Peptidyl-prolyl cis-trans isomerase NIMA interacting 1 regulates skeletal muscle fusion through structural modification of Smad3 in the linker region.

Myoblast fusion is critical for muscle growth, regeneration, and repair. We previously reported that the enzyme peptidyl-prolyl cis-trans isomerase NIMA interacting 1 (Pin1) is involved in osteoclast fusion. The objective of this study was to investigate the possibility that Pin1 also inhibits myoblast fusion. Here, we show the increased number of nuclei in the Pin1+/- mice muscle fiber compared to that in wild-type mice. Moreover, we show that low dose of the Pin1 inhibitor dipentamethylene thiuram monosulfide treatment caused enhanced fusion in C2C12 cells. The R-Smads are well-known mediators of muscle hypertrophy and hyperplasia as well as being substrates of Pin1. We found that Pin1 is crucial for maintaining the stability of Smad3 (homologues of the Drosophila protein, mothers against decapentaplegic (Mad) and the Caenorhabditis elegans protein Sma). Our results show that serine 204 within Smad3 is the key Pin1-binding site during inhibition of myoblast fusion and that both the transforming growth factor-ß receptor and extracellular signal-regulated kinase (ERK)-mediated phosphorylation are required for the interaction of Pin1 with Smad3. These findings suggest that a precise level of Pin1 activity is essential for regulating myoblast fusion during myogenesis and muscle regeneration.

Pin1-mediated Modification Prolongs the Nuclear Retention of ß-Catenin in Wnt3a-induced Osteoblast Differentiation.

The canonical Wnt signaling pathway, in which ß-catenin nuclear localization is a crucial step, plays an important role in osteoblast differentiation. Pin1, a prolyl isomerase, is also known as a key enzyme in osteogenesis. However, the role of Pin1 in canonical Wnt signal-induced osteoblast differentiation is poorly understood. We found that Pin1 deficiency caused osteopenia and reduction of ß-catenin in bone lining cells. Similarly, Pin1 knockdown or treatment with Pin1 inhibitors strongly decreased the nuclear ß-catenin level, TOP flash activity, and expression of bone marker genes induced by canonical Wnt activation and vice versa in Pin1 overexpression. Pin1 interacts directly with and isomerizes ß-catenin in the nucleus. The isomerized ß-catenin could not bind to nuclear adenomatous polyposis coli, which drives ß-catenin out of the nucleus for proteasomal degradation, which consequently increases the retention of ß-catenin in the nucleus and might explain the decrease of ß-catenin ubiquitination. These results indicate that Pin1 could be a critical target to modulate ß-catenin-mediated osteogenesis.

Pin1, the Master Orchestrator of Bone Cell Differentiation.

Pin1 is an enzyme that specifically recognizes the peptide bond between phosphorylated serine or threonine (pS/pT-P) and proline. This recognition causes a conformational change of its substrate, which further regulates downstream signaling. Pin1-/- mice show developmental bone defects and reduced mineralization. Pin1 targets RUNX2 (Runt-Related Transcription Factor 2), SMAD1/5, and ß-catenin in the FGF, BMP, and WNT pathways, respectively. Pin1 has multiple roles in the crosstalk between different anabolic bone signaling pathways. For example, it controls different aspects of osteoblastogenesis and increases the transcriptional activity of Runx2, both directly and indirectly. Pin1 also influences osteoclastogenesis at different stages by targeting PU.1 (Purine-rich nucleic acid binding protein 1), C-FOS, and DC-STAMP. The phenotype of Pin1-/- mice has led to the recent identification of multiple roles of Pin1 in different molecular pathways in bone cells. These roles suggest that Pin1 can be utilized as an efficient drug target in congenital and acquired bone diseases. J. Cell. Physiol. 232: 2339-2347, 2017. © 2016 Wiley Periodicals, Inc.

Direct Delivery of Recombinant Pin1 Protein Rescued Osteoblast Differentiation of Pin1-Deficient Cells.

Pin1 is a peptidyl prolyl cis-trans isomerase that specifically binds to the phosphoserine-proline or phosphothreonine-proline motifs of several proteins. We reported that Pin1 plays a critical role in the fate determination of Smad1/5, Runx2, and ß-catenin that are indispensable nuclear proteins for osteoblast differentiation. Though several chemical inhibitors has been discovered for Pin1, no activator has been reported as of yet. In this study, we directly introduced recombinant Pin1 protein successfully into the cytoplasm via fibroin nanoparticle encapsulated in cationic lipid. This nanoparticle-lipid complex delivered its cargo with a high efficiency and a low cytotoxicity. Direct delivery of Pin1 leads to increased Runx2 and Smad signaling and resulted in recovery of the osteogenic marker genes expression and the deposition of mineral in Pin1-deficient cells. These result indicated that a direct Pin1 protein delivery method could be a potential therapeutics for the osteopenic diseases. J. Cell. Physiol. 232: 2798-2805, 2017. © 2016 Wiley Periodicals, Inc.

Prolyl isomerase Pin1-mediated conformational change and subnuclear focal accumulation of Runx2 are crucial for fibroblast growth factor 2 (FGF2)-induced osteoblast differentiation.

Fibroblast growth factor 2 (FGF2) signaling plays a pivotal role in bone growth/differentiation through the activation of osteogenic master transcription factor Runx2, which is mediated by the ERK/MAPK-dependent phosphorylation and the p300-dependent acetylation of Runx2. In this study, we found that Pin1-dependent isomerization of Runx2 is the critical step for FGF2-induced Runx2 transactivation function. We identified four serine or threonine residues in the C-terminal domain of Runx2 that are responsible for Pin1 binding and structural modification. Confocal imaging studies indicated that FGF2 treatment strongly stimulated the focal accumulation of Pin1 in the subnuclear area, which recruited Runx2. In addition, active forms of RNA polymerase-II also colocalized in the same subnuclear compartment. Dipentamethylene thiuram monosulfide, a Pin1 inhibitor, strongly attenuated their focal accumulation as well as Runx2 transactivation activity. The Pin1-mediated structural modification of Runx2 is an indispensable step connecting phosphorylation and acetylation and, consequently, transcriptional activation of Runx2 by FGF signaling. Thus, the modulation of Pin1 activity may be a target for the regulation of bone formation.

Pin1 plays a critical role as a molecular switch in canonical BMP signaling.

Pin1 is a peptidyl prolyl cis-trans isomerase that specifically binds to the phosphoserine-proline or phosphothreonine-proline motifs of numerous proteins. Previously, we reported that Pin1 deficiency resulted in defects in osteoblast differentiation during early bone development. In this study, we found that adult Pin1-deficient mice developed osteoporotic phenotypes compared to age-matched controls. Since BMP2 stored in the bone matrix plays a critical role in adult bone maintenance, we suspected that BMP R-Smads (Smad1 and Smad5) could be critical targets for Pin1 action. Pin1 specifically binds to the phosphorylated linker region of Smad1, which leads to structural modification and stabilization of the Smad1 protein. In this process, Pin1-mediated conformational modification of Smad1 directly suppresses the Smurf1 interaction with Smad1, thereby promoting sustained activation of the Smad1 molecule. Our data demonstrate that post-phosphorylational prolyl isomerization of Smad1 is a converging signal to stabilize the Smad1 molecule against the ubiquitination process mediated by Smurf1. Therefore, Pin1 is a critical molecular switch in the determination of Smad1 fate, opposing the death signal transmitted to the Smad1 linker region by phosphorylation cascades after its nuclear localization and transcriptional activation. Thus, Pin1 could be developed as a major therapeutic target in many skeletal diseases.

Pin1-mediated prolyl isomerization of Runx1 affects PU.1 expression in pre-monocytes.

Regulation of the hematopoietic transcription factor PU.1, a member of the ETS family, plays a critical role in the development of blood cells and in leukemia. The dosage of PU.1 has been shown to cause a shift in myelomonocytic progenitor fate. Pin1 is a unique substrate-specific enzyme that can isomerize phospho-Ser/Thr-Pro peptide bonds, accelerating the conformational change in its substrates between a cis and a trans form. Such activity has been demonstrated to be a tightly controlled mechanism regulating a wide variety of protein functions under both normal physiological and pathological conditions. We have previously reported that a conformational change in Runx2 induced by Pin1 is essential for its function in osteogenesis in vitro and in vivo. In this study, we show that the Pin1-mediated conformational change in Runx1 enhances its acetylation and stabilization and, consequently, enhances its transacting activity. The increased acetylation of Runx1 represses PU.1 transcription in pre-monocytes. Conversely, the lack of (or the inhibition of) Pin1 increases PU.1 transcription in vitro and in vivo in pre-monocytes and in the spleen tissue. Pin1 KO mice have an increased CD11b(+) /F4/80(+) cell population and F4/80 protein expression in spleen. From our data, we can conclude that the conformational change in Runx1 induced by Pin1 represses PU.1 transcription in pre-monocytes and influences the commitment to the monocyte lineage. The dosage of PU.1 is a crucial factor in acute myeloid leukemia (AML), and Pin1 may thus be a useful target for controlling PU.1-dependent hematopoiesis, as well as leukemogenesis.

Pin1 regulates osteoclast fusion through suppression of the master regulator of cell fusion DC-STAMP.

Cell fusion is a fundamental biological event that is essential for the development of multinucleated cells such as osteoclasts. Fusion failure leads to the accumulation of dense bone such as in osteopetrosis, demonstrating the importance of fusion in osteoclast maturity and bone remodeling. In a recent study, we reported that Pin1 plays a role in the regulation of bone formation and Runx2 regulation. In this study, we explored the role of Pin1 in osteoclast formation and bone resorption. Pin1 null mice have low bone mass and increased TRAP staining in histological sections of long bones, compared to Pin1 wild-type mice. In vitro osteoclast forming assays with bone marrow-derived monocyte/macrophage revealed that Pin1-deficient osteoclasts are larger than wild-type osteoclasts and have higher nuclei numbers, indicating greater extent of fusion. Pin1 deficiency also highly enhanced foreign body giant cell formation both in vitro and in vivo. Among the known fusion proteins, only DC-STAMP was significantly increased in Pin1(-/-) osteoclasts. Immunohistochemistry showed that DC-STAMP expression was also significantly increased in tibial metaphysis of Pin1 KO mice. We found that Pin1 binds and isomerizes DC-STAMP and affects its expression levels and localization at the plasma membrane. Taken together, our data indicate that Pin1 is a determinant of bone mass through the regulation of the osteoclast fusion protein DC-STAMP. The identification of Pin1 as a factor involved in cell fusion contributes to the understanding of osteoclast-associated diseases, including osteoporosis, and opens new avenues for therapeutic targets.

Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases.

Cerebrovascular diseases and their sequalae, such as ischemic stroke, chronic cerebral hypoperfusion, and vascular dementia are significant contributors to adult disability and cognitive impairment in the modern world. Astrocytes are an integral part of the neurovascular unit in the CNS and play a pivotal role in CNS homeostasis, including ionic and pH balance, neurotransmission, cerebral blood flow, and metabolism. Astrocytes respond to cerebral insults, inflammation, and diseases through unique molecular, morphological, and functional changes, collectively known as reactive astrogliosis. The function of reactive astrocytes has been a subject of debate. Initially, astrocytes were thought to primarily play a supportive role in maintaining the structure and function of the nervous system. However, recent studies suggest that reactive astrocytes may have both beneficial and detrimental effects. For example, in chronic cerebral hypoperfusion, reactive astrocytes can cause oligodendrocyte death and demyelination. In this review, we will summarize the (1) roles of ion transporter cascade in reactive astrogliosis, (2) role of reactive astrocytes in vascular dementia and related dementias, and (3) potential therapeutic approaches for dementing disorders targeting reactive astrocytes. Understanding the relationship between ion transporter cascade, reactive astrogliosis, and cerebrovascular diseases may reveal mechanisms and targets for the development of therapies for brain diseases associated with reactive astrogliosis.

Unraveling the Enigma of Aortic Dissection: From Genetics to Innovative Therapies.

Aortic dissection (AD) presents a critical medical emergency characterized by a tear in the aortic wall, necessitating prompt recognition and management to mitigate catastrophic complications. Despite advancements in medical technology and therapeutic interventions, AD remains a formidable challenge, often resulting in severe morbidity and mortality. This narrative review provides a comprehensive overview of AD, encompassing its clinical presentation, diagnostic modalities, and management strategies, while also exploring emerging trends and innovations in its management. Genetic predispositions significantly influence AD pathogenesis, with over 30 contributory genes identified, emphasizing the importance of genetic screening and counseling. Classification systems such as Stanford and DeBakey, alongside their revised counterparts, aid in categorizing AD and guiding treatment decisions. Advancements in diagnostic imaging, including transesophageal echocardiography and computed tomography angiography, have enhanced diagnostic precision, augmented by artificial intelligence and machine learning algorithms. Pharmacological innovations focus on optimizing medical therapy, while surgical and endovascular approaches offer minimally invasive treatment options. Hybrid procedures and aortic valve-sparing techniques broaden treatment avenues, while bioresorbable stent grafts hold promise for tissue regeneration. Collaborative efforts and ongoing research are essential to address remaining challenges and improve outcomes in managing AD. This review contributes to the understanding of AD's complexity and facilitates informed decision-making in clinical practice, underscoring the imperative for continued innovation and research in AD management.

Integrated Approaches in the Management of Gastrointestinal Disorders: A Biopsychosocial Perspective.

Gastrointestinal (GI) disorders, including gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastritis/peptic ulcer disease (PUD), and celiac disease, significantly impact global health and economic stability. This review synthesizes current literature to elucidate the pathophysiology, clinical manifestations, diagnostic challenges, and management strategies of these prevalent conditions. Through a biopsychosocial lens, we examine the role of the gut microbiome in disease modulation and explore innovative therapeutic advancements, including microbiome-targeting interventions. The review highlights the necessity of a multidisciplinary approach to patient care, integrating medical treatment with dietary, psychological, and lifestyle modifications. By addressing these disorders holistically, the article aims to foster a deeper understanding of their biopsychosocial impacts and encourage more effective, patient-centered treatment paradigms. The findings underscore the imperative for continued research and interdisciplinary collaboration to enhance patient outcomes and reduce healthcare burdens associated with GI disorders.

Efficacy of Metformin-Cabergoline Compared to Metformin Monotherapy for Management of PCOS With Hyperprolactinemia: A Systematic Review and Meta-analysis.

Background: Metformin plays a major part in the treatment of polycystic ovarian syndrome .Trials are being conducted to compare the effectiveness of combination of metformin with cabergoline in the treatment of hyperprolactinemia and polycystic ovarian syndrome. Objectives: The purpose of this study is to compare the effectiveness of metformin monotherapy and combination therapy with cabergoline versus metformin for the management of polycystic ovarian syndrome with hyperprolactinemia. Methodology: An extensive search up until 31 May 2024 of electronic databases (PubMed, Registry of Controlled Clinical Trials, Web of Sciences, SCOPUS) to find pertinent studies. An analysis was conducted with both observational data and randomized clinical trials . To compute the standard mean difference, weighted mean difference, odds ratio, and 95% confidence interval, RevMan (v5.3) was utilized. Primary outcomes that were assessed included body-mass index, regular menstruation, weight change, prolactin, testosterone, and dehydroepiandrosterone-sulfate levels. Results: Three randomized controlled trials and 1 observational study, taking a total patient population of n = 535, were part of our final analysis. Prolactin (SMD = -3.23 95% CI: (-4.90, -1.55)) and dehydroepiandrosterone-sulfate levels (SMD = -0.27 95% CI: (-0.52, -0.01)) were significantly lower in the metformin and cabergoline combination therapy group; monthly regularity was also significantly higher (OR = 3.07 95% CI: (2.09, 4.51)). Statistically, there was no significant difference in weight, body-mass index, or testosterone levels. Conclusions: In the treatment of polycystic ovarian syndrome, the combination of metformin and cabergoline significantly lowers prolactin levels and encourages regular menstrual cycles. Although metformin has the potential to suppress testosterone levels, more investigation is required to determine how combination therapy affect dehydroepiandrosterone-sulfate and testosterone levels. It's interesting to note that while neither intervention had a substantial impact on weight or body-mass index, metformin and cabergoline combination therapy outperformed metformin monotherapy in terms of supporting regular menstrual cycles. Customized therapy approaches are essential, and large-scale trials involving a variety of groups are required to comprehend the safety and effectiveness of treatments.

Efficacy of metformin compared to metformin and cabergoline combination In this study, 2 therapies for women with high prolactin levels­a hormone associated with PCOS­were examined. Their goal was to determine which combination of metformin and cabergoline produced the best results.Observational data and randomized clinical trials were included while searching through several databases for pertinent studies. Researchers discovered that the combination of metformin and cabergoline was superior to using metformin alone in reducing prolactin and another hormone called DHEAS. The menstrual periods of women receiving the combined therapy were also more regular. However, there wasn't much difference in weight, body mass index (BMI), or testosterone levels between the 2 groups. In summary, it appears that the combination of cabergoline and metformin is a more effective way to treat the symptoms of PCOS, which include irregular periods and elevated prolactin levels. To find out how it impacts other hormones and whether it's long-term safe and effective, further research is still required.

NSAID-induced Gastric Ulcer Disease: A Deleterious Connection.

Gastric ulcers induced by non-steroidal anti-inflammatory drug (NSAID) usage have become a common public health problem, and several studies have established chronic NSAID usage to be one of the risk factors for the pathogenesis of peptic ulcers in patients. This review includes numerous articles that link NSAID usage with peptic mucosal erosion, especially among patients under anticoagulant therapy or with other risk factors. Risk factors for NSAID-induced peptic ulcers are reviewed, in addition to pathogenesis, clinical signs, symptoms, diagnosis, prevention, and treatments. We also emphasize effective methods for the prevention and management of peptic ulcers among NSAID users. Such methods include the use of selective Cyclo-oxygenase (COX-2) inhibitors as an alternative to aspirin or other Cyclo-oxygenase (COX-1) inhibitors, or using the lowest dosage possible in patients with other comorbidities. We have conducted a thorough review of the literature on diagnostic tests and alternative medication that can be used in the management of NSAID toxicity-induced ulcers.

Efficacy and Safety of Intravenous Diltiazem Versus Metoprolol in the Management of Atrial Fibrillation with Rapid Ventricular Response in the Emergency Department: A Comprehensive Umbrella Review of Systematic Reviews and Meta-analyses.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the United States, affecting 2.7-6.1 million people. AF can cause symptoms, but when it triggers a rapid ventricular response (RVR), most patients suffer from decompensation. Therefore, we performed an umbrella review of systematic reviews and meta-analyses comparing intravenous (IV) metoprolol and diltiazem to identify discrepancies, fill in knowledge gaps, and develop standardized decision-making guidelines for physicians to manage AF with RVR. A comprehensive search was conducted in PubMed, the Cochrane Library, and Scopus to identify studies for this umbrella review. The overall certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation method, while the quality of the included reviews was evaluated using AMSTAR 2, the Cochrane Collaboration tool, and the Newcastle-Ottawa scale. This study comprehensively analyzed four meta-analyses covering 11 randomized controlled trials and 19 observational studies. The analysis showed that IV diltiazem treatment was significantly more successful in rate control for AF with rapid ventricular response (RVR) than IV metoprolol (risk ratio [RR], 1.30; 95% confidence interval [CI], 1.09-1.56; I 2 = 0%; P = .003). IV diltiazem also led to a significantly greater reduction in ventricular rate (mean difference, -14.55; 95% CI, -16.93 to -12.16; I 2 = 72%; P < .00001), particularly at 10 min. The analysis also revealed a significantly increased risk of hypotension associated with treatment with IV diltiazem (RR, 1.43; 95% CI, 1.14-1.79; I 2 = 0%; P = .002). In conclusion, IV diltiazem therapy achieved better rate control and ventricular rate decrease than metoprolol therapy in AF with RVR. Future clinical trials should compare calcium channel blockers and ß-blockers for heart rate control efficacy and safety, considering adverse events.

Comparative Analysis of Clinical Outcomes of High-power, Short-duration Ablation versus Low-power, Long-duration Ablation Strategy in Patients with Atrial Fibrillation: A Comprehensive Umbrella Review of Meta-analyses.

Atrial fibrillation (AF) affects around 33 million people worldwide, rendering it a common cardiac arrhythmia. Catheter ablation (CA) has evolved as a leading therapeutic intervention for symptomatic AF. This umbrella review systematically evaluates existing systematic reviews and meta-analyses to assess the safety, efficacy, and potential of high-power, short-duration (HPSD) ablation as an alternative therapy option for AF. A thorough exploration was undertaken across PubMed, the Cochrane Library, and Embase to identify pertinent studies for inclusion in this umbrella review. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method was employed to assess the overall certainty of the evidence comprehensively, and the quality of the incorporated reviews was meticulously evaluated through use of the AMSTAR 2 tool, the Cochrane Collaboration tool, and the Newcastle-Ottawa scale. In this study, we initially identified 35 systematic reviews and meta-analyses, narrowing them down to a final selection of 11 studies, which collectively integrated data from 6 randomized controlled trials and 26 observational studies. For primary efficacy outcomes, the HPSD approach led to a non-significant decrease in the risk of atrial tachyarrhythmia recurrence (risk ratio [RR], 0.88; 95% confidence interval [CI], 0.70-1.12; I 2 = 90%; P = .31) and a significantly reduced risk of AF recurrence (RR, 0.53; 95% CI, 0.42-0.67; I 2 = 0%; P < .00001) compared to the low-power, long-duration (LPLD) approach. In terms of primary safety outcomes, the HPSD approach significantly reduced the risk of esophageal thermal injury (ETI) (RR, 0.71; 95% CI, 0.61-0.83; I 2 = 0%; P < .00001) and facilitated a non-significant decrease in the risk of other major complications (RR, 0.87; 95% CI, 0.73-1.03; I 2 = 0%; P = .10). In conclusion, HPSD therapy is safer and more effective than LPLD therapy, facilitating decreased AF recurrence rates along with reductions in ETI, total procedure duration, ablation number, ablation time, fluoroscopy time, and acute pulmonary vein reconnection.

Evaluating the Efficacy of Antioxidant Therapy in Enhancing the Quality of Life of Chronic Pancreatitis Patients: A Systematic Review.

Chronic pancreatitis (CP), an inflammatory disease characterized by irreversible pancreatic changes and progressive fibrosis, significantly impairs patients' quality of life. This systematic review aims to assess the efficacy of antioxidant therapy in enhancing the quality of life of CP patients. Focusing on the role of oxidative stress in CP pathogenesis, we explored several databases for studies evaluating the impact of antioxidant supplementation. The review included randomized controlled trials and cohort studies reporting pain frequency, intensity, and overall quality of life measures. Findings from these studies present a mixed view of the efficacy of antioxidants in CP, with some suggesting benefits in symptom management, while others show inconsistency in improving patient outcomes. The review concludes that while antioxidant therapy holds potential, especially in symptom alleviation, there is a need for more rigorous, larger-scale studies to confirm its effectiveness in CP management and to establish standardized treatment protocols. The incorporation of antioxidants into CP treatment plans should be approached with personalized care, considering the varied responses observed in different patient populations.

From Sugar Spikes to Pressure Peaks: Navigating the World of Diabetes, Hypertension, Obesity, and Kidney Health.

Diabetes, hypertension, obesity, and chronic kidney disease (CKD) are major public health challenges globally, contributing significantly to morbidity and mortality. The co-occurrence and interplay among these conditions exacerbate health outcomes, highlighting the need for an integrated understanding and approach to management. This narrative review aims to explore the complex relationships between diabetes, hypertension, obesity, and CKD, elucidating their collective impact on health. It discusses the epidemiological trends, underlying pathophysiological mechanisms, genetic predispositions, current treatment strategies, and the future direction of research and therapy. An extensive review of current literature was conducted, focusing on the epidemiology, pathophysiology, risk factors, diagnosis, and treatment of diabetes, hypertension, obesity, and CKD. Additionally, the review delves into the genetic and molecular biology underlying these conditions, the potential for personalized medicine, and the importance of a multidisciplinary approach to care. The review identifies key areas where these conditions intersect, enhancing disease progression and complicating management. It highlights the role of genetic and environmental factors in disease etiology, the critical need for personalized treatment strategies, and the gaps in current management approaches. Innovations in pharmacotherapy, monitoring technologies, and the potential of pharmacogenomics are discussed as avenues for advancing patient care. Diabetes, hypertension, obesity, and CKD are intricately linked, necessitating an integrated, patient-centered approach to care that goes beyond traditional treatment modalities. Future research should focus on collaborative models and interdisciplinary strategies to address the multifaceted challenges posed by these conditions. Emphasizing personalized medicine and leveraging technological advancements offer promising pathways to improve outcomes and reduce the global health burden of these metabolic disorders.

SPAK inhibitor ZT-1a attenuates reactive astrogliosis and oligodendrocyte degeneration in a mouse model of vascular dementia.

BACKGROUND: Astrogliosis and white matter lesions (WML) are key characteristics of vascular contributions to cognitive impairment and dementia (VCID). However, the molecular mechanisms underlying VCID remain poorly understood. Stimulation of Na-K-Cl cotransport 1 (NKCC1) and its upstream kinases WNK (with no lysine) and SPAK (the STE20/SPS1-related proline/alanine-rich kinase) play a role in astrocytic intracellular Na+ overload, hypertrophy, and swelling. Therefore, in this study, we assessed the effect of SPAK inhibitor ZT-1a on pathogenesis and cognitive function in a mouse model of VCID induced by bilateral carotid artery stenosis (BCAS). METHODS: Following sham or BCAS surgery, mice were randomly assigned to receive either vehicle (DMSO) or SPAK inhibitor ZT-1a treatment regimen (days 14-35 post-surgery). Mice were then evaluated for cognitive functions by Morris water maze, WML by ex vivo MRI-DTI analysis, and astrogliosis/demyelination by immunofluorescence and immunoblotting. RESULTS: Compared to sham control mice, BCAS-Veh mice exhibited chronic cerebral hypoperfusion and memory impairments, accompanied by significant MRI DTI-detected WML and oligodendrocyte (OL) death. Increased activation of WNK-SPAK-NKCC1-signaling proteins was detected in white matter tissues and in C3d+ GFAP+ cytotoxic astrocytes but not in S100A10+ GFAP+ homeostatic astrocytes in BCAS-Veh mice. In contrast, ZT-1a-treated BCAS mice displayed reduced expression and phosphorylation of NKCC1, decreased astrogliosis, OL death, and WML, along with improved memory functions. CONCLUSION: BCAS-induced upregulation of WNK-SPAK-NKCC1 signaling contributes to white matter-reactive astrogliosis, OL death, and memory impairment. Pharmacological inhibition of the SPAK activity has therapeutic potential for alleviating pathogenesis and memory impairment in VCID.

The Potential of Fecal and Urinary Biomarkers for Early Detection of Pancreatic Ductal Adenocarcinoma: A Systematic Review.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer often diagnosed at advanced stages, highlighting the urgent need for early detection strategies. This systematic review explores the potential of fecal and urinary biomarkers for early PDAC detection. A comprehensive search identified eight relevant studies investigating various biomarkers, including proteins, metabolites, microbial profiles, DNA mutations, and non-coding RNAs. Promising findings suggest that urinary biomarkers related to metabolic alterations, inflammatory processes, fecal microbiome profiles, and fecal miRNAs hold diagnostic potential even at early stages of PDAC. Combining biomarkers into panels may enhance diagnostic accuracy. Challenges such as validation in larger cohorts, standardization of protocols, and regulatory approval must be addressed for clinical translation. Despite these hurdles, non-invasive urinary and fecal biomarkers represent a promising avenue for improving PDAC outcomes through early detection.

Pin1-mediated Runx2 modification is critical for skeletal development.

Runx2 is the master transcription factor for bone formation. Haploinsufficiency of RUNX2 is the genetic cause of cleidocranial dysplasia (CCD) that is characterized by hypoplastic clavicles and open fontanels. In this study, we found that Pin1, peptidyl prolyl cis-trans isomerase, is a critical regulator of Runx2 in vivo and in vitro. Pin1 mutant mice developed CCD-like phenotypes with hypoplastic clavicles and open fontanels as found in the Runx2+/- mice. In addition Runx2 protein level was significantly reduced in Pin1 mutant mice. Moreover Pin1 directly interacts with the Runx2 protein in a phosphorylation-dependent manner and subsequently stabilizes Runx2 protein. In the absence of Pin1, Runx2 is rapidly degraded by the ubiquitin-dependent protein degradation pathway. However, Pin1 overexpression strongly attenuated uniquitin-dependent Runx2 degradation. Collectively conformational change of Runx2 by Pin1 is essential for its protein stability and possibly enhances the level of active Runx2 in vivo.