in patients with AD and the protective function of histone deacetylase inhibitors. The histone acetylases in the MYST family are involved in a number of key nuclear processes, such as gene-specific transcriptional regulation, DNA replication, and DNA damage response. Therefore, it is not surprising that they contribute to epigenetic regulation as an intermediary between genetic and environmental factors. MYST proteins also exert acetylation activity on non-histone proteins that are closely associated with the pathogenesis of AD. In this review, we summarized the current understanding of the roles of MYST acetyltransferases in physiological functions and pathological processes related to AD. Additionally, using published RNA-seq, ChIP-seq, and ChIP-chip data, we identified enriched pathways to further evaluate the correlation between MYST and AD. The recent research described in this review supports the importance of epigenetic modifications and the MYST family in AD, providing a basis for future functional studies.

Stroke is a leading cause of disability and mortality worldwide, resulting in substantial economic costs for post-stroke care each year. Neuroimaging, such as cranial computed tomography or magnetic resonance imaging, is the backbone of stroke management strategies, which can guide treatment decision-making (thrombolysis or hemostasis) at an early stage. With advances in computational technologies, particularly in machine learning, visual image information can now be converted into numerous quantitative features in an objective, repeatable, and high-throughput manner, in a process known as radiomics. Radiomics is mainly used in the field of oncology, which remains an area of active research. Over the past few years, investigators have attempted to apply radiomics to stroke in the hope of gaining benefits similar to those obtained in cancer management, i.e., in promoting the development of personalized precision medicine. Currently, radiomic analysis has shown promise for a variety of applications in stroke, including the diagnosis of stroke lesions, early prediction of outcomes, and evaluation for long-term prognosis. In this article, we elaborate the contributions of radiomics to stroke, as well as the subprocesses and techniques involved in radiomics studies. We also discuss the potential challenges facing its widespread implementation in routine practice and the directions for future research.

Currently, the world is challenged by the coronavirus disease 2019 (COVID-19) pandemic. Epidemiologists and researchers worldwide are invariably trying to understand and combat this precarious new disease. Scrutinizing available drug options and developing potential new drugs are urgent needs to subdue this pandemic. Several intervention strategies are being considered and handled worldwide with limited success, and many drug candidates are yet in the trial phase. Despite these limitations, the development of COVID-19 treatment strategies has been accelerated to improve the clinical outcome of patients with COVID-19, and some countries have efficiently kept it under control. Recently, the use of natural and traditional medicine has also set the trend in coronavirus treatment. This review aimed to discuss the prevailing COVID-19 treatment strategies available globally by examining their efficacy, potential mechanisms, limitations, and challenges in predicting a future potential treatment candidate and bridging them with the effective traditional Chinese medicine (TCM). The findings might enrich the knowledge on traditional alternative medication and its complementary role with Western medicine in managing the COVID-19 epidemic.

Physical activity, together with its ameliorative effects on Parkinson’s disease (PD) symptoms, remains a relatively unappreciated factor which may be beneficial for the treatment outcome. Contemporary evidence supports the positive effects of non-pharmacological approaches to PD symptom management, in particular the effects of the exercise on both, motor and non-motor symptoms. The aim of the study was to review the mechanisms of exercise-induced amelioration of PD symptoms. Methods: Electronic databases (PubMed, Web of Science and Google Scholar) were searched using the following key words: “Parkinson and physical activity” OR “Parkinson disease and exercise” OR “Parkinson disease and lifestyle factors” OR “Parkinson disease and longevity”. A total of 97 studies which investigated PD genetics and various forms of exercise and their etiologic impact on PD were reviewed. The studies were subdivided into four topic groups: 1) genetics of PD, 2) exercise and the brain, 3) physical activity and PD, 4) mind-body interventions, and discussed accordingly. Adequate levels of physical activity are associated with higher quality of life in PD patients. Physical activity may have protective and stimulatory effects for better functional efficiency in higher-level cognitive networks. It can also improve balance and motor functions by improving muscle strength. Given the etiologic evidence of the beneficial effects of physical activity on PD, albeit tentative, a concerted effort to elucidate the processes and outcomes of physical activity on ameliorating symptoms of PD must be undertaken.

In keeping with its status as one of the major causes of disability and mortality worldwide, brain damage induced by cerebral arterial disease has been the subject of several decades of scientific investigation, which has resulted in a vastly improved understanding of its pathogenesis. Brain injury mediated by venous etiologies, however, such as cerebral, jugular, and vertebral venous outflow disturbance, have been largely ignored by clinicians. Unfortunately, this inattention is not proportional to the severity of cerebral venous diseases, as the impact they exact on the quality of life of affected patients may be no less than that of arterial diseases. This is evident in disease sequelae such as cerebral venous thrombosis (CVT)-mediated visual impairment, epilepsy, and intracranial hypertension; and the long-term unbearable head noise, tinnitus, headache, dizziness, sleeping disorder, and even severe intracranial hypertension induced by non-thrombotic cerebral venous sinus (CVS) stenosis and/or internal jugular venous (IJV) stenosis. In addition, the vertebral venous system (VVS), a large volume, valveless vascular network that stretches from the brain to the pelvis, provides a conduit for diffuse transmission of tumors, infections, or emboli, with potentially devastating clinical consequences. Moreover, the lack of specific features and focal neurologic signs seen with arterial etiologies render cerebral venous disease prone to both to misdiagnoses and missed diagnoses. It is therefore imperative that awareness be raised, and that as comprehensive an understanding as possible of these issues be cultivated. In this review, we attempt to facilitate these goals by systematically summarizing recent advances in the diagnosis and treatment of these entities, including CVT, CVS stenosis, and IJV stenosis, with the aim of providing a valid, practical reference for clinicians.

Parkinson’s disease (PD) ranks second among the most common neurodegenerative diseases, characterized by progressive and selective loss of dopaminergic neurons. Various cross-species preclinical models, including cellular models and animal models, have been established through the decades to study the etiology and mechanism of the disease from cell lines to nonhuman primates. These models are aimed at developing effective therapeutic strategies for the disease. None of the current models can replicate all major pathological and clinical phenotypes of PD. Selection of the model for PD largely relies on our interest of study. In this review, we systemically summarized experimental PD models, including cellular and animal models used in preclinical studies, to understand the pathogenesis of PD. This review is intended to provide current knowledge about the application of these different PD models, with focus on their strengths and limitations with respect to their contributions to the assessment of the molecular pathobiology of PD and identification of the therapeutic strategies for the disease.

Idiopathic inflammatory myopathies (IIMs) are chronic autoimmune disorders involving multiple organs, such as the muscle, skin, lungs and joints. Although the detailed pathogenesis of IIMs remains unclear, immune mechanisms have long been recognised as of key importance. Immune cells contribute to many inflammatory processes via intercellular interactions and secretion of inflammatory factors, and many studies have demonstrated the participation of a variety of immune cells, such as T cells and B cells, in the development of IIMs. Here, we summarise the current knowledge regarding immune cells in IIM patients and discuss their potential roles in IIM pathogenesis.

Ferroptosis is a form of programmed cell death caused by production of reactive oxygen species and disequilibrium of iron homeostasis. Many chemical compounds and clinical drugs induce ferroptosis in normal and cancer cells, while peroxidation inhibitors, iron chelators, and antioxidants can block ferroptosis. Glutathione peroxidase 4, ferroptosis suppressor protein 1, nuclear factor erythroid 2-related factor 2, and system Xc^- are the negative regulators of ferroptosis, whereas nicotinamide adenine dinucleotide phosphate oxidase, p53, mitochondria voltage-dependent anion channel, and cysteinyl-tRNA synthetase function as positive regulators. Ferroptosis plays important roles in pathogen infection and tumor immunology. Recent studies suggest that ferroptosis plays a vital role in the pathogenesis of cardiovascular diseases (CVDs), which seriously threaten human health. Potential therapies designed around ferroptosis may alter the pathological progression of CVDs. Therefore, we redacted an overview of the discovery of ferroptosis, its regulatory mechanisms, and its potential impact on CVDs treatment.

Sepsis is a form of life-threatening organ dysfunction caused by dysregulated host responses to an infection that can be partly attributed to immune dysfunction. Although sepsis affects patients of all ages, elderly individuals display increased susceptibility and mortality. This is partly due to immunosenescence, a decline in normal immune system function associated with physiological aging that affects almost all cell types in the innate and adaptive immune systems. In elderly patients with sepsis, these alterations in immune cells such as endothelial cells, neutrophils, monocytes, macrophages, natural killer cells, dendritic cells, T lymphocytes, and B lymphocytes, are largely responsible for their poor prognosis and increased mortality. Here, we review recent studies investigating the events affecting both innate and adaptive immune cells in elderly mice and patients with sepsis, including alterations in their number, phenotype, and function, to shed light on possible new therapeutic strategies.

Cartilage is a relatively simple connective tissue that plays a variety of roles in the human body, including joint support and protection, load bearing of the intervertebral discs, joint lubrication, formation of the external structure of the ears and nose and support of the trachea. The maintenance of cartilage homeostasis is therefore crucial. Cartilage-related diseases are difficult to diagnose and treat because their molecular and pathological mechanisms are not fully understood. Melatonin, which has a wide range of physiological effects, is an endocrine hormone mainly secreted by the pineal gland. Its biological effects include its antioxidant, antiaging, analgesic, and hypnotic effects and its ability to stabilize the circadian rhythm. In recent years, research on cartilage homeostasis and melatonin has been increasing, and melatonin has gradually been used in the treatment of cartilage-related diseases. Therefore, this article will briefly review the role of melatonin in cartilage homeostasis, including its anti-inflammatory effects and effects in protecting cartilage from damage by other factors and promoting chondrocyte growth and the expression of cartilage-related genes. Based on the above, the current status and future developmental direction of melatonin in the treatment of cartilage-related diseases are also discussed, demonstrating the broad prospects of melatonin in maintaining cartilage homeostasis and treating cartilage injury-related diseases.

Vascular dementia (VaD) is a neurodegenerative disease, with cognitive dysfunction attributable to cerebrovascular factors. At present, it is the second most frequently occurring type of dementia in older adults (after Alzheimer’s disease). The underlying etiology of VaD has not been completely elucidated, which limits its management. Currently, there are no approved standard treatments for VaD. The drugs used in VaD are only suitable for symptomatic treatment and cannot prevent or reduce the occurrence and progression of VaD. This review summarizes the current status of pharmacological treatment for VaD, from the perspective of the molecular mechanisms specified in various pathogenic hypotheses, including oxidative stress, the central cholinergic system, neuroinflammation, neuronal apoptosis, and synaptic plasticity. As VaD is a chronic cerebrovascular disease with multifactorial etiology, combined therapy, targeting multiple pathophysiological factors, may be the future trend in VaD.