Physiological and metabolic functions of the ß3-adrenergic receptor and an approach to therapeutic achievements.

A specific type of beta-adrenergic receptor was discovered in the decade of 1980s and subsequently recognized as a new type of beta-adrenergic receptor, called beta3-adrenoceptor (ß3-AR). ß3-AR expresses in different tissues, including adipose tissue, gall bladder, stomach, small intestine, cardiac myocytes, urinary bladder, and brain. Structurally, ß3-AR is very similar to ß1- and ß2-AR and belongs to a G-protein coupled receptor that uses cAMP as an intracellular second messenger. Alternatively, it also activates the NO-cGMP cascade. Stimulation of the ß3-AR increases lipolysis, fatty acid oxidation, energy expenditure, and insulin action, leading to anti-obesity and anti-diabetic activity. Moreover, ß3-AR differentially regulates the myocardial contraction and relaxes the urinary bladder to balance the cardiac activity and delay the micturition reflex, respectively. In recent years, this receptor has served as an attractive target for the treatment of obesity, type 2 diabetes, congestive heart failure, and overactive bladder syndrome. Several ß3-AR agonists are in the emerging stage that can exert novel pharmacological benefits in different therapeutic areas. The present review focuses on the structure, signaling, physiological, and metabolic activities of ß3-AR. Additionally, therapeutic approaches of ß3-AR have also been considered.

Corrigendum: The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: focus on the role of oxidative stress.

[This corrects the article DOI: 10.3389/fphar.2022.1015835.].

Role of Alpha-Fetoprotein in the Pathogenesis of Cancer.

Alpha-fetoprotein (AFP) belongs to the albuminoid protein family and is considered as the fetal analog of serum albumin. This plasma protein is initially synthesized in the fetal liver and yolk sac and shows a maximum peak near the end of the first trimester. Later, concentrations begin to decline prenatally and drop precipitously after birth. This protein has three key ligand-binding pockets for interactions with various biomolecules. It contains multiple phosphorylation and acetylation sites for the regulation of physiological and pathophysiological states. High serum AFP titer is an established biomarker for yolk sac, embryonal and hepatocellular carcinoma. The present review critically analyzes the chemical nature, receptors, clinical implications, and therapeutic aspects of AFP, underpinning the development of different types of cancer.

Pathogenesis of Neurodegenerative Diseases and the Protective Role of Natural Bioactive Components.

Neurodegenerative diseases are a serious problem throughout the world. There are several causes of neurodegenerative diseases; these include genetic predisposition, accumulation of misfolded proteins, oxidative stress, neuroinflammation, and excitotoxicity. Oxidative stress increases the production of reactive oxygen species (ROS) that advance lipid peroxidation, DNA damage, and neuroinflammation. The cellular antioxidant system (superoxide dismutase, catalase, peroxidase, and reduced glutathione) plays a crucial role in scavenging free radicals. An imbalance in the defensive actions of antioxidants and overproduction of ROS intensify neurodegeneration. The formation of misfolded proteins, glutamate toxicity, oxidative stress, and cytokine imbalance promote the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Antioxidants are now attractive molecules to fight against neurodegeneration. Certain vitamins (A, E, C) and polyphenolic compounds (flavonoids) show excellent antioxidant properties. Diet is the major source of antioxidants. However, diet medicinal herbs are also rich sources of numerous flavonoids. Antioxidants prevent ROS-mediated neuronal degeneration in post-oxidative stress conditions. The present review is focused on the pathogenesis of neurodegenerative diseases and the protective role of antioxidants. KEY TEACHING POINTSThis review shows that multiple factors are directly or indirectly associated with the pathogenesis of neurodegenerative diseases.Failure to cellular antioxidant capacity increases oxidative stress that intensifies neuroinflammation and disease progression.Different vitamins, carotenoids, and flavonoids, having antioxidant capacity, can be considered protective agents.

Corrigendum: The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress.

[This corrects the article DOI: 10.3389/fphar.2022.1015835.].

Melatonin: A Potential Antineoplastic Agent in Breast Cancer.

Melatonin is primarily synthesized in the pineal gland under the influence of noradrenergic stimulation at night. It regulates the sleep-wake cycle, gonadal activity, redox homeostasis, immune functions, and anticarcinogenic effects at the normal physiological state. The activity of melatonin is mediated by membrane-bound G protein-coupled receptors MT1 and MT2. Circadian deregulation, exposure to light-at-night, shift work, and jet lag disrupt the melatonin rhythm. A low level of circulatory melatonin concentration influences the development of many cancers, including breast cancer. Melatonin acts as an anticancer agent in breast tissue. It suppresses metabolic activity, regulates cell-signaling pathways, and subsequently blocks cell proliferation. This indolamine induces apoptosis, inhibits chronic inflammation and metastasis. Melatonin restricts the functions of estrogen receptor α and also inhibits aromatase activity. Melatonin is a potent antioxidant that reduces the chemoresistance capacity of breast cancer cells. At therapeutic levels, it potentially increases the efficacy of chemotherapeutic agents and decreases their adverse effects during the treatment of breast cancer. The present review focuses on the antineoplastic activity of melatonin against breast cancer. Emphasis has been given to the possible use of melatonin in the treatment of breast cancer.

The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress.

Oxidative stress (OS) disrupts the chemical integrity of macromolecules and increases the risk of neurodegenerative diseases. Fisetin is a flavonoid that exhibits potent antioxidant properties and protects the cells against OS. We have viewed the NCBI database, PubMed, Science Direct (Elsevier), Springer-Nature, ResearchGate, and Google Scholar databases to search and collect relevant articles during the preparation of this review. The search keywords are OS, neurodegenerative diseases, fisetin, etc. High level of ROS in the brain tissue decreases ATP levels, and mitochondrial membrane potential and induces lipid peroxidation, chronic inflammation, DNA damage, and apoptosis. The subsequent results are various neuronal diseases. Fisetin is a polyphenolic compound, commonly present in dietary ingredients. The antioxidant properties of this flavonoid diminish oxidative stress, ROS production, neurotoxicity, neuro-inflammation, and neurological disorders. Moreover, it maintains the redox profiles, and mitochondrial functions and inhibits NO production. At the molecular level, fisetin regulates the activity of PI3K/Akt, Nrf2, NF-κB, protein kinase C, and MAPK pathways to prevent OS, inflammatory response, and cytotoxicity. The antioxidant properties of fisetin protect the neural cells from inflammation and apoptotic degeneration. Thus, it can be used in the prevention of neurodegenerative disorders.

Potential Impacts of Prebiotics and Probiotics on Cancer Prevention.

BACKGROUND: Cancer is a serious problem throughout the world. The pathophysiology of cancer is multifactorial and is also related to gut microbiota. Intestinal microbes are the useful resident of the healthy human. They are significant for various aspects of human health, including nutritional biotransformation, flushing of the pathogens, toxin neutralization, immune response, and onco-suppression. Disruption in the interactions among the gut microbiota, intestinal epithelium, and the host immune system are associated with gastrointestinal disorders, neurodegenerative diseases, metabolic syndrome, and cancer. Probiotic bacteria (Lactobacillus spp., Bifidobacterium spp.) have been regarded as beneficial to health. Moreover, they also play a significant role in immunomodulation and a preventive measure against obesity, diabetes, liver disease, inflammatory bowel disease, tumor progression, and cancer. OBJECTIVE: The involvement of gut microorganisms in cancer development and prevention has been recognized as a balancing factor. The events of dysbiosis emphasize metabolic disorder and carcinogenesis. The gut flora potentiates immunomodulation and minimizes the limitations of usual chemotherapy. The significant role of prebiotics and probiotics on the improvement of immunomodulation and antitumor properties has been considered. METHODS: I had reviewed the literature on the multidimensional activities of prebiotics and probiotics from the NCBI website database PubMed, Springer Nature, Science Direct (Elsevier), Google Scholar database to search relevant articles. Specifically, I had focused on the role of prebiotics and probiotics in immunomodulation and cancer prevention. RESULTS: Prebiotics are the nondigestible fermentable sugars that selectively influence the growth of probiotic organisms that exert immunomodulation over the cancerous growth. The oncostatic properties of bacteria are mediated through the recruitment of cytotoxic T cells, natural killer cells, and oxidative stress-induced apoptosis in the tumor microenvironment. Moreover, approaches have also been taken to use probiotics as an adjuvant in cancer therapy. CONCLUSION: The present review has indicated that dysbiosis is a crucial factor in many pathological situations, including cancer. Applications of prebiotics and probiotics exhibit the immune-surveillance as oncostatic effects. These events increase the possibilities of new therapeutic strategies for cancer prevention.

Potential Bioactive Components and Health Promotional Benefits of Tea (Camellia sinensis).

Tea is prepared from the young leaves, buds, stalks of the plant Camellia sinensis. The cultivation process of tea plants and the habit of tea drinking were initiated in China from ancient times. Now, the consumption of tea is very popular throughout the world and it is an integral part of our social culture. Tea contains polyphenolic compounds (catechins and epicatechins), theaflavins, flavonol glycosides, L-theanine, caffeine, theobromine, and volatile organic substances. These bioactive components are responsible for the astringency, flavor, aroma, and taste of the tea as well as its health beneficial effects. Moreover, tea has several medicinal values. The phytochemical components are involved in the prevention and cure of many illnesses like cardiovascular diseases, malignancy, digestive dysfunction, and metabolic disorders like obesity, diabetes. Tea flavonoids show strong antioxidant properties. Caffeine and other methylxanthine regulate the intracellular second messenger levels. Additionally, catechins exhibit anti-inflammatory effects. All these multidimensional actions make some positive attributes in favor of neuroprotection, cardioprotection, and cancer prevention. Various approaches are also taken to use tea ingredients as an adjuvant in cancer therapy. This review emphasizes the importance of bioactive components, and their health promotional activities.KEY TEACHING POINTSOrigin and brief history of tea.Processing steps and characteristics of different types of teas. Bioactive components of teas (green and black tea), their biochemical characteristics and health promotional effects.Role of different bioactive components to control the various physiological and metabolic disorders.Possibilities of use of tea component in cancer therapy.

Physiological and pharmacological perspectives of melatonin.

The pineal gland is a interface between light-dark cycle and shows neuro-endocrine functions. Melatonin is the primary hormone of pineal gland, secreted at night. The night-time melatonin peak regulates the physiological functions at dark. Melatonin has several unique features as it synchronises internal rhythm with daily and seasonal variations, regulates circadian rhythm and sleep-wake cycle. Physiologically melatonin involves in detoxification of free radicals, immune functions, neuro-protection, oncostatic effects, cardiovascular functions, reproduction, and foetal development. The precise functions of melatonin are exhibited by specific receptors. In relation to pathophysiology, impaired melatonin secretion promotes sleep disorder, cancer progression, type-2 diabetes, and neurodegenerative diseases. Several reports have highlighted the therapeutic benefits of melatonin specially related to cancer protection, sleep disorder, psychiatric disorders, and jet lag problems. This review will touch the most of the area of melatonin-oriented health impacts and its therapeutic aspects.

A Profound Relationship between Circadian Rhythm Dysfunction and Cancer Progression: An Approach to Exploration.

Circadian (~ 24-hour) rhythm has been observed in all living organisms. In humans, the circadian system governs different physiological functions such as metabolism, sleep-wake cycle, body temperature, hormone secretion, and cellular proliferation. The suprachiasmatic nucleus (SCN) of the anterior hypothalamus is the principal circadian pacemaker. The SCN receives input signals primarily from the retinohypothalamic tract (RHT), sends output signals to different parts of the hypothalamus, pineal gland, and the peripheral clocks through the neural or humoral network. The functions of the circadian clock are mediated by the rhythmic expression of the core clock genes through a complex feedback loop. Disruption of clock functions influences the development of several pathologic conditions, including cancer, shift work, chronic or acute jet lag, and light-at-night affect the circadian activity, leading to development of several physiological disorders, more specifically cancer. Circadian dysfunction alters the expression of core clock genes that promote the deregulation of the cell cycle, increase cell proliferation and survival, decrease apoptotic activity, alter metabolic functions, increase metastatic property, collectively induces cancer progression.

The Potential Oncostatic Effects of Melatonin against Prostate Cancer.

Melatonin is an endogenous indolamine, synthesized and secreted from the pineal gland. The environmental light-dark cycle is the primary regulator of melatonin synthesis. Darkness during the subjective night induces noradrenaline secretion, which stimulates pinealocytes for melatonin production. Melatonin exhibits anticancer effects and different physiological functions through the membrane-bound G-protein-coupled MT1 and MT2 receptors. Impaired circadian activity, indoor or outdoor light pollution, shift work, night work, and jet lag suppress normal melatonin synthesis. Decreased melatonin concentration causes impaired anticancer effects that adversely affect the progression of different cancers, including prostate. Melatonin differentially regulates the cell cycle, cell survival, and metabolism in malignant cells in contrast to normal prostate epithelial cells. Melatonin promotes the nuclear exclusion of androgen receptors without suppressing the expression of this receptor. This indirect effect blocks the androgenic response in prostate cancer cells. It acts as a cytostatic and cytotoxic agent, prevents cell proliferation, and activates an apoptotic response. Melatonin also inhibits HIF-1α activity and the expression of vascular endothelial growth factors to suppress angiogenesis. This indolamine restricts alteration of metabolic activity, invasion, and metastasis. Melatonin has therapeutic importance. It decreases the side effects of anticancer treatment and mitigates adverse effects after prostatectomy and radiotherapy. Melatonin blocks the recurrence of prostate cancer as well as hormone-refractory effects during androgen deprivation therapy. The present review discusses the multifaceted effects of melatonin against prostate cancer.

Melatonin: an endogenous miraculous indolamine, fights against cancer progression.

PURPOSE: Melatonin is an amphipathic indolamine molecule ubiquitously present in all organisms ranging from cyanobacteria to humans. The pineal gland is the site of melatonin synthesis and secretion under the influence of the retinohypothalamic tract. Some extrapineal tissues (skin, lens, gastrointestinal tract, testis, ovary, lymphocytes, and astrocytes) also enable to produce melatonin. Physiologically, melatonin regulates various functions like circadian rhythm, sleep-wake cycle, gonadal activity, redox homeostasis, neuroprotection, immune-modulation, and anticancer effects in the body. Inappropriate melatonin secretion advances the aging process, tumorigenesis, visceral adiposity, etc. METHODS: For the preparation of this review, I had reviewed the literature on the multidimensional activities of melatonin from the NCBI website database PubMed, Springer Nature, Science Direct (Elsevier), Wiley Online ResearchGate, and Google Scholar databases to search relevant articles. Specifically, I focused on the roles and mechanisms of action of melatonin in cancer prevention. RESULTS: The actions of melatonin are primarily mediated by G-protein coupled MT1 and MT2 receptors; however, several intracellular protein and nuclear receptors can modulate the activity. Normal levels of the melatonin protect the cells from adverse effects including carcinogenesis. Therapeutically, melatonin has chronomedicinal value; it also shows a remarkable anticancer property. The oncostatic action of melatonin is multidimensional, associated with the advancement of apoptosis, the arrest of the cell cycle, inhibition of metastasis, and antioxidant activity. CONCLUSION: The present review has emphasized the mechanism of the anti-neoplastic activity of melatonin that increases the possibilities of the new approaches in cancer therapy.

Hepatoprotective effect of food preservatives (butylated hydroxyanisole, butylated hydroxytoluene) on carbon tetrachloride-induced hepatotoxicity in rat.

Carbon tetrachloride (CCl4), a hepatotoxic agent is widely used to study the toxic mechanisms in experimental animals. This study was carried out to establish the hepatoprotective measures of food preservative antioxidants butylated hydroxyanisole and butylated hydroxytolune (BHA, BHT) when mixed with food towards carbon tetrachloride (CCl4) intoxication (230 mg/ kg b wt/rat/day) in rat. Biochemical markers like serum glutamate pyruvate tranaminase (AST), serum glutamate oxaloacetate transaminase (ALT), alkaline phosphatase (ALP) and bilirubin content, antioxidant enzymes such as SOD, CAT, GPx, and malondialdehyde (MDA) as the end product of lipid peroxidanion were measured. The results had shown the elevated level of AST (121.16%), ALT (124.68%), ALP (122.41%) an, bilirubin content (57.14%) after CCl4 treatment. Marked decrease of activity of antioxidant enzymes such as SOD (85.36%), CAT (67.47%), GPx (50.7%) had indicated that the ROS mediated toxicity and pretreatment of BHA and BHT restored the activity of these enzymes. High level of MDA content with reduced GSH value was also observed due to oxidative stress. The hepatic antioxidant status was restored with the food preservative (BHA, BHT) antioxidant treatment which had indicated the significant protective effect against CCl4 induced hepatotoxicity and finally confirmed by histopathological studies.

Production of xylanase by immobilized Trichoderma reesei SAF3 in Ca-alginate beads.

In the present study, the optimum conditions for the production of xylanase by immobilized spores of Trichoderma reesei SAF3 in calcium alginate beads were determined. The operational stability of the beads during xylanase production under semi-continuous fermentation was also studied. The influence of alginate concentration (1, 2, 3, and 4%) and initial cell loading (100, 200, 300, 400, and 500 beads per flask) on xylanase production was considered. The production of xylanase was found to increase significantly with increasing concentration of alginate and reached a maximum yield of 3.12+/-0.18 U ml(-1) at 2% (w/v). The immobilized cells produced xylanase consistently up to 10 cycles and reached a maximum level at the forth cycle (3.36+/-0.2 U ml(-1)).