Molecular basis of phytochemical-gut microbiota interactions.

Dysbiosis-associated molecular pathology is significantly involved in developing and perpetuating metabolic disorders, disrupting host energy regulation, and triggering inflammatory signaling cascades, insulin resistance, and metabolic dysfunction. Concurrently, numerous phytoconstituents are able to interact with the gut microbiota and produce bioactive metabolites that influence host cellular pathways, inflammation, and metabolic processes. These effects include improved insulin sensitivity, lipid metabolism regulation, and suppression of chronic inflammation, highlighting the therapeutic potential of phytoconstituents against metabolic abnormalities. Understanding this symbiotic relationship and the underlying molecular cascades offers innovative strategies for tailored interventions and promising therapeutic approaches to address the growing burden of metabolic disease.

Dysbiosis versus diabesity: Pathological signaling and promising therapeutic strategies.

A healthy life depends on the inseparable relationship between a host and the gut microbiota. A healthy gut microbiota regulates intestinal integrity, whereas an unbalanced gut microbiota contributes to junctional remodeling and leads to dysbiosis. Bacterial infiltration and dysbiosis are reported to activate a series of pathological cascades that trigger metabolic abnormalities, including diabesity. Conversely, recent studies revealed that the incidence of dysbiosis itself is fuelled by diabesity. In this review, we highlight the molecular aspects of multifaceted pathological signaling between dysbiosis and diabetes that could pave the way for new drug discovery. Moreover, to reinstate the gut microbiota and restrict the epidemic of dysbiosis and diabesity, we also scrutinize a promising therapeutic strategy that can challenge the pathological interlink.

2,3-Diarylindoles as COX-2 Inhibitors: Exploring the Structure-activity Relationship through Molecular Docking Simulations.

BACKGROUND: Arylindole derivatives are promising scaffolds in the design of new drugs. These scaffolds exhibit a wide biological activity, including inhibition of COX-2, antitumor activity, receptor GABA agonism, and estrogen receptor modulation. OBJECTIVES: Taking this into account, this paper presents a study to understand the inhibitory action of certain 2-arylindole derivatives, specifically a series of 2,3-diarylindoles with IC50 values from 0.006 nM to 100 nM, on the COX-2 enzyme and supports its structural-activity relationship (SAR) through molecular docking simulations. METHODS: Applying molecular modelling, especially molecular docking, we assessed the SAR of a series of 2,3-arylindoles derivatives in the COX-2 enzyme. RESULTS: The results indicated that Gly 526 and Phe 381 residues are relevant for improving inhibitory activity on para-substituted 3-phenyl- compounds. Arg 120 was also demonstrated to be an important residue for COX-2 inhibition since it enables a π-cation interaction with the best compound in series A5 (experimental IC50 = 0.006 nM determined in advance). Furthermore, COX-2 presents flexibility in some regions of the active site to adequately accommodate 5-substituted compounds containing an indole ring. CONCLUSION: Therefore, such structural features can be used as support for further Structural-Based Drug Design (SBDD) and/or Ligand-Based Drug Design (LBDD) studies on new selective COX-2 inhibitors.

Efficacy of Cannabis and its Constituents in Disease Management: Insights from Clinical Studies.

There is a long history of informal use of Cannabis sativa (commonly called cannabis) for many purposes, including treating various ailments worldwide. However, the legalization of cannabis in multiple countries, specifically for medical purposes, has grabbed the researchers' attention to discover the scientific evidence regarding cannabis's beneficial effects. Among over 500 identified compounds (cannabinoids), Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two major active cannabinoids derived from cannabis. Cannabinoids exert their effects through cannabinoid receptors (CB1R and CB2R). In the recent past, clinical trials have shown the efficacy of cannabis and cannabinoids for various human ailments, such as cancer, neurological disorders, inflammatory bowel disease, chronic pain, and metabolic disorders. The commonly used constituents and derivatives of cannabis include CBD, THC, THCV, dronabinol, nabilone, and nabiximol. The cannabis constituents have also been used in combination with other agents, such as megestrol acetate, in some clinical trials. The common routes for the administration of cannabis are oral, sublingual, or topical. Cannabis has also been consumed through smoking, inhalation, or with food and tea. A maximum of 572 patients and a minimum of nine patients have participated in a single clinical trial. Cannabis is legalized in some countries with restrictions, such as Belize, Canada, Colombia, Costa Rica, The Czech Republic, Jamaica, Netherlands, South Africa, Spain, and Uruguay. This article provides a compilation of published studies focusing on clinal trials on the therapeutic effects of cannabis. The adverse effects of cannabis and its constituents are also discussed.

Cannabis and its constituents for cancer: History, biogenesis, chemistry and pharmacological activities.

Cannabis has long been used for healing and recreation in several regions of the world. Over 400 bioactive constituents, including more than 100 phytocannabinoids, have been isolated from this plant. The non-psychoactive cannabidiol (CBD) and the psychoactive Δ9-tetrahydrocannabinol (Δ9-THC) are the major and widely studied constituents from this plant. Cannabinoids exert their effects through the endocannabinoid system (ECS) that comprises cannabinoid receptors (CB1, CB2), endogenous ligands, and metabolizing enzymes. Several preclinical studies have demonstrated the potential of cannabinoids against leukemia, lymphoma, glioblastoma, and cancers of the breast, colorectum, pancreas, cervix and prostate. Cannabis and its constituents can modulate multiple cancer related pathways such as PKB, AMPK, CAMKK-ß, mTOR, PDHK, HIF-1α, and PPAR-γ. Cannabinoids can block cell growth, progression of cell cycle and induce apoptosis selectively in tumour cells. Cannabinoids can also enhance the efficacy of cancer therapeutics. These compounds have been used for the management of anorexia, queasiness, and pain in cancer patients. Cannabinoid based products such as dronabinol, nabilone, nabiximols, and epidyolex are now approved for medical use in cancer patients. Cannabinoids are reported to produce a favourable safety profile. However, psychoactive properties and poor bioavailability limit the use of some cannabinoids. The Academic Institutions across the globe are offering training courses on cannabis. How cannabis and its constituents exert anticancer activities is discussed in this article. We also discuss areas that require attention and more extensive research.

A therapeutic update on PARP inhibitors: implications in the treatment of glioma.

Central nervous system (CNS) cancers are among the most aggressive and devastating. Further, due to unavailability of neuro-oncologists and neurosurgeons, the specialized treatment options of CNS cancers are still not completely available in most parts of the world. Among various strategies of inducing death in cancer cells, inhibition of poly(ADP-ribose) polymerase (PARP) has emerged as a beneficial therapy when combined with other anticancer agents. In this review, we provide a detailed therapeutic update of PARP inhibitors that have shown clinical activity against glioma.

Aromatic amides and ureas as novel molecular probes for diagnosing disease.

It is firmly established that control over the three-dimensional shape (i.e., the conformation) of aromatic amides and ureas can be achieved using a variety of methods, all of which rely on the addition of a substituent to a central nitrogen atom; exactly which conformation is adopted in solution can be determined using a variety of analytical techniques, such as: fluorescence, NMR and HPLC. We hypothesise that if the central nitrogen atoms were suitably functionalised with enzyme-cleavable groups, then the associated change in shape could be exploited upon the removal of a group, and these compounds could thus be exploited as diagnostic probes for the detection of analytes (i.e., enzymes) in solution or biological samples. The exquisite selectivity of naturally-occurring enzymes therefore makes it possible that the enzyme-cleavable group could be rationally designed and tailored for each enzyme of interest, thus making an analytical toolkit of diagnostic probes for detecting enzymes which are over-expressed in disease. If the sensitivity of such probes was sufficiently low enough, then they could potentially be used to detect the on-set of disease in a non-invasive manner from bodily fluids.