Carbon dioxide regulates cholesterol levels through SREBP2.

In mammals, O2 and CO2 levels are tightly regulated and are altered under various pathological conditions. While the molecular mechanisms that participate in O2 sensing are well characterized, little is known regarding the signaling pathways that participate in CO2 signaling and adaptation. Here, we show that CO2 levels control a distinct cellular transcriptional response that differs from mere pH changes. Unexpectedly, we discovered that CO2 regulates the expression of cholesterogenic genes in a SREBP2-dependent manner and modulates cellular cholesterol accumulation. Molecular dissection of the underlying mechanism suggests that CO2 triggers SREBP2 activation through changes in endoplasmic reticulum (ER) membrane cholesterol levels. Collectively, we propose that SREBP2 participates in CO2 signaling and that cellular cholesterol levels can be modulated by CO2 through SREBP2.

Circadian regulation of liver function: from molecular mechanisms to disease pathophysiology.

A wide variety of liver functions are regulated daily by the liver circadian clock and via systemic circadian control by other organs and cells within the gastrointestinal tract as well as the microbiome and immune cells. Disruption of the circadian system, as occurs during jetlag, shift work or an unhealthy lifestyle, is implicated in several liver-related pathologies, ranging from metabolic diseases such as obesity, type 2 diabetes mellitus and nonalcoholic fatty liver disease to liver malignancies such as hepatocellular carcinoma. In this Review, we cover the molecular, cellular and organismal aspects of various liver pathologies from a circadian viewpoint, and in particular how circadian dysregulation has a role in the development and progression of these diseases. Finally, we discuss therapeutic and lifestyle interventions that carry health benefits through support of a functional circadian clock that acts in synchrony with the environment.

Input integration by the circadian clock exhibits nonadditivity and fold-change detection.

Circadian clocks are synchronized by external timing cues to align with one another and the environment. Various signaling pathways have been shown to independently reset the phase of the clock. However, in the body, circadian clocks are exposed to a multitude of potential timing cues with complex temporal dynamics, raising the question of how clocks integrate information in response to multiple signals. To investigate different modes of signal integration by the circadian clock, we used Circa-SCOPE, a method we recently developed for high-throughput phase resetting analysis. We found that simultaneous exposure to different combinations of known pharmacological resetting agents elicits a diverse range of responses. Often, the response was nonadditive and could not be readily predicted by the response to the individual signals. For instance, we observed that dexamethasone is dominant over other tested inputs. In the case of signals administered sequentially, the background levels of a signal attenuated subsequent resetting by the same signal, but not by signals acting through a different pathway. This led us to examine whether the circadian clock is sensitive to relative rather than absolute levels of the signal. Importantly, our analysis revealed the involvement of a signal-specific fold-change detection mechanism in the clock response. This mechanism likely stems from properties of the signaling pathway that are upstream to the clock. Overall, our findings elucidate modes of input integration by the circadian clock, with potential relevance to clock resetting under both physiological and pathological conditions.

MYC-Associated Factor MAX is a Regulator of the Circadian Clock.

The circadian transcriptional network is based on a competition between transcriptional activator and repressor complexes regulating the rhythmic expression of clock-controlled genes. We show here that the MYC-associated factor X, MAX, plays a repressive role in this network and operates through a MYC-independent binding to E-box-containing regulatory regions within the promoters of circadian BMAL1 targets. We further show that this "clock" function of MAX is required for maintaining a proper circadian rhythm and that MAX and BMAL1 contribute to two temporally alternating transcriptional complexes on clock-regulated promoters. We also identified MAX network transcriptional repressor, MNT, as a fundamental partner of MAX-mediated circadian regulation. Collectively, our data indicate that MAX regulates clock gene expression and contributes to keeping the balance between positive and negative elements of the molecular clock machinery.

Hypoxia induces a time- and tissue-specific response that elicits intertissue circadian clock misalignment.

The occurrence and sequelae of disorders that lead to hypoxic spells such as asthma, chronic obstructive pulmonary disease, and obstructive sleep apnea (OSA) exhibit daily variance. This prompted us to examine the interaction between the hypoxic response and the circadian clock in vivo. We found that the global transcriptional response to acute hypoxia is tissue-specific and time-of-day-dependent. In particular, clock components differentially responded at the transcriptional and posttranscriptional level, and these responses depended on an intact circadian clock. Importantly, exposure to hypoxia phase-shifted clocks in a tissue-dependent manner led to intertissue circadian clock misalignment. This differential response relied on the intrinsic properties of each tissue and could be recapitulated ex vivo. Notably, circadian misalignment was also elicited by intermittent hypoxia, a widely used model for OSA. Given that phase coherence between circadian clocks is considered favorable, we propose that hypoxia leads to circadian misalignment, contributing to the pathophysiology of OSA and potentially other diseases that involve hypoxia.

Docosahexaenoic Acid Increases the Potency of Soluble Epoxide Hydrolase Inhibitor in Alleviating Streptozotocin-Induced Alzheimer's Disease-Like Complications of Diabetes.

Diabetes is a risk factor for Alzheimer's disease and it is associated with significant memory loss. In the present study, we hypothesized that the soluble epoxide hydrolase (sEH) inhibitor N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl)-urea (also known as TPPU) could alleviate diabetes-aggravated Alzheimer's disease-like symptoms by improving memory and cognition, and reducing the oxidative stress and inflammation associated with this condition. Also, we evaluated the effect of edaravone, an antioxidant on diabetes-induced Alzheimer's-like complications and the additive effect of docosahexaenoic acid (DHA) on the efficacy of TPPU. Diabetes was induced in male Sprague-Dawley rats by intraperitoneally administering streptozotocin (STZ). Six weeks after induction of diabetes, animals were either treated with vehicle, edaravone (3 or 10 mg/kg), TPPU (1 mg/kg) or TPPU (1 mg/kg) + DHA (100 mg/kg) for 2 weeks. The results demonstrate that the treatments increased the memory response of diabetic rats, in comparison to untreated diabetic rats. Indeed, DHA + TPPU were more effective than TPPU alone in reducing the symptoms monitored. All drug treatments reduced oxidative stress and minimized inflammation in the brain of diabetic rats. Expression of the amyloid precursor protein (APP) was increased in the brain of diabetic rats. Treatment with edaravone (10 mg/kg), TPPU or TPPU + DHA minimized the level of APP. The activity of acetylcholinesterase (AChE) which metabolizes acetylcholine was increased in the brain of diabetic rats. All the treatments except edaravone (3 mg/kg) were effective in decreasing the activity of AChE and TPPU + DHA was more efficacious than TPPU alone. Intriguingly, the histological changes in hippocampus after treatment with TPPU + DHA showed significant protection of neurons against STZ-induced neuronal damage. Overall, we found that DHA improved the efficacy of TPPU in increasing neuronal survival and memory, decreasing oxidative stress and inflammation possibly by stabilizing anti-inflammatory and neuroprotective epoxides of DHA. In the future, further evaluating the detailed mechanisms of action of sEH inhibitor and DHA could help to develop a strategy for the management of Alzheimer's-like complications in diabetes.

Insulin signaling: An opportunistic target to minify the risk of Alzheimer's disease.

Alzheimer's disease (AD) is progressive neurodegenerative disorder characterized by accumulation of senile plaques, neurofibrillary tangles (NFT) and neurodegeneration. The diabetes mellitus (DM) is one of the risk factors for AD pathogenesis by impairment in insulin signaling and glucose metabolism in central as well as peripheral system. Insulin resistance, impaired glucose and lipid metabolism are leading to the Aß (Aß) aggregation, Tau phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, memory impairment and also mark over Aß transport through central to peripheral and vice versa. Several pathways, like enzymatic degradation of Aß, forkhead box protein O1 (FOXO) signaling, insulin signaling shared common pathological mechanism for both AD and DM. Recent evidence showed that hyperinsulinemia and hyperglycemia affect the onset and progression of AD differently. Some researchers have suggested that hyperglycemia influences vascular tone, while hyperinsulinemia may underlie mitochondrial deficit. The objective of this review is to determine whether existing evidence supports the concept that impairment in insulin signaling and glucose metabolism play an important role in pathogenesis of AD. In the first part of this review, we tried to explain the interconnecting link between AD and DM, whereas the second part includes more information on insulin resistance and its involvement in AD pathogenesis. In the final part of this review, we have focused more toward the AD treatment by targeting insulin signaling like anti-diabetic, antioxidant, nutraceuticals and dietary supplements. To date, more researches should be done in this field in order to explore the pathways in insulin signaling, which might ameliorate the treatment options and reduce the risk of AD due to DM.

Diosmin Modulates the NF-kB Signal Transduction Pathways and Downregulation of Various Oxidative Stress Markers in Alloxan-Induced Diabetic Nephropathy.

Hyperglycaemia-mediated oxidative stress plays an imperative role in the progression of diabetic nephropathy. NF-kB is an important transcription factor in eukaryotes which regulates a diverse array of cellular process, including inflammation, immunological response, apoptosis, growth and development. Increased expression of NF-kB plays a vital role in the pathogenesis of many inflammatory diseases including diabetic nephropathy. Hence, the present study was designed to explore the nephroprotective nature of diosmin by assessing the various biochemical parameters, markers of oxidative stress and proinflammatory cytokine levels in alloxan-induced diabetic Wistar rats. Type 2 diabetes was induced in Wistar rats by single intraperitoneal injection of alloxan (120 mg/kg body weight). Seventy-two hours after the conformation of diabetes (blood glucose level ≥ 250 mg/dl), the rats were segregated into four groups, each group having six animals. Diabetic rats were treated with diosmin at a dose of 50 mg and 100 mg/kg body weight respectively. After the 28th day of treatment, rats were sacrificed, blood serum, plasma and kidney tissue were collected for various biochemical analysis. Inflammatory cytokine levels were measured through ELISA kit. Diosmin treatment produces significant reduction in the blood glucose and plasma insulin level and increases the body weight when compared with diabetic rats. Elevated level of malondialdehyde (MDA) and decrease levels of superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and nitric oxide (NO) were significantly restored after 28 days of diosmin treatment. Diosmin treatment group also restores the normal architecture of the kidney tissue which was confirmed by histopathological examination. Moreover, oral administration of diosmin shows a significant normalization in the level of NF-kB, proving its pivotal role in maintaining renal function. The above ameliorative effects were more pronounced with diosmin at a dose of 100 mg/kg body weight. The above results permit us to conclude that treatment with diosmin halts hyperglycaemia-mediated oxidative stress and decline in pro-inflammatory cytokines and thus has beneficial anti-diabetic activity.

The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease.

The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age-related neurodegenerative diseases. However, its exact cause and pathogenesis are unknown. Currently approved medications for AD provide symptomatic relief; however, they fail to influence disease progression. Moreover, the components of the cellular quality control system represent an important focus for the development of targeted and potent therapies for managing AD. This review aims to evaluate whether existing evidence supports the hypothesis that UPS impairment causes the early pathogenesis of neurodegenerative disorders. The first part presents basic information about the UPS and its molecular components. The next part explains how the UPS is involved in neurodegenerative disorders. Finally, we emphasize how the UPS influences the management of AD. This review may help in the design of future UPS-related therapies for AD.

Role of toll-like receptors in multiple myeloma and recent advances.

Multiple myeloma (MM) is a hematologic malignancy characterized as an abnormal proliferation and invasion of plasma cells into the bone marrow. Toll-like receptors (ТLRs) connect the innate and adaptive immune responses and represent a significant and potentially linking element between inflammation and cancer. When TLRs bind to their ligands, they trigger two major signaling pathways such that both share overlapping downstream signals: one is a myeloid differentiation primary response 88 (MyD88)-dependent production and activation of nuclear factor-κB, whereas the other is a MyD88-independent production of type-I interferon. Whereas the MyD88 pathway results in proinflammatory cytokine production, the other pathway stimulates cell proliferation. Dysregulations of these pathways may eventually lead to abnormal cell proliferation and MM. Despite recent biomedical advances, MM continues to be an incurable disease. There are an increasing number of TLR-based therapeutic approaches currently being tested in a number of preclinical and clinical studies. We here attempt to outline in detail the currently available information on TLRs in various types of cancer.