Molecular mechanisms interlinking biological clock and diabetes mellitus: Effective tools for better management.

BACKGROUND AND AIM: Advances in circadian biology have delineated the link between perturbed biological clock and metabolic diseases. Circadian disturbances are associated with the onset, progression and severity of diabetes mellitus. METHODS: We conducted a literature survey using the key terms - circadian, diabetes, circadian and diabetes, clock genes and diabetes, chronotherapy and peripheral clocks in science direct, PubMed, Google, and Embase till August 23, 2021. RESULTS: Misalignment between peripheral clocks located in pancreas, intestine, liver, adipose tissue and skeletal muscle and with the central oscillator alters the secretion of insulin, incretins, adipokines and soluble factors resulting in the derangement of metabolism leading to chronic hyperglycemia. CONCLUSION: Management of circadian health restores glucose homeostasis confirming that chronotherapy will help in the management of diabetes mellitus. Further, administration of circadian clock modifiers has proved potential therapeutic agents to treat diabetes mellitus. The aim of the review is to highlight the molecular mechanisms linking biological clock and diabetes mellitus and how they are useful for effective management of the disease.

Basic chronobiology: what do sleep physicians need to know?

Sleep is an essential physiological process, which profoundly affects a wide range of biological activities. It is now known that sleep supports myriad vital functions in the central nervous system. This includes neural plasticity, learning, memory, cognition and emotional regulation. Additionally, it affects basic processes such as cardiovascular, immunological and metabolic activity. Evidence from multiple lines of research has thus shown that good quality of sleep is essential for both survival and optimal functioning of life. Considerable evidence also supports the conclusion that even minimal dysfunctions in circadian regulation can significantly disrupt sleep and broadly affect body physiology. As a consequence, it is now appreciated that the therapy of sleep disorders is more complex than was once thought. At present, several clinical disciplines have recognized the significance of the biological clock in health and illness, and are incorporating this knowledge into treatment programs. Recent decades have seen the emergence of chronotherapies, i.e., treatment strategies that are aimed at producing adjustments in the circadian clock. The final objective of these approaches is to affect basic cellular and physiological processes, which in turn may be at the root of disorders such as physiological aging, immune functioning, metabolic activity, and psychiatric disturbance. It is suggested that the integration of chronobiological perspectives into many mainstream medical disciplines would be of significant benefit, both for the reduction of the prevalence of diseases and their treatment. This review considers the physiology of sleep and the importance of timekeeping mechanisms in the regulation of overall health.

Chronotherapeutics: Recognizing the Importance of Timing Factors in the Treatment of Disease and Sleep Disorders.

This review describes the characteristics of a number of pathologies, which are considered from the point of view of chronobiology, that is, the way in which biological processes are expressed throughout the 24-hour day. This perspective is a relatively new way of thinking about disease and additionally about how to treat diseases. It has called attention to the importance of not only the quantity of a drug that is administered but also when it is administered. In addition, the review presents an overview of the emerging clinical strategies known as chronotherapeutics, that is, the effects of the daily scheduling of drug administration and the consequences of the activity and efficacy of therapies that are applied in this manner. This article also reviews innovative ways in which physicians are applying time-specified drug treatment (chronopharmacology) for sleep disorders. Here, we present a systematic description of chronopharmacology as well as definitions of key terms that, we believe, will be helpful for newcomers to the field. It is hoped that greater awareness of this new perspective on pharmacology will promote its adoption by researchers and clinicians.

Chronotherapeutic effect of fisetin on expression of urea cycle enzymes and inflammatory markers in hyperammonaemic rats.

BACKGROUND: Elevated blood ammonia leads to hyperammonaemia that affects vital central nervous system (CNS) functions. Fisetin, a naturally occurring flavonoid, exhibits therapeutic benefits, such as anti-cancer, anti-diabetic, anti-oxidant, anti-angiogenic, neuroprotective and neurotrophic effects. METHODS: In this study, the chronotherapeutic effect of fisetin on ammonium chloride (AC)-induced hyperammonaemic rats was investigated, to ascertain the time point at which the maximum drug effect is achieved. The anti-hyperammonaemic potential of fisetin (50mg/kg b.w. oral) was analysed when administered to AC treated (100mg/kg b.w. i.p.) rats at 06:00, 12:00, 18:00 and 00:00h. Amelioration of pathophysiological conditions by fisetin at different time points was measured by analysing the levels of expression of liver urea cycle enzymes (carbamoyl phosphate synthetase-I (CPS-I), ornithine transcarbamoylase (OTC) and argininosuccinate synthetase (ASS)), nuclear transcription factor kappaB (NF-κB p65), brain glutamine synthetase (GS) and inducible nitric oxide synthase (iNOS) by Western blot analysis. RESULTS: Fisetin increased the expression of CPS-I, OTC, ASS and GS and decreased iNOS and NF-κB p65 in hyperammonaemic rats. Fisetin administration at 00:00h showed more significant effects on the expression of liver and brain markers, compared with other time points. CONCLUSIONS: Fisetin could exhibit anti-hyperammonaemic effect owing to its anti-oxidant and cytoprotective influences. The temporal variation in the effect of fisetin could be due to the (i) chronopharmacological, chronopharmacokinetic properties of fisetin and (ii) modulations in the endogenous circadian rhythms of urea cycle enzymes, brain markers, redox enzymes and renal clearance during hyperammonaemia by fisetin. However, future studies in these lines are necessitated.

Role of Bacopa monnieri in the temporal regulation of oxidative stress in clock mutant (cryb) of Drosophila melanogaster.

Accruing evidences imply that circadian organization of biochemical, endocrinological, cellular and physiological processes contribute to wellness of organisms and in the development of pathologies such as malignancy, sleep and endocrine disorders. Oxidative stress is known to mediate a number of diseases and it is notable to comprehend the orchestration of circadian clock of a model organism of circadian biology, Drosophila melanogaster, under oxidative stress. We investigated the nexus between circadian clock and oxidative stress susceptibility by exposing D. melanogaster to hydrogen peroxide (H2O2) or rotenone; the reversibility of rhythms following exposure to Bacopa monnieri extract (ayurvedic medicine rich in antioxidants) was also investigated. Abolishment of 24h rhythms in physiological response (negative geotaxis), oxidative stress markers (protein carbonyl and thiobarbituric acid reactive substances) and antioxidants (superoxide dismutase, catalase, glutathione-S-transferase and reduced glutathione) were observed under oxidative stress. Furthermore, abolishment of per mRNA rhythm in H2O2 treated wild type flies and augmented susceptibility to oxidative stress in clock mutant (cry(b)) flies connotes the role of circadian clock in reactive oxygen species (ROS) homeostasis. Significant reversibility of rhythms was noted following B. monnieri treatment in wild type flies than cry(b) flies. Our experimental approach revealed a relationship involving oxidative stress and circadian clock in fruit fly and the utility of Drosophila model in screening putative antioxidative phytomedicines prior to their use in mammalian systems.

Inhibitory effect of naringenin (citrus flavonone) on N-nitrosodiethylamine induced hepatocarcinogenesis in rats.

We evaluated the effects of naringenin on N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in rats. Administration of NDEA induced hepatocellular carcinoma (HCC), as evidenced by changes in histopathological architecture, increased activity of cytochrome P450, decreased activity of glutathione S-transferase (GST) as well as decreased antioxidant status, enhanced lipid peroxidation and increased liver marker enzymes. Pre- and post-treatment with naringenin effectively suppressed NDEA-initiated hepatocarcinoma and the associated preneoplastic lesions by modulating xenobiotic-metabolizing enzymes (XMEs), alleviating lipid peroxidation (through both free radical scavenging and the enhanced antioxidant status), and decreased levels of liver marker enzymes. These results indicate that naringenin prevents lipid peroxidation and hepatic cell damage and also protects the antioxidant system in N-nitrosdithylamine-induced hepatocarcinogenesis.

Renal protective effect of hesperidin on gentamicin-induced acute nephrotoxicity in male Wistar albino rats.

OBJECTIVES: The aim of the study was to investigate the renoprotective effect of hesperidin (HDN), a citrus flavanoid with anti-oxidant properties against gentamicin (GEN)-induced nephrotoxicity in male Wistar albino rats. METHODS: Urea, uric acid, creatinine, thiobarbituric acid reactive substances (TBARS), nitric oxide (NO), total cholesterol, free fatty acids, and triglyceride levels were measured in the serum. Further, glutathione (GSH), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities were determined in the erythrocytes. Morphological changes in renal tissues were examined using light microscopy. RESULTS: Acute renal injury was evidenced by: (1) increased serum urea, uric acid, creatinine, TBARS, and NO, (2) decreased SOD, GPx, and GSH levels, and (3) necrosis in proximal tubules and glomerular atrophy. HDN supplementation to GEN-induced rats significantly decreased serum urea, uric acid, creatinine, TBARS, NO generation, but SOD, GPx activities, and GSH content increased when compared with GEN alone. Moreover, HDN supplementation resulted in complete reversal of GEN-induced tubular necrosis, and an increase in total cholesterol, free fatty acids, and triglycerides to normal levels. DISCUSSION: Our results suggested that HDN acts as a potent scavenger of free radicals in the kidney to prevent the toxic effects of GEN both at the biochemical and histopathological levels.

Protective effect of Withania somnifera root powder on lipid peroxidation and antioxidant status in gentamicin-induced nephrotoxic rats.

We investigated the protective effect of Withania somnifera root powder (used in ayurvedic medicine in India) on gentamicin (GEN) induced nephrotoxicity in male Wistar rats. The root powder was administered orally to rats for 14 days before GEN treatment and thereafter with GEN for 8 days. Nephrotoxicity was manifested in GEN-treated rats as significant increases in urea, creatinine, uric acid, non protein nitrogen, urinary protein, N-acetyl-beta-D-glucosaminidase, thiobarbituric acid reactive substances, hydroperoxides, followed by a significant reduction in glutathione peroxidase, superoxide dismutase, catalase, and reduced glutathione in liver and kidney tissues, histopathologically confirmed by tubular necrosis. W. somnifera treatment altered the antioxidant status and significantly reversed the levels as seen microscopically. The results show that the root powder of W. somnifera with the presence of natural antioxidants, bioflavanoids, and other bioactive compounds scavenged the free radicals generated by GEN and ameliorated the severity of GEN-induced nephrotoxicity by enhancing the antioxidant system and protecting the cellular integrity of kidney and liver tissues.

Nephroprotective effect of Withania somnifera: a dose-dependent study.

In the present study, we investigated the protective effect of Withania somnifera, an indigenous medicinal herb used in ayurvedic traditional systems for more than 3000 years in India, on gentamicin (GEN)-induced nephrotoxicity. The root extract of three different doses of W. somnifera (viz., 250, 500, and 750 mg/kg) was administered orally to rats for 14 days before GEN treatment and thereafter concurrently with GEN (100 mg/kg) for 8 days. Nephrotoxicity was evident in GEN-treated rats by significant increase in kidney weight, urea, creatinine, urinary protein, and glucose, and significant reduction in body weights and potassium, which was histopathologically confirmed by tubular necrosis. In contrast W. somnifera (500 mg/kg) significantly reversed these changes as evidenced microscopically when compared to other two doses of W. somnifera (250 and 750 mg/kg), and there were no significant changes in the levels of sodium in the experimental animals compared to control. Thus, our results suggested the nephroprotective effect of Withania somnifera, which could be by enhancing antioxidant activity with natural antioxidants and scavenging the free radicals.

Temporal patterns of lipid peroxidation product formation and antioxidants activity in oral cancer patients.

The aim of this study was to assess the temporal patterns of (the formation of) thiobarbituric acid reactive substances and the activities of antioxidant enzymes in the erythrocytes of ten healthy adult subjects and ten oral cancer patients of comparable age. The levels of thiobarbituric acid reactive substances and the activities of antioxidant enzymes were assayed at 6-hour intervals using colorimetric methods. The Cosinorwin computer software program was used to analyse the characteristics of biochemical rhythms, such as acrophase, amplitude, and mesor (rhythms: acrophase, amplitude, mesor, etc.). There is a phase delay in erythrocyte thiobarbituric acid reactive substance levels and enzymatic antioxidant activities in oral cancer patients as compared to healthy subjects. The desynchronisation of thiobarbituric acid reactive substance production and enzymatic antioxidant rhythms reflected an alteration of circadian clock function in oral cancer patients and may require specific measures for chronotherapy.