Terazosin produces an antidepressant-like effect in mice exposed to chronic unpredictable mild stress behavioral alteration.

Terazosin is an α1-adrenergic receptor antagonist that can relax smooth muscle and is prescribed to treat benign prostatic hyperplasia and, rarely, hypertension. The present study investigated the antidepressant-like actions of terazosin (TZ) in mice. They were first subjected to chronic unpredictable mild stress (CUMS) and then the effects of TZ were assessed using the forced swimming test (FST) and tail suspension test (TST), sucrose preference test (SPT), actophotometer test (APT). The changes in the PGK1 levels, neurotransmitters, and proinflammatory cytokines levels after chronic stress and TZ treatment were examined. It was found that TZ exhibited an antidepressant-like effect in the FST, TST, SPT, and APT. It was effective in the CUMS model of depression. It was also found that TZ treatment reduced the levels of proinflammatory cytokines and elevated the neurotransmitter levels in mice. Results of this study suggest that TZ has antidepressant-like actions in mice models of CUMS induced depression.

An Overview of Recent Findings that Shed Light on the Connection between Fat and Cancer.

Obesity and cancer have been found to have a direct link in epidemiological studies. Obesity raises the risk of cancer and associated chronic disorders. Furthermore, an imbalance of adipokines, like leptins, plays a crucial role in neoplasm pathogenesis, cell migration, and thereby, cancer metastasis. Also, leptin increases human epidermal growth factor receptor 2 (HER2) protein levels through the STAT3-mediated (signal transducer and activator of transcription) upregulation of heat shock protein (Hsp90) in breast cancer cells. It has been noticed that insulin and insulin-like growth factors (IGFs) act as mitosis activators in the host and cancerous breast epithelial cells. The condition of hyperinsulinemia explains the positive association between colorectal cancer and obesity. Furthermore, in prostate cancer, an alteration in sex hormone levels, testosterone and dihydrotestosterone, has been reported to occur, along with increased oxidative stress, which is the actual cause of the tumors. Whereas, there have been two interconnected factors that play a crucial role in the psychological cycle concerned with lung cancer. The review article focuses on all the prospects of etiological mechanisms that have found linkage with obesity and breast, colon, lung, and prostate cancers. Furthermore, the article has also highlighted how these new insights into the processes occur and, due to which reasons, obesity contributes to tumorigenesis. This review provides a detailed discussion on the progression, which can assist in the development of new and innovative techniques to interfere in this process, and it has been supported with insights based on evidence literature on approved clinical treatments for obesity and cancer.

Thearubigins/Polymeric black tea polyphenols (PBPs) do not prevent benzo[a]pyrene (B[a]P) induced lung tumors in A/J mice.

OBJECTIVES: Previously we have demonstrated the chemopreventive effect of Thearubigins/Polymeric Black-tea Polyphenols (PBPs) upon pre-treatment to a combination of carcinogens, that is, Benzo[a]pyrene (B[a]P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) which are present in Tobacco smoke (TS). However, the chemopreventive effect in response to B[a]P as a single carcinogen remains unexplored. B[a]P is a universal carcinogen and an important constituent of particulate matter 2.5 (PM2.5) found in the environment and in TS. METHODS: We investigated the pre-treatment of Thearubigins/PBPs as a chemopreventive agent at three doses (1.5, 5, 10%) against B[a]P-induced lung carcinogenesis at early & late time points. We also investigated the effect of PBPs at early time points to understand molecular changes by employing western blotting in xenobiotic metabolism pathways, DNA damage, inflammation, apoptosis, and proliferation as they are modulated in response to carcinogens. We used 6-8 weeks male A/J mice for tumorigenicty and western blotting to probe the molecular biomarkers. RESULTS: We report no decrease in tumor incidence and multiplicity upon pre and concurrent treatment of Thearubigins/PBPs. Further, we also report no changes in molecular markers at early time points, in agreement with former observations. CONCLUSION: Our results suggest that chemopreventive agents need to be tested with different combinations of carcinogens and regimens to fully understand the complex interplay between carcinogenesis and the efficacy of chemopreventive agents. Studies like these will provide meaningful data before initiating large-scale clinical trials.

Acquisition and annotation in high resolution in vivo digital biopsy by confocal microscopy for diagnosis in oral precancer and cancer.

Introduction: Scanned fibre endomicroscopes are full point-scanning confocal microscopes with submicron lateral resolution with an optical slice thickness thin enough to isolate individual cell layers, allow active positioning of the optical slice in the z-axis and collection of megapixel images. Here we present descriptive findings and a brief atlas of an acquisition and annotation protocol high resolution in vivo capture of oral mucosal pathology including oral squamous cell carcinoma and dysplasia using a fluorescence scanned fibre endomicroscope with 3 topical fluorescent imaging agents: fluorescein, acriflavine and PARPi-FL. Methods: Digital biopsy was successfully performed via an acquisition protocol in seventy-one patients presenting for investigation of oral mucosal abnormalities using a miniaturized, handheld scanned fibre endoscope. Multiple imaging agents were utilized and multiple time points sampled. Fifty-nine patients had a matched histopathology correlating in location with imaging. The images were annotated back to macrographic location using a purpose-built software, MouthMap™. Results: Acquisition and annotation of cellular level resolved images was demonstrated with all 3 topical agents. Descriptive observations between clinically or histologically normal oral mucosa showed regular intranuclear distance, a regular nuclear profile and fluorescent homogeneity. This was dependent on the intraoral location and type of epithelium being observed. Key features of malignancy were a loss of intranuclear distance, disordered nuclear clustering and irregular nuclear fluorescence intensity and size. Perinuclear fluorescent granules were seen in the absence of irregular nuclear features in lichenoid inflammation. Discussion: High resolution oral biopsy allows for painless and rapid capture of multiple mucosal sites, resulting in more data points to increase diagnostic precision. High resolution digital micrographs can be easily compared serially across multiple time points utilizing an annotation software. In the present study we have demonstrated realization of a high-resolution digital biopsy protocol of the oral mucosa for utility in the diagnosis of oral cancer and precancer..

Metoclopramide as a Potential Antipsychotic Against Long-Term Methionine Exposure in Zebrafish.

Methionine (MET) contributes to brain function and is required for proper functioning of the central nervous system. However, exceptionally high levels of MET and its metabolites in plasma have been found to be toxic and can lead to cell alterations. Long-term exposure to MET has been shown to mimic psychotic symptoms in schizophrenic patients and rodents. The present study evaluated behavioral and neurochemical effects of long-term exposure to MET in zebrafish. Five groups of zebrafish were exposed to MET at a concentration of 4.5 mM for 7 days, along with acute exposure to 25 µM of clozapine and 750, 1000, and 1250 µM of metoclopramide. In contrast, the normal group was exposed to only water and dimethyl sulfoxide. After the treatment, social interaction, anxiety, memory, and locomotion of zebrafish and serotonin levels in zebrafish brains were evaluated. Our results showed that metoclopramide was not only beneficial in improving MET-induced cognitive impairment but it also prevented social withdrawal in zebrafish exposed to MET. In addition, metoclopramide reversed anxiety-like behavior, as indicated by significant changes in locomotion activity. Despite slight changes in serotonin levels in the zebrafish brain, an in vitro serotonin assay failed to demonstrate significant differences between the disease control, normal, and two treatment groups. Finally, results from the study showed that repeated administration of MET induced schizophrenia-like symptoms, although metoclopramide ameliorated the MET-mediated negative symptoms and cognitive deficits in zebrafish. Overall, our findings suggest a new perspective to further explore the antipsychotic properties of metoclopramide.

Gut-Brain Axis and Neurological Disorders-How Microbiomes Affect our Mental Health.

The gut microbiota is an essential part of the gastrointestinal tract and recent research, including clinical and preclinical studies, shed light on the interaction between the gut and the brain. A rising amount of evidence strongly proves the involvement of gut microbes in brain function and their contribution in altering behavior, mood, and ultimately in the pathogenesis of certain neurological conditions. The gut microbiota produces and modulates neurotransmitters such as GABA, serotonin, dopamine, glutamate, etc. Furthermore, there is a presence of a biological link between the microbiota, immune signaling, and CNS suggesting that microbial metabolites could regulate both neurological and immunological activities in the brain. Thus, this review focuses on the bidirectional communication between the gut and brain, its impact and role in the modulation of various neurological disorders, such as schizophrenia, depression, anxiety, etc., and attempts to explore the underlying mechanism for the same. The article also discusses studies involving germ-free mice, studies on the effects of faeces transfer of microbiota, and research involving gut microbiota composition in animal models. The effects of probiotics and prebiotics on neurological disorders are also discussed, along with the clinical studies for each of them. In a nutshell, extensive studies are required to explore this bidirectional communication between the gut and brain, which might help researchers develop new therapeutic targets in treating neurological disorders and increase our understanding of the gut-brain axis.

Exploring Cytokines as Potential Target in Peptic Ulcer Disease: A Systematic Update.

Peptic ulcer disease (PUD) is a widespread condition that affects millions of people each year, with an incidence rate of 0.1%-1.5%, and has a significant impact on human health. A range of stimuli, such as Helicobacter pylori, non-steroidal anti-inflammatory drugs, hyperacidity, stress, alcohol, smoking, and idiopathic disease states, can produce a sore in the gastrointestinal mucosal layer. For individuals infected with H. pylori, 2%-3% remain asymptomatic throughout their life. Although PUD treatments are available, genetic variations occurring in individuals because of geographical dissimilarity and antibiotic resistance pose limitations. Specifically, inflammatory cytokine gene polymorphisms have received immense attention in recent years because they appear to affect the severity and duration of stomach inflammation, which is induced by H. pylori infection, contributing to the initiation of PUD. In such a context, in-depth knowledge of interleukins may aid in the discovery of new targets and provide precautionary approaches for the treatment of PUD. This review aims to give insights into the importance of several interleukins that cognate with PUD and contribute to ulcer progression or healing by activating or dampening the host immunity. Furthermore, the available targets with clinical evidence have been explored in this review.

Update on Oxytocin, Phosphodiesterase, Neurokinin, Glycine as a Therapeutic Approach in the Treatment of Schizophrenia.

BACKGROUND: Schizophrenia is a chronic psychiatric disorder characterized by disrupted thoughts, perception, mood, and behavior. It has a heterogeneous genetic and neurobiological background and affects about 0.5-1% of the adult population worldwide. Herein, we review the current approaches and advances in schizophrenia. The potential therapeutic compounds for the treatment of schizophrenia act on the oxytocin receptor, phosphodiesterase system, neurokinin receptor, and glycine transport 1 receptor. Therefore, this article provides an update on the pharmacology of different receptors in addition to the dopaminergic system. These findings would guide the readers on novel targets for schizophrenia with the potential to be therapeutic agents in the future. OBJECTIVE: To provide the researchers an update on the emerging role of oxytocin, phosphodiesterase, neurokinin, and glycine which can be explored as potential pharmacotherapeutic targets in the treatment of schizophrenia. METHODS: An extensive literature search was conducted using PubMed, Science Direct, and NCBI with the following keywords: schizophrenia, novel receptors, oxytocin, phosphodiesterase, neurokinin, and glycine. Furthermore, to provide insights into newer drug treatments for Schizophrenia, Furthermore, Clinicaltrials.gov website was searched for newer receptor-based drugs. RESULTS: Current literature supported by preclinical and clinical provides substantial evidence that oxytocin, phosphodiesterase, neurokinin, and glycine play a crucial role in Schizophrenia. CONCLUSION: Our findings indicate that though multiple antipsychotic drugs are prescribed to treat schizophrenia, novel approaches and/or mechanisms are plausible. Moreover, sensitive and specific diagnostic tools and safe and effective interventions, including novel therapeutic agents, are required to yield substantially improved future outcomes.

An Update On Proficiency of Voltage-gated Ion Channel Blockers in the Treatment of Inflammation-associated Diseases.

Inflammation is the body's mechanism to trigger the immune system, thereby preventing bacteria and viruses from manifesting their toxic effect. Inflammation plays a vital role in regulating inflammatory mediator levels to initiate the wound healing process depending on the nature of the stimuli. This process occurs due to chemical release from white blood cells by elevating blood flow to the site of action, leading to redness and increased body temperature. Currently, there are numerous Non-steroidal anti-inflammatory drugs (NSAIDs) available, but these drugs are reported with adverse effects such as gastric bleeding, progressive kidney damage, and increased risk of heart attacks when prolonged use. For such instances, alternative options need to be adopted. The introduction of voltage-gated ion channel blockers can be a substantial alternative to mask the side effects of these currently available drugs. Chronic inflammatory disorders such as rheumatoid and osteoarthritis, cancer and migraine, etc., can cause dreadful pain, which is often debilitating for the patient. The underlying mechanism for both acute and chronic inflammation involves various complex receptors, different types of cells, receptors, and proteins. The working of voltage-gated sodium and calcium channels is closely linked to both inflammatory and neuropathic pain. Certain drugs such as carbamazepine and gabapentin, which are ion channel blockers, have greater pharmacotherapeutic activity for sodium and calcium channel blockers for the treatment of chronic inflammatory pain states. This review intends to provide brief information on the mechanism of action, latest clinical trials, and applications of these blockers in treating inflammatory conditions.

Importance of Exploring N-Methyl-D-Aspartate (NMDA) as a Future Perspective Target in Depression.

Major depressive disorder (MDD) is a serious and complex mental illness. Currently, many antidepressants are available in the market for the treatment of MDD. However, these agents are associated with side effects, which restricts their use. This warrants the development of advanced antidepressive medications with a novel mechanism of action or novel targets and with minimal adverse effects. The traditional neurobiological hypothesis of depression, the monoamine hypothesis, is unable to properly explain all the aspects of depressive conditions. In this review, we discuss novel approaches that could be used for the treatment of depression, including glutamatergic and serotonergic system modulation. The pathogenesis of depression is greatly affected by glutamatergic neurotransmission dysfunction. Previous investigations have shown that ketamine, an N-methyl-D-aspartate receptor antagonist, exerts fast and long-lasting antidepressant effects. Several glutamatergic modulators, such as esketamine, sarcosine, and others, have also shown potential antidepressant action in animal as well as clinical studies. Lastly, drugs that alter neurotransmission by NMDA receptors could open up new avenues for more effective treatment of depression. Besides, understanding the underlying mechanisms will aid in the development of novel and fast-acting antidepressant drugs in the future.

Assessment of a decision making protocol to improve the efficacy of VELscope™ in general dental practice: a prospective evaluation.

BACKGROUND: VELscope™ is a device designed to help detect potentially malignant disorders of the oral mucosa at an early stage using direct tissue autofluorescence. Previous research indicates a high rate of false positives using this device. This study assesses a decision making protocol for the detection of oral mucosal lesions using conventional oral examination and VELscope™ in a general dental practice setting. MATERIALS AND METHODS: 305 patients presenting for general dental treatment were screened by a general dental practitioner (GDP) for oral mucosal lesions using incandescent light (conventional oral examination - COE), followed by VELscope™ and then by correlating the findings from these two examinations. A decision making protocol was followed. Patients were either reviewed or referred to an Oral Medicine specialist (OMS) for consultation, and biopsy was undertaken as required for definitive diagnosis. RESULTS: 146 patients presented with at least one oral mucosal lesion, and a total of 222 lesions were detected. COE detected 161 oral mucosal lesions and an additional 61 lesions were detected with VELscope™. COE alone showed a sensitivity of 44.0% and specificity of 99.0% while VELscope™ alone showed a sensitivity of 64.0% and specificity of 54.3%. Using the decision making protocol, the sensitivity and specificity were 73.9% and 97.9% respectively. CONCLUSION: Using the decision making protocol proposed in this study allows for the detection of additional oral mucosal lesions requiring specialist referral by incorporating VELscope™ into routine general dental practice, without compromising patient care.

Advances in optical adjunctive AIDS for visualisation and detection of oral malignant and potentially malignant lesions.

Traditional methods of screening for oral potentially malignant disorders and oral malignancies involve a conventional oral examination with digital palpation. Evidence indicates that conventional examination is a poor discriminator of oral mucosal lesions. A number of optical aids have been developed to assist the clinician to detect oral mucosal abnormalities and to differentiate benign lesions from sinister pathology. This paper discusses advances in optical technologies designed for the detection of oral mucosal abnormalities. The literature regarding such devices, VELscope and Identafi, is critically analysed, and the novel use of Narrow Band Imaging within the oral cavity is also discussed. Optical aids are effective in assisting with the detection of oral mucosal abnormalities; however, further research is required to evaluate the usefulness of these devices in differentiating benign lesions from potentially malignant and malignant lesions.