Search Results (691)

Nephrogenic diabetes insipidus (NDI) is a rare hereditary disorder characterized by renal resistance to arginine vasopressin (AVP), resulting in the kidneys’ inability to concentrate urine. Approximately 90% of NDI cases follow an X-linked inheritance pattern and are associated with pathogenic variants in the AVPR2 gene, which encodes the vasopressin receptor type 2. The remaining 10% are attributed to mutations in the AQP2 gene, which encodes aquaporin-2, and may follow either autosomal dominant or recessive inheritance patterns. We present the case of a male infant, younger than nine months of age, who was clinically diagnosed with NDI at six months. The patient presented recurrent episodes of polydipsia, polyuria, dehydration, hypernatremia, and persistently low urine osmolality. Despite adjustments in pharmacologic treatment and strict monitoring of urinary output, the clinical response remained suboptimal. Given the lack of improvement and the radiological finding of an absent posterior pituitary (neurohypophysis), the possibility of coexistent central diabetes insipidus (CDI) was raised, prompting a therapeutic trial with desmopressin. Nevertheless, in the absence of clinical improvement, desmopressin was discontinued. The patient’s management was continued with hydrochlorothiazide, ibuprofen, and a high-calorie diet restricted in sodium and protein, resulting in progressive clinical stabilization. Whole-exome sequencing identified a novel homozygous missense variant in the AQP2 gene (c.398T > A; p.Val133Glu), classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria: PM2 (absent from population databases), PP2 (missense variant in a gene with a low rate of benign missense variation), and PP3 (multiple lines of computational evidence supporting a deleterious effect)]. NDI is typically diagnosed during early infancy due to the early onset of symptoms and the potential for severe complications if left untreated. In this case, although initial clinical suspicion included concomitant CDI, the timely initiation of supportive management and the subsequent incorporation of molecular diagnostics facilitated a definitive diagnosis. The identification of a previously unreported homozygous variant in AQP2 contributed to diagnostic confirmation and therapeutic decision-making. The diagnosis and comprehensive management of NDI within the context of polyuria-polydipsia syndrome necessitates a multidisciplinary approach, integrating clinical evaluation with advanced molecular diagnostics. The novel AQP2 c.398T > A (p.Val133Glu) variant described herein was associated with early and severe clinical manifestations, underscoring the importance of genetic testing in atypical or treatment-refractory presentations of diabetes insipidus. Full article

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic condition characterized by hepatic lipid deposits, insulin resistance, and inflammation which may progress to non-alcoholic steatohepatitis (NASH) and fibrosis. Protein kinases play an important role in NAFLD development by regulating metabolic and inflammatory pathways. Mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), AMP-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K)/AKT, and mechanistic target of rapamycin (mTOR) are all involved in NAFLD and NASH progression. Emerging evidence indicates that Farnesoid X Receptor (FXR) agonists have therapeutic potential by modulating bile acid metabolism, lipid balance, and inflammatory responses. This review examines the mechanistic interplay between FXR agonists and important protein kinases in NAFLD and NASH. FXR agonists activate AMPK, which promotes fatty acid oxidation and reduces hepatic steatosis. They also regulate MAPK signaling, which reduces c-Jun NH2-terminal kinase (JNK)- and p38 MAPK-mediated inflammation. Furthermore, FXR agonists activate the PI3K/AKT pathway, enhancing insulin sensitivity and modulating mTOR signaling to reduce hepatic fibrosis. Clinical studies in NAFLD/NASH indicate that FXR agonists confer metabolic and anti-inflammatory benefits, although optimizing efficacy and minimizing adverse effects remain challenging. Future studies should focus on combination therapies targeting FXR alongside specific kinases to improve therapeutic outcomes. This review highlights the potential of FXR agonists to modulate protein kinase signaling, opening new avenues for targeted NAFLD/NASH therapy. Full article

Next to adrenergic signalling, purinergic pathways mediated by extracellular adenine nucleotides have been described to shape thermogenic and metabolic functions in brown adipose tissue (BAT). Here we describe high expression of P2X5 that is activated by ATP in mature adipocytes of BAT and differentiated brown adipocytes in vitro. The levels of other P2X family members were much lower, or expression was restricted to tissue-resident macrophages or endothelial cells. Global and brown adipocyte-specific P2rx5 deficiency resulted in lower expression of the uncoupling protein 1 (UCP1). However, indirect calorimetry studies showed that P2X5 did not affect systemic energy expenditure. Of note, glucose tolerance was impaired under chow and obesogenic high-fat diet conditions, which can be explained by lower glucose disposal into BAT but not into other organs. In summary, these data indicate a modulatory role of P2X5 in systemic and BAT-specific glucose metabolism. Full article

Purinergic P2X receptors have a wide distribution within the body and modulate a number of physiological processes, being also involved in the development and progression of inflammation-, neuroinflammation-, neurodegeneration-, and cancer-related diseases. Radioligands that can detect specific P2X receptor subtypes and reveal their level of expression are of key importance for the development of novel P2X modulators, for the depiction of the involvement of these proteins in physio-pathological processes, and for the availability of novel diagnostic tools to be used for imaging experiments in vivo. Here we review and summarise the various P2X-targeting radioligands developed and reported to date, ranging from analogues of the endogenous P2X agonist ATP to the more recent and P2X subtype-selective allosteric modulators. Many of the high-affinity radioligands described are only suitable as in vitro receptor probes. No viable P2X3 or P2X4 radioligands for in vivo positron emission tomography (PET) imaging have been developed and reported to date. However, P2X7 antagonists, such as [¹¹C]SMW139, [¹¹C]GSK1482160, [¹¹C]JNJ-54173717, and [¹⁸F]JNJ-64413739, have been successfully applied to PET imaging in the brain. Full article

This retrospective cohort study investigated the effects of statin use on 5-year clinical outcomes, particularly all-cause mortality, in patients with breast cancer. Clinical data of 971,808 patients who received a diagnosis of breast cancer between 2010 and 2020 were collected from the TriNetX platform. Eligible patients were classified as statin users (98,761) or nonusers (691,644). Statin use was defined by a prescription of statins being given within 3 years after breast cancer diagnosis. All-cause mortality and cardiovascular incidence were evaluated from Aalen–Johansen cumulative incidence curves. After 1:1 propensity score matching, all-cause mortality outcomes were analyzed in terms of hazard ratios and risk ratios. Our studies revealed that the risk of all-cause mortality was lower in statin users than in nonusers (hazard ratio: 0.798; risk ratio: 0.721; p < 0.001). Subgroup analysis revealed that the protective effect of statins against all-cause mortality was more pronounced in older patients; those with a higher body mass index; and those with higher cholesterol, triglyceride, or low-density lipoprotein levels. The effects were prominent also in patients with estrogen receptor-negative or progesterone receptor-negative tumors. Statin use was associated with improved survival in patients with breast cancer, particularly older patients, those with hormone receptor-negative tumors, and those with metabolic dysregulation. Our findings indicate a possible link between statin use and reduced mortality in breast cancer patients, warranting further investigation in prospective controlled studies. Full article

Background/Objectives: Chronic inflammation and inappropriate NLRP3 inflammasome regulation are related to many brain diseases. Purinergic mediators may play an important role in inflammation regulation and could be targeted for effective therapies for these illnesses. We evaluated resveratrol’s anti-neuroinflammatory potential in BV-2 microglia cells using an innovative in vitro method of NLRP3 inflammasome activation, correlating with the P2X7 purinergic receptor. Methods: In silico analyses were used to estimate resveratrol’s interaction with NLRP3, and its cytotoxicity was measured for 24, 48, and 72 h. Moreover, microglia were exposed to lipopolysaccharide and nigericin to activate the NLRP3 inflammasome and treated with resveratrol between these inflammatory agents. Results: It was found that resveratrol has binding compatible with modulating NLRP3. Specifically, 0.1–25 µM of resveratrol presented a favorable safety profile in BV-2 cells. Microglia exposed to the inflammatory agents had increased levels of oxidative species, the P2X7 receptor, and pro-inflammatory cytokines. However, resveratrol decreased the NLRP3, caspase-1, IL-1β, IL-6, and TNF-α mRNA levels and protein density; on the other hand, IL-10 was increased, acting as a protector, preventing exacerbated inflammation. Under resveratrol exposure, P2X7 was negatively expressed, regulating inflammation to establish homeostasis and microglial proliferation. Additionally, resveratrol activates the A1 adenosine receptor, possibly correlated with neuroprotective effects. Conclusions: We confirmed the anti-neuroinflammatory action of resveratrol via the P2X7 receptor and NLRP3’s combined modulation, regulating the cell cycle and reducing pro-inflammatory and oxidant agents. Considering this pathway, resveratrol could be a candidate for further investigations as a potential treatment against neuroinflammatory diseases. Full article

Neurosteroids pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone have been actively studied in the last years as candidates for the treatment of neurodegenerative diseases and postinjury rehabilitation. The neuroprotective mechanisms of these neurosteroids have been shown in clinical studies of depression, epilepsy, status epilepticus, traumatic brain injury, fragile X syndrome, and chemical neurotoxicity. However, only the allopregnanolone analogs brexanolone and zuranolone have been recently approved by the FDA for the treatment of depression. The aim of this review was to evaluate whether the endogenous neurosteroids can be used in clinical practice as neuroprotectors. Neurosteroids are multitarget compounds with strong anti-inflammatory, immunomodulatory, and cytoprotective action; they stimulate the synthesis and release of BDNF and increase remyelination and regeneration. In addition to nuclear and membrane steroid hormone receptors, such as PR, mPR, PGRMC1,2, ER, AR, CAR, and PXR, they can bind to GABAA receptors, NMDA receptors, Sigma-1 and -2 receptors (σ1-R/σ2-R). Among these, mPRs, PGRMC1,2, sigma receptors, and mitochondrial proteins attract comprehensive attention because of strong binding with the P4 and DHEA, but subsequent signaling is poorly studied. Other plasma membrane and mitochondrial proteins are involved in the rapid nongenomic neuroprotective action of neurosteroids. P-glycoprotein, BCL-2 proteins, and the components of the mitochondrial permeability transition pore (mPTP) play a significant role in the defense against the injuries of the brain and the peripheral nervous system. The role of these proteins in the molecular mechanisms of action in neuroprotection and neuroinflammation has not yet been clearly established. The aspects of their participation in these pathological processes are discussed. New formulations, such as lipophilic emulsions, nanogels, and microneedle array patches, are attractive strategies to overcome the low bioavailability of these neurosteroids for the amelioration and treatment of various nervous disorders. Full article

Chronic pain affects a significant portion of the population, with fewer than 30% achieving adequate relief from existing treatments. This study describes the humanization methodology and characterization of an effective non-opioid single-chain fragment variable (scFv) biologic that reverses pain-related behaviors, in this case by targeting P2X4. After nerve injury, ATP release activates/upregulates P2X4 receptors (P2X4R) sequestered in late endosomes, triggering a cascade of chronic pain-related events. Nine humanized scFv (hscFv) variants targeting a specific extracellular 13-amino-acid peptide fragment of human P2X4R were generated via CDR grafting. ELISA analysis revealed nanomolar binding affinities, with most humanized molecules exhibiting comparable or superior affinity compared to the original murine antibody. Octet measurements confirmed that the lead, HC3-LC3, exhibited nanomolar binding kinetics (KD = 2.5 × 10⁻⁹ M). In vivo functional validation with P2X4R hscFv reversed nerve injury-induced chronic pain-related behaviors with a single dose (0.4 mg/kg, intraperitoneal) within two weeks. The return to naïve baseline remained durably reduced > 100 days. In independent confirmation, the spared nerve injury (SNI) model was similarly reduced. This constitutes an original method whereby durable reversals of chronic nerve injury pain, anxiety and depression measures are accomplished. Full article

Cellular therapeutics, encompassing stem cell-based regeneration and engineered immune cell platforms, have demonstrated efficacy in treating degenerative diseases, immune-related diseases, and oncology. However, low engraftment rates and limited long-term efficacy remain critical translational barriers. This review compiled clinical projects on cell therapy in China over the past five years (over 1200 patients across 172 clinical trials) to highlight its rapid development in recent years and illustrate the directions of indications for application. This review also analyzes published clinical achievements all over the world, revealing significant therapeutic improvements in degenerative disorders (40–60% improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and oncology (78% ctDNA clearance, p < 0.001)). We propose integrating traditional Chinese medicine (TCM) bioactive compounds to enhance cell viability via C-X-C motif chemokine receptor (CXCR4) upregulation and mitochondrial biogenesis. Despite mechanistic insights, translational barriers include limited TCM validation (72% lacking single-cell omics) and regulatory misalignment. Future efforts should prioritize randomized trials and standardized TCM-cell therapy protocols to bridge discovery and clinical translation. Full article

Objective:Burning mouth syndrome (BMS) is a chronic, intractable orofacial pain condition characterized by a burning sensation in the oral mucosa without discernible lesions. The syndrome predominantly affects menopausal and postmenopausal women and is considered a form of nociplastic pain, where the processing of pain stimuli is altered. Given the significant sex disparity, it is crucial to consider underlying neurobiological differences that may inform treatment. This review explores potential pharmacological targets by examining the pathological mechanisms of BMS. Method of Research: A narrative review approach was utilized to systematically explore and synthesize literature regarding the pathophysiology of BMS and to identify receptors implicated in the enhancement of sensory transmission and the altered processing of pain stimuli. Results: The mechanism of enhanced sensory transmission points to receptors such as TRPV1, P2X3, and CB2 as potential targets. However, considering the nociplastic nature of BMS and its prevalence in women, mechanisms involving altered central pain processing are paramount. Research indicates significant sex differences in glutamate transmission and plasticity within reward-related brain regions. This suggests that the N-methyl-D-aspartate (NMDA) receptor, a cornerstone of glutamate signaling and synaptic plasticity, is a primary therapeutic target. Furthermore, the altered processing of pain and reward, which is a key feature of chronic pain, implicates the brain’s dopaminergic system. A decrease in dopamine D2 receptor function within this system is believed to contribute to the pathology of BMS. Estrogen receptors are also considered relevant due to the menopausal onset. Conclusions: Based on the evidence, the most promising targets for pharmacotherapy in BMS are likely the NMDA receptor and the dopamine D2 receptor. The high prevalence of BMS in women, coupled with known sex differences in the glutamate and dopamine pathways of the reward system, provides a strong rationale for this focus. Effective treatment strategies should therefore aim to modulate these specific systems, directly or indirectly controlling NMDE receptor hyperactivity and addressing the decreased D2 receptor function. Further research into therapies that specifically target this sex-linked neurobiology is essential for developing effective pharmacotherapy for BMS. Full article

Anesthesia is a cornerstone of modern medicine, enabling surgery, pain management, and critical care. Despite its widespread use, the precise molecular mechanisms of anesthetic action remain incompletely understood. Recent advancements in structural biology, including cryo-electron microscopy (Cryo-EM), X-ray crystallography, and computational modeling, have provided high-resolution insights into anesthetic–target interactions. This review examines key molecular targets, including GABA_A receptors, NMDA receptors, two-pore-domain potassium (K2P) channels (e.g., TREK-1), and voltage-gated sodium (Nav) channels. General anesthetics modulate GABA_A and NMDA receptors, affecting inhibitory and excitatory neurotransmission, while local anesthetics primarily block Nav channels, preventing action potential propagation. Structural studies have elucidated anesthetic binding sites and gating mechanisms, providing a foundation for drug optimization. Advances in computational drug design and AI-assisted modeling have accelerated the development of safer, more selective anesthetics, paving the way for precision anesthesia. Future research aims to develop receptor-subtype-specific anesthetics, Nav1.7-selective local anesthetics, and investigate the neural mechanisms of anesthesia-induced unconsciousness and postoperative cognitive dysfunction (POCD). By integrating structural biology, AI-driven drug discovery, and neuroscience, anesthesia research is evolving toward safer, more effective, and personalized strategies, enhancing clinical outcomes and patient safety. Full article

Background/Objectives: Neurofibromatosis type 1 (NF1) is a prevalent inherited disorder, with approximately 50% of affected individuals developing plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). While selumetinib is FDA-approved for PNFs, its efficacy in MPNSTs is limited and associated with dose-limiting toxicities. NF1 deficiency drives tumorigenesis and alters immune dynamics via RAS hyperactivation. Given the substantial macrophage infiltration in NF1 lesions and its association with disease progression, we hypothesized that targeting tumor-promoting immune cells with the retinoid X receptor (RXR) agonist MSU-42011 could be an alternative therapeutic strategy, as it has shown promise in KRAS-driven cancers by decreasing pERK levels and reducing tumor-promoting immune cells. Methods: We examined the effects of MSU-42011 and selumetinib, alone and in combination, on NF1-deficient cells and in a syngeneic MPNST model. Results: In vivo, the combination of MSU-42011 and selumetinib significantly reduced tumor growth, pERK levels, and tumor-promoting macrophages and increased activated CD8⁺ T cells in syngeneic MPNST models. In NF1-deficient cells, MSU-42011 or selumetinib reduced pERK levels, with combination treatment achieving greater reductions. Conditioned media (CM) from NF1-deficient cells increased the protein and mRNA levels of several cytokines and chemokines in human THP1 cells and bone marrow-derived macrophages (BMDMs). MSU-42011 and selumetinib, alone or in combination, partially reversed this induction. Conclusions: These findings suggest RXR agonists may have therapeutic potential against NF1, and their combination with MEK inhibitors could represent a promising strategy for NF1-associated tumors. Further studies are needed to validate these results and assess their translational relevance. Full article

The homotrimeric P2X7 receptor (P2X7R) contains three ATP⁴⁻ binding sites in its ectodomain. Here, we investigated the role of individual ATP⁴⁻ activation sites in rat P2X7R (rP2X7R) using trimeric concatemers consisting of either three wild-type subunits (7-7-7) or one to three subunits with ATP binding sites knocked out by the K64A mutation. Following expression in Xenopus laevis oocytes, ATP⁴⁻-elicited ion currents were recorded using the two-microelectrode voltage clamp technique. The 7-7-7 concatamer exhibited a biphasic ATP⁴⁻ concentration dependence, best fit by the sum of two Hill functions, confirming the existence of functionally distinct ATP⁴⁻ activation sites. The activation time course of the 7-7-7 was best approximated by the sum of a fast and a slow exponential saturating activation component. Similarly, deactivation exhibited both fast and slow exponential decay. Only one Hill function was required to best fit the ATP⁴⁻ concentration dependence of concatamers with only two or one ATP⁴⁻ binding sites, and their deactivation time courses largely lacked the slowly deactivating components. We conclude that the binding of one ATP⁴⁻ is sufficient for partial activation of the rP2X7R and that allosteric effects occur when all three ATP⁴⁻ binding sites are occupied, leading to distinct functional activation sites. Full article

Backgrounds: Approximately 18 million individuals were diagnosed with cancer in 2018. The rate is predicted to exceed 22 million by 2030. Radiotherapy is an essential part of cancer therapy, with well documented local and systemic side effects, including oxidative stress and apoptosis. Kidney tissues are also exposed to the deleterious effects of radiotherapy, resulting in acute or chronic kidney function impairment. This study compared the effects of the potent selective α2-adrenoreceptor agonist dexmedetomidine and amifostine on oxidative stress and apoptosis in kidney damage induced by x-irradiation in rats. Methods: Forty Sprague Dawley rats were assigned into five groups: control, x-irradiation, x-irradiation + amifostine, x-irradiation + dexmedetomidine 100 µg/kg, and X-ray irradiation + dexmedetomidine 200 µg/kg. Results: Necrotic tubules and degenerative Bowman’s capsules were present in the x-irradiation group. An increase was determined in malondialdehyde (MDA), Cleaved Caspase-3, and 8-OHdG levels compared to the control group (p ≤ 0.05). In contrast, there was a decrease in necrotic tubules, degenerative Bowman’s capsules, and the levels of MDA, Cleaved Caspase-3, and 8-OHdG in the amifostine and dexmedetomidine 100 µg/kg and 200 µg/kg treatment groups (p ≤ 0.05). Conclusions: Alpha 2 adrenergic receptor agonists exhibit protective effects against kidney injury induced in association with x-irradiation by reducing oxidative stress and apoptosis. Full article

Neurodegenerative diseases, including Alzheimer’s disease (AD), are a global problem affecting millions of people. Thanks to years of research and huge efforts, it has been possible to discover the pathophysiological changes accompanying Alzheimer’s disease at the cellular level. It turns out that the formation of amyloid-beta plaques and hyperphosphorylation of tau protein in the brain play a key role in disease development. Purinergic signaling (PS) is implicated in the pathophysiology of several disorders in the central nervous system, and recent findings link some disturbances in PS with Alzheimer’s disease. The primary objective of our review is to comprehensively explore and identify key purinergic signaling targets that hold therapeutic potential in the treatment of patients suffering from the disease. In particular, we focus on the dual role of purinergic compounds and extracellular vesicles (EVs), which have emerged as critical components in cellular communication and disease modulation. The extracellular vesicles that are naturally released by various cells fulfill the role of communication tools, also by harnessing the purinergic compounds. In this context, our review presents a thorough and integrative analysis of how extracellular vesicles can influence purinergic signaling and how this interaction might be leveraged to develop novel, targeted treatment strategies. Ultimately, this line of research may lead to innovative therapeutic approaches that are not only effective in slowing or halting disease progression but also demonstrate a high degree of biocompatibility and safety for the human organism. Full article