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Increased Aβ clearance from brain is essential for restoring the pathological manifestation of Alzheimer's disease (AD) and attenuating the cognitive disorder. The blood-brain barrier (BBB) plays a critical role in maintaining homeostasis of the brain, and transporters e.g. P-glycoprotein (P-gp) are essential for Aβ clearance from the brain. In addition, the Wnt/β-catenin signaling pathway contributes to BBB formation, induction and maturation, and induces BBB function. Dysfunctional Wnt/β-catenin signaling in the BBB reveals the importance of this pathway, since this contributes to the neurodegeneration characteristic of AD. Based on the above evidence, we propose that targeting the canonical Wnt signaling pathway could be promising therapeutic approach for treatment of AD. [ABSTRACT FROM AUTHOR]

Highlights: [•] Icaritin was a novel antidepressant. [•] It restored social defeat-induced impairment of glucocorticoid sensitivity. [•] These effects are attributed to normalization of the GR function. [ABSTRACT FROM AUTHOR]

Both reactive oxygen species (ROS) from redox-biology and pro-inflammatory cytokines from innate immunity/and other sources, in addition to their role in redox-biology, and in defense and repair, have long been regarded as potentially harmful factors associated with oxidative stress and inflammatory states. However, their important physiological functions as signaling molecules have been demonstrated to be of importance, also in Geroscience, particularly when ROS are at balanced basal levels (redox-biology) and pro-inflammatory cytokines are at very low levels (cold-inflammaging). Under these conditions, both of these components (alone or in combination) may act as signaling/response molecules involved in regulating/maintaining or restoring adaptive homeostasis during aging, particularly in the early phases of even very-mild non-damaging internal or external environmental stimuli that could nevertheless elicit low-grade warnings-signals for homeostatic stability. If signals potentially perturbing homeostasis persist, the levels of ROS and pro-inflammatory mediators increase resulting in a switch from adaptive to maladaptive responses which may lead to oxidative stress and overt-inflammaging (or even to an overt inflammatory state), thus paving the way to the risks of aging-related diseases (ARDs). Conversely, upon adaptive-responses, low-levels of ROS and very-low-levels of pro-inflammatory-cytokines, alone or in combination, can result in an amplified capacity to prevent or slow-down overt-inflammaging (2-fold to 4-fold increase of pro-inflammatory cytokines) thus maintaining or restoring homeostasis. Therefore, these signaling molecules may also have the sequential incremental potential to prevent or slow the subsequent decline of adaptive homeostasis that will occur later in the lifespan. These scenarios may lead us to conceive of, and conceptualize, both these molecules and their basal-low levels, as well as their dynamics and the time-course of responses, as 'potential important pillars of adaptive-homeostasis in aging' since the earliest phases of the occurrence of any even very- mild environmental potential imbalance. • ROS and pro-inflammatory cytokines as molecules that cause damage (e.g., oxidative stress and inflammaging), but to appreciate their role in regulating signaling pathways that affect normal physiological and biological responses. • The effects of these two pathways: (a) basal-low levels ROS and (b) very low levels of pro-inflammatory mediators, can, working alone or in concert, prevent and/or intervene on even minor homeostatic imbalances since the very early phases, thus initiating signal transductions for the regulation maintenance or restoration of adaptive homeostasis in aging. • "Basic Pillars of adaptive-homeostasis in ageing", whose combination can also prevent or slow-down the transition from cold-inflammaging tot overt-inflammaging. [ABSTRACT FROM AUTHOR]

Studies have shown that misfolded proteins and endoplasmic reticulum (ER) stress play pivotal roles in the progression of Alzheimer's disease (AD). It has also been reported that ER stress is considered to be a common mediator of apoptosis in neurodegenerative disorders like AD. However, the precise mechanisms leading to neuronal cell death caused by ER stress in AD remain unclear. Hsp70, the major inducible form of the heat shock protein family, functions at the level of chaperone-mediated protein folding. Enhanced expression of Hsp70 suppresses the neurotoxicity caused by protein misfolding. EGb761, an accepted traditional Chinese medicine used to treat AD, was used here to examine the molecular mechanism underlying its protective effect on ER stress and Hsp70. Our study shows that pretreatment with EGb761 overcomes the neurotoxicity of the Aβ 1-42 oligomer by increasing Hsp70, Grp78, IRE1α and pAkt expression in a dose-dependent manner and significantly decreases cell apoptosis-related protein expression. Our findings suggest that the neuroprotective effect of EGb761 is related to ER stress activation and increased Hsp70 expression, and subsequent activation of Akt. However, the effect of EGb761 on these processes is not direct. [ABSTRACT FROM AUTHOR]

Highlights: [•] Icaritin attenuates cigarette smoke-mediated oxidative stress. [•] Icaritin activates PI3K-AKT and Nrf2 signal pathways. [•] Inactivation of PI3k and Nrf2 reserves icaritin-induced GCL upregulation. [Copyright &y& Elsevier]

Diabetes mellitus increases the risk of dementia, and evidence suggests hyperglycemia is a key contributor to neurodegeneration. However, our understanding of diabetes-associated cognitive decline, an important complication of diabetes mellitus, is lacking and the underlying mechanism is unclear. Blood brain barrier (BBB) breakdown is a possible cause of dementia in diabetes mellitus and Alzheimer's disease. Accumulating evidence shows BBB dysfunction caused by hyperglycemia contributes to cognitive decline. A specific type of inflammatory programmed cell death, called pyroptosis, has potential as a therapeutic target for BBB-associated diseases. Potential inducers of pyroptosis include inflammasomes such as NLRP3, whose activation relies on damage-associated molecular patterns. High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein found in most cell types, and acts as a damage-associated molecular pattern when released from the nucleus. We propose that HMGB1 influences vascular inflammation by activating the NLRP3 inflammasome and thereby initiating pyroptosis in vascular cells. Moreover, HMGB1 plays a pivotal role in the pathogenesis of diabetes mellitus and diabetic complications. Here, we review the role of HMGB1 in BBB dysfunction induced by hyperglycemia and propose that HMGB1 is a promising therapeutic target for countering diabetes-associated cognitive decline. [Display omitted] • Diabetes mellitus makes a contribution to blood brain barrier breakdown. • Blood brain barrier disturbances in diabetes could be the possible link between dementia and diabetes. • Pyroptosis contributes to hyperglycemia induced BBB breakdown. • HMGB1 plays an important role in pyroptosis of injured blood brain barrier via activating NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]

Particulate matter (PM)-induced airway inflammation contributes to the development and exacerbation of chronic airway diseases. Circular RNA (circRNA) is a new class of non-coding RNA that participates in gene regulation in various respiratory diseases, but the regulatory role of circRNA in PM-induced airway inflammation has not been fully elucidated. In this study, we performed the human circRNA microarray to reveal differentially expressed circRNAs in PM-induced human bronchial epithelial cells (HBECs). A total of 176 upregulated and 15 downregulated circRNAs were identified. Of these, a new circRNA termed circTXNRD1 was upregulated by PM exposure in a dose- and time-dependent manner. Knockdown of circTXNRD1 significantly attenuated PM-induced expression of proinflammatory cytokine interleukin 6 (IL-6). CircRNA pull-down, dual-luciferase reporter assay and fluorescence in situ hybridization showed that circTXNRD1 acted as an endogenous sponge to decrease miR-892a levels in HBECs. Downregulation of miR-892a could increase cyclooxygenase-2 (COX-2) expression and eventually promote IL-6 secretion in PM-induced HBECs. Taken together, our findings reveal circTXNRD1 as a novel inflammatory mediator in PM-induced inflammation in HBECs via regulating miR-892a/COX-2 axis. These results provide new insight into the biological mechanism underlying PM-induced inflammation in chronic airway diseases. [Display omitted] • The differential circRNAs expression profile was identified in PM-exposed HBECs. • The circTXNRD1 was significantly upregulated by PM in HBECs. • The circTXNRD1 promoted PM-induced inflammation via miR-892a/COX-2 axis in HBECs. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) is a new infectious respiratory disease, which has caused a pandemic that has become the world's leading public health emergency, threatening people of all ages worldwide, especially the elderly. Complications of COVID-19 are closely related to an upregulation of the inflammatory response revealed by the pro-inflammatory profile of plasma cytokines (to the point of causing a cytokine storm), which is also a contributing cause of the associated coagulation disorders with venous and arterial thromboembolisms, causing multiple organ dysfunction and failure. In severe fulminant cases of COVID-19, there is an activation of coagulation and consumption of clotting factors leading to a deadly disseminated intravascular coagulation (DIC). It is well established that human immune response changes with age, and also that the pro-inflammatory profile of plasma cytokines is upregulated in both healthy and diseased elderly people. In fact, normal aging is known to be associated with a subclinical, sterile, low-grade, systemic pro-inflammatory state linked to the chronic activation of the innate immune system, a phenomenon known as "inflammaging". Inflammaging may play a role as a condition contributing to the co-occurrence of the severe hyper-inflammatory state (cytokine storm) during COVID-19, and also in other severe infections (sepsis) in older people. Moreover, we must consider the impact of inflammation on coagulation due to the crosstalk between inflammation and coagulation. The systemic inflammatory state and coagulation disorders are closely related, a phenomenon that here we call "coagul-aging" (Giunta S.). In this review, we discuss the various degrees of inflammation in older adults after being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the adverse effects of aging on the inflammatory response and coagulation system. It is important to note that although there is no gender difference in susceptibility to COVID-19 infection, however, due to differences in angiotensin-converting enzyme 2 (ACE2) expression, innate immunity, and comorbidities, older men exhibit more severe disease and higher mortality than older women. There are currently no FDA-approved specific antiviral drugs that can be used against the virus. Therapies used in patients with COVID-19 consist of remdesivir, dexamethasone, low-molecular-weight heparin, in addition to monoclonal antibodies against the spike protein of SARS-CoV-2 in the early phase of the disease. Future pharmacological research should also consider targeting the possible role of the underlying scenario of inflammaging in healthy older people to prevent or mitigate disease complications. It is worth mentioning that some specific cytokine antagonists and traditional Chinese medicine preparations can reduce the elderly's inflammatory state. • The elderly have seriously been threatened in this COVID-19 epidemic, especially older men. • Inflammaging and coagul-aging are important factors for the poor prognosis of the elderly. • Some specific cytokine antagonists and traditional Chinese medicine preparations can alleviate the inflammatory state. [ABSTRACT FROM AUTHOR]