Release of GLP-1 and PYY in response to the activation of G protein-coupled bile acid receptor TGR5 is mediated by Epac/PLC-ε pathway and modulated by endogenous H2S

Activation of plasma membrane TGR5 receptors in enteroendocrine cells by bile acids is known to regulate gastrointestinal secretion and motility and glucose homeostasis. The endocrine functions of the gut are modulated by microenvironment of the distal gut predominantly by sulfur-containing bacteria of the microbiota that produce H2S. However, the mechanisms involved in the release of peptide hormones, GLP-1 and PYY in response to TGR5 activation by bile acids and the effect of H2S on bile acid-induced release of GLP-1 and PYY are unclear. In the present study, we have identified the signaling pathways activated by the bile acid receptor TGR5 to mediate GLP-1 and PYY release and the mechanism of inhibition of their release by H2S in enteroendocrine cells. The TGR5 ligand oleanolic acid (OA) stimulated Gs and cAMP formation, and caused GLP-1 and PYY release. OA-induced cAMP formation and peptide release were blocked by TGR5 siRNA. OA also caused an increase in PI hydrolysis and intracellular Ca2+. Increase in PI hydrolysis was abolished in cells transfected with PLC-ε siRNA. 8-pCPT-2’-O-Me-cAMP, a selective activator of Epac, stimulated PI hydrolysis, and GLP-1 and PYY release. L-Cysteine, which activates endogenous H2S producing enzymes cystathionine--lyase and cystathionine--synthase, and NaHS and GYY4137, which generate H2S, inhibited PI hydrolysis and GLP-1 and PYY release in response to OA or 8-pCPT-2’-O-Me-cAMP. Propargylglycine, an inhibitor of CSE, reversed the effect of L-cysteine on PI hydrolysis and GLP-1 and PYY release. We conclude: i) activation of Gs-coupled TGR5 receptors causes stimulation of PI hydrolysis, and release of GLP-1 and PYY via a PKA-independent, cAMP-dependent mechanism involving Epac/PLC-/Ca2+ pathway, and ii) H2S has potent inhibitory effects on GLP-1 and PYY release in response to TGR5 activation, and the mechanism involves inhibition of PLC-/Ca2+ pathway

Neuroinflammation—the role of heteroreceptor complexes

Neuroinflammation is a hallmark of various neurodegenerative and neuropsychiatric disorders, driven by complex interactions between neurotransmitter receptors and immune signaling pathways. Among these, heteroreceptor complexes—functional assemblies formed by the physical interaction of different G protein-coupled or ionotropic receptor subtypes within the same membrane microdomain—play a crucial role in modulating synaptic activity, neuroimmune responses, and inflammatory cascades. For example, the A2A-D2 receptor complex modulates dopaminergic signaling in the striatum and has been implicated in Parkinson’s disease pathology. These receptor-receptor interactions influence key signaling pathways involving dopamine, serotonin, glutamate, adenosine, and cannabinoid systems, thereby contributing to the pathophysiology of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, schizophrenia, and depression. Dysregulation of heteroreceptor complexes disrupts neuronal homeostasis, exacerbates neuroinflammatory responses, and influences microglial and astrocytic activation. Understanding the molecular mechanisms governing these interactions, including allosteric modulation and biased agonism, offers novel therapeutic avenues for targeting neuroinflammation. Pharmacological strategies, such as selective allosteric modulators, biased agonists, and receptor-specific ligands, aim to restore heteroreceptor function and mitigate neuroinflammatory damage. Emerging clinical trials—such as those evaluating A2A receptor antagonists like istradefylline for Parkinson’s disease and 5-HT2A antagonists for schizophrenia—have shown promising neuroprotective and anti-inflammatory effects, although larger-scale, long-term studies are needed to confirm efficacy. This review highlights the pivotal role of heteroreceptor complexes in neuroinflammation, discusses their therapeutic potential, and underscores the need for further research into their functional dynamics to develop effective interventions for neurodegenerative and neuropsychiatric diseases

Guardians of giants: a bibliometric analysis of mahout-elephant relationships and management takeaways for the Nilgiris

The study presents a systematic bibliometric review of mahout-elephant relations and management with specific applications for the Nilgiris region. Asian elephants face significant survival threats including habitat loss and captivity-based exploitation, with approximately 15,000 individuals in captivity across their range countries. Effective conservation strategies require a deep understanding of captive elephant management and welfare issues. Through a systematic review of 63 peer-reviewed articles from 2014-2024, spanning disciplines including animal welfare science, conservation biology, and veterinary medicine, this study identifies critical trends and knowledge gaps. Bibliometric analysis revealed two distinct research clusters with minimal overlap: elephant welfare/management studies and computational approaches. Thailand, particularly Chiang Mai University, emerged as a key research hub with strong international collaborations. Research output has increased significantly since 2016, with a notable acceleration around 2020. Thematic analysis identified concerning shifts in mahout demographics, with younger, less experienced individuals replacing traditional mahouts, compromising vital knowledge transmission. Tourism significantly impacts elephant welfare, with 82% of surveyed Thai camps chaining elephants for extended periods. Health concerns include tuberculosis, with seroprevalence reaching 36% in some populations. Research gaps include limited studies on long-term training effects, elephant psychology, rewilding outcomes, and technological applications in welfare assessment. This review highlights the need for interdisciplinary approaches targeting both elephant and human welfare, emphasizing collaborative efforts among mahouts, local communities, researchers, and conservation agencies to ensure sustainable Asian elephant conservation. The findings and recommendations provide a framework for evidence-based management strategies at the Theppakadu Elephant Camp in the Nilgiris and other similar facilities

Pilot Randomized Clinical Trial of a Passive Non-invasive Positive End-Expiratory Pressure (PEEP) Device for Delivering Positive Pressure Therapy Compared to Standard Care in Non-critically Ill Patients With COVID-19

BACKGROUND: During the COVID-19 pandemic, there were reports of a shortage of ventilators and oxygen supply, particularly in resource-limited settings. We report the preliminary evaluation of a non-invasive positive end-expiratory pressure (PEEP) mask in hospitalized non-critically ill patients with COVID-19. METHODS: We randomly assigned hospitalized adult patients with confirmed COVID-19 infection and requiring greater than 40% supplemental oxygen to either standard care oxygen delivery (control) or via Materialise passive non-invasive PEEP device mask (intervention; Belgium). The primary outcome was a change in mean respiratory rate from baseline over the first three hours after the commencement of the intervention. Secondary outcomes included dyspnea score, need for escalation of respiratory or cardiovascular support, days alive and free of ICU, and day-28 mortality. RESULTS: Between April 30, 2021, and October 10, 2021, we enrolled 132 (65 control, 67 intervention) patients in the study. The mean respiratory rates at baseline were 23 ± 3 and 23 ± 3 in the control and intervention groups, with no significant differences at three hours (23 ± 2.3 vs. 23 ± 2.1, p=0.14). The control group had a higher mean dyspnea score compared to the intervention group (day 5: 5.4 ± 1.6 vs. 4.7 ± 1.4, p=0.015; day 6: 4.7 ± 1.7 vs. 4.0 ± 0.7, p=0.008). A higher proportion of patients in the control group required escalation of respiratory support (38%), as compared to intervention (12%) (p=0.0004). The two groups had no significant differences across other secondary outcomes or with respect to adverse events (barotrauma, aspiration pneumonia, need for vasopressor support). CONCLUSIONS: The use of the novel mask compared to standard care in hospitalized non-critically ill patients with COVID-19 was not associated with reductions in the respiratory rate but was associated with a reduction in the need for escalation of respiratory support without an increase in adverse effects. Large-scale clinical trials of this device are warranted

Modulatory Action of Voltage Gated Ion Channels in Inflammation and Inflammatory Pain

Pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described by the patient in terms of such damage”. The origin of every pain syndrome is inflammation. A group of voltage-gated channels that are permeable to calcium ions enhances sensory transduction witnessed during inflammation. Hence, understanding calcium signaling is an essential step towards recognizing neural network activity associated with pain management. In this review, we attempted to understand the impact of calcium-permeable ion channels in the recognition, processing, transduction and modulation of pain signals. Results obtained revealed that calcium being one of the most ubiquitous secondary messengers play a significant role in modulating numerous biological processes, including inflammation and pain. Though almost all subtypes of calcium channels are highly expressed in the central nervous system (CNS), the “N-type calcium ion-channels” play an important function at the time of neurotransmitter release from the afferent terminals within the spinal dorsal. Hence, they serve as a key therapeutic target during the treatment of analgesics. Migraine is also reported to involve neurogenic inflammation. “P/Q-type calcium channels” is suggested to have important role in migraine. The inhibition of these channels through various analgesics serves as a treatment against inflammatory and neuropathic pain. However, few of these inhibitors have numerous side effects, including cancer. Hence, these inhibitors may be consumed under the supervision of medical practitioners. In this review, we revealed the understanding and regulation of ion channels in inflammation causing pain and its treatment.</jats:p

Silk Fibroin: A Promising Tool for Wound Healing and Skin Regeneration

Silk is a functional protein biomaterial produced by a variety of insects like flies, silkworms, scorpions, spiders, and mites. Silk synthesized by silkworms is extensively studied for its applications in tissue engineering and wound healing. Silk is undoubtedly a natural biocompatible material with humans and has its role in medical treatments from ancient times. The silk worm protein comprises two types of proteins namely fibroin and sericin. Silk fibroin makes up approximately 70% of cocoon weight and has wide applications in textiles and in all biomedical applications owing to its biocompatible, nontoxic, biodegradable, less immunogenic, and noncarcinogenic nature. It possesses outstanding toughness and mechanical strength, while silk sericin possesses high defensive ability against ultraviolet light and oxidation. Silk fibroin has been known to induce wound healing by increasing cell proliferation and growth and migrating various types of cells which are involved in different stages of wound healing process. With several silk varieties like silk worm fibroin, silk sericin, recombinant silk materials, and native spider silk have been investigated for its wound healing applications over the last several decades. With an objective of harnessing the silk regenerative properties, plentiful strategies have been studied and applied to develop bioartificial skin grafts and bioactive wound dressings in recent times. This review gives a detailed insight into the structure, general properties, fibroin structure-properties relationship, and biomedical applications of silk fibroin