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.

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.

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.

Sertraline versus escitalopram in South Asians with moderate to severe major depressive disorder: (SOUTH-DEP) a double-blind, parallel, randomized controlled trial.

Objective: The study design included the double-blind, parallel, randomized controlled trial. The aim of this randomized controlled trial was to compare the efficacy and safety of sertraline and escitalopram in participants with moderate to severe major depressive disorder (MDD). Methods: The study was conducted in South Asian participants. A total of 744 participants with moderate to severe MDD were randomly assigned to receive either sertraline or escitalopram for 8 weeks. Drug dosages and titration schedules were based on the recommendations of the prescribing information for each product and according to the judgment of the clinicians involved in the study. The primary outcome measures were changes from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the clinical global impression (CGI) scale as well as the frequency of adverse events in both groups. Baseline MADRS scores in the escitalopram and sertraline groups were 28.2±0.47 (mean±SD) and 29.70±0.46 (mean±SD) respectively, and was no variability in the baseline assessments. Changes in MADRS as well as CGI scales at the end of the study were significant only for the sertraline group whereas they remained statistically nonsignificant for the escitalopram group. Results: The results of the study showed that sertraline was more efficacious than escitalopram in reducing depression rating scales such as MADRS and CGI, and that participants subjectively felt better regarding their symptoms in the sertraline group. Sertraline displays enhanced safety or tolerability than other groups of antidepressants, which frequently cause high levels of drowsiness, dizziness, blurred vision, and other undesirable effects. Adverse events were seen in both groups, but delayed ejaculation was the most frequent adverse event seen in both groups. However, a greater number of participants reported having nausea and insomnia in the sertraline group compared to the escitalopram group. Conclusion: Our study clearly highlights that there is a statistically significant difference in efficacy between sertraline and escitalopram at the doses used in our study. Sertraline was able to significantly lower the depression rating scales like MADRS and CGI in participants with moderate to severe MDD. Participants subjectively felt better regarding their symptoms in the sertraline group. The most frequent adverse event in both groups was delayed ejaculation. From an efficacy standpoint, sertraline was more efficacious than escitalopram. The study indicates that the prevalence of depressive disorders in South Asia is comparable to the global estimate, and Bangladesh and India has higher proportions of people with depressive disorders in South Asia. Additionally, females and older adults (75-79 years) have the highest burden of depressive disorders across all countries in the region. This study's limitation included the absence of a placebo arm. An additional limitation of the current study was the lack of an evaluation of inter-rater reliability and the research sample could not have been uniform in terms of the kind of depressive disorders and bipolarity.

Fluoroquinolone-Induced Sweet Syndrome: A Case Report.

Sweet syndrome (SS) is a rare non-vasculitic neutrophilic dermatosis. Fever, the abrupt emergence of tender erythematous plaques and nodules, with an occasional presentation of vesicles and pustules along with dense neutrophilic infiltrates on skin biopsy are the hallmarks of the illness. Tender plaques or nodules develop along with other systemic manifestations suddenly in affected people which is considered to occur due to immune-mediated hypersensitivity. We report a case of Sweet syndrome in Pakistan presenting in a 55-year-old female. It is worth reporting due to the rarity of such cases in this region. The patient was diagnosed after profound investigations and was treated with corticosteroid therapy.

Ulcerative Colitis-Induced Colorectal Carcinoma: A Deleterious Concatenation.

Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal ailment that encompasses Crohn's disease (CD) and ulcerative colitis (UC). UC is an idiopathic, chronic inflammatory condition of the colonic mucosa that begins in the rectum and progresses proximally in a continuous way over a portion of the entire colon. Chronic inflammation is linked to cancer, and IBD-related chronic colonic inflammation raises the risk of colorectal cancer. Chronic inflammation has been linked to cancer, and chronic colonic inflammation caused by IBD increases the risk of colorectal cancer (CRC). When CRC arises in people with IBD, unlike sporadic CRC, the lesions are difficult to identify due to mucosal alterations produced by inflammation. The total prevalence of IBD-associated CRC is increasing due to the rapidly increasing frequency of IBD. Screening and surveillance colonoscopy in IBD patients is considered to allow for the early diagnosis of dysplasia and cancer, improving the prognosis of IBD-related CRC by giving patients proactive therapy. This article has reviewed literature pertaining to the mechanisms related to CRC development in UC and its clinical and therapeutic implications.

Multiple Myeloma and Renal Failure: Mechanisms, Diagnosis, and Management.

Multiple myeloma (MM) is the second most common hematologic malignancy that involves monoclonal immunoglobulin (Ig)-producing plasma cells. Due to its multifaceted clinical manifestations and complications, it draws attention to various medical specialties like neurology, nephrology, orthopedics, cardiology, etc. Renal failure (RF) is one of the most common and most serious complications of MM that can be caused either by excess immunoglobulins that are nephrotoxic or some other causes like hypercalcemia, infection, etc. In this review article, we have discussed the pathogenesis of RF in MM, described the different diagnostic tools to diagnose RF in MM, and explained different treatment modalities to treat RF in MM, including certain general measures (i.e., hydration, withholding any nephrotoxic agents), renal replacement therapy, serum free light chain (SFLC) removal by plasma exchange and high cut-off dialyzer (HCO-HD), chemotherapy, hematopoietic stem cell transplantation (HSCT), and renal transplantation.

Blood-testis barrier integrity depends on Pin1 expression in Sertoli cells.

The conformation and function of a subset of serine and threonine-phosphorylated proteins are regulated by the prolyl isomerase Pin1 through isomerization of phosphorylated Ser/Thr-Pro bonds. Pin1 is intensely expressed in Sertoli cells, but its function in this post mitotic cell remains unclear. Our aim was to investigate the role of Pin1 in the Sertoli cells. Lack of Pin1 caused disruption of the blood-testis barrier. We next investigated if the activin pathways in the Sertoli cells were affected by lack of Pin1 through immunostaining for Smad3 protein in testis tissue. Indeed, lack of Pin1 caused reduced Smad3 expression in the testis tissue, as well as a reduction in the level of N-Cadherin, a known target of Smad3. Pin1-/- testes express Sertoli cell marker mRNAs in a pattern similar to that seen in Smad3+/- mice, except for an increase in Wt1 expression. The resulting dysregulation of N-Cadherin, connexin 43, and Wt1 targets caused by lack of Pin1 might affect the mesenchymal-epithelial balance in the Sertoli cells and perturb the blood-testis barrier. The effect of Pin1 dosage in Sertoli cells might be useful in the study of toxicant-mediated infertility, gonadal cancer, and for designing male contraceptives.

An HDAC Inhibitor, Entinostat/MS-275, Partially Prevents Delayed Cranial Suture Closure in Heterozygous Runx2 Null Mice.

Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disorder caused by mutations in RUNX2, coding a key transcription factor of early osteogenesis. CCD patients suffer from developmental defects in cranial bones. Despite numerous investigations and clinical approaches, no therapeutic strategy has been suggested to prevent CCD. Here, we show that fetal administration of Entinostat/MS-275, a class I histone deacetylase (HDAC)-specific inhibitor, partially prevents delayed closure of cranial sutures in Runx2+/- mice strain of C57BL/6J by two mechanisms: 1) posttranslational acetylation of Runx2 protein, which stabilized the protein and activated its transcriptional activity; and 2) epigenetic regulation of Runx2 and other bone marker genes. Moreover, we show that MS-275 stimulates osteoblast proliferation effectively both in vivo and in vitro, suggesting that delayed skeletal development in CCD is closely related to the decreased number of progenitor cells as well as the delayed osteogenic differentiation. These findings provide the potential benefits of the therapeutic strategy using MS-275 to prevent CCD. © 2017 American Society for Bone and Mineral Research.

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.

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.

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-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-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.