Heat shock factor 2 (HSF2) and hypoxia-inducible factor 1α are activated by angiotensin II (ANGII) in cardiomyocytes. The endoplasmic reticulum (ER) stress plays a critical role in cardiac hypertrophy. Moreover, HIF-1α is known to be regulated by HSF2 in tumour cells. In this study, we hypothesised and clarified whether HSF2 trans-activated HIF-1α through initiation of ER stress in hypertrophic cardiomyocytes. Myocardial hypertrophy was induced by the treatment of ANGII. Expression of the gene or protein was assessed by applying RT-PCR, WB, ICC and IHC. Luciferase and CHIP were applied to detect the transcription of HIF-1α by HSF2. Both in vitro and in vivo, the expression of HIF-1α, ER stress markers and HSF2 was increased in ANGII-treated hypertrophic cardiomyocytes. Blocking ER stress suppressed the expression of HSF2 and HIF-1α in ANGII-treated cardiomyocytes. Silencing HSF2 inhibited HIF-1α, thereby reducing hypertrophy but had no effect on ER stress. Similarly, silencing HIF-1α reduced hypertrophy without affecting ER stress or HSF2 expression. HSF2 transcriptionally activated HIF-1α. We concluded that ER stress induced by ANGII activates HSF2, which then trans-activates HIF-1α, promoting cardiac hypertrophy.
Hypertrophic Cardiomyopathy (HCM) is one of the significant causes of heart failure. This study aimed to identify and validate potential therapeutic targets for HCM through bioinformatics analysis and in vitro and in vivo experiments. By analysing differentially expressed genes in HCM patients and combining multiple analytical approaches, key genes were screened. The functions of these genes were validated using AC16 cells under different mechanical force environments and Ang-II induction. HCM-like pathological cardiac remodelling mouse model was established to evaluate myocardial hypertrophy, fibrosis and cardiac remodelling. The results demonstrated that DUSP1 expression was downregulated in the myocardium of HCM patients. Mechanical force transduction activated the MAPK pathway and overexpression of DUSP1 suppressed ERK/MAPK activation and attenuated mechanotransduction-associated cardiomyocyte hypertrophy and hypertrophic gene expression. In vivo experiments showed that cardiac-specific restoration of DUSP1 expression alleviated pathological cardiac remodelling and fibrosis. This study suggests that DUSP1 functions as an endogenous regulator of mechanically activated MAPK signalling, thereby limiting pathological myocardial hypertrophy. These findings identify a previously underappreciated role of DUSP1 in linking mechanical stress-induced signalling with MAPK activation and pathological cardiac remodelling, suggesting DUSP1 restoration as a potential therapeutic strategy for HCM-like cardiac remodelling.
OBJECTIVE:This study aims to elucidate the molecular mechanisms by which Polyphyllin I (PPI), a potent steroidal saponin, attenuates non-small cell lung cancer (NSCLC) progression via mechanistic reprogramming of an autophagy-dependent immunogenic response. METHODS:Integrated in vitro (A549, H460) and in vivo (LLC xenograft) models were deployed to evaluate PPI's efficacy on autophagic flux and the tumour immune microenvironment. The regulatory role of autophagy in macrophage-mediated antigen presentation was scrutinised via ATG3-mediated genetic silencing or overexpression in tumour-macrophage co-culture systems. Concurrently, the capacity of PPI to sensitise NSCLC cells to cisplatin (DDP) and counteract chemoresistance was evaluated. RESULTS:PPI activated the AMPK/p53/mTOR signalling axis, robustly inducing core autophagic markers (LC3-II and Beclin-1) in a dose-dependent manner. Mechanistically, PPI-induced autophagic flux served as a prerequisite for antitumoural M1 macrophage polarisation, characterised by significant upregulation of iNOS and MHC-II in co-cultured THP-1 cells. Genetic knockdown of ATG3 effectively abrogated these immunostimulatory profiles, whereas ATG3 overexpression potentiated PPI-driven antigen presentation. Furthermore, PPI administration markedly delayed the onset of DDP resistance sustained by functional autophagic flux. In vivo, PPI significantly suppressed tumour burden, accompanied by enhanced CD8+ T-cell infiltration and elevated cytotoxic effector levels (IFN-γ and Granzyme B). CONCLUSION:Our findings establish PPI as a dual autophagic-immune modulator that re-engineers the immunosuppressive microenvironment. By coupling intracellular autophagic stress with macrophage-mediated antigen presentation, PPI reinstates antitumour immunity and abrogates chemoresistance, offering a compelling therapeutic framework for managing recalcitrant NSCLC.
BACKGROUND:Food allergy (FA) is a disorder marked by a significant incidence of detrimental immunological responses to certain dietary constituents, while preventive measures and regulatory treatments are scarce. Mast cells (MCs) are integral to the pathogenesis of FA mediated by Immunoglobulin E (IgE). The activation of MCs is modulated by their intracellular Ca2+ concentrations, with CaV1.2 serving as a voltage-gated calcium channel that regulates calcium influx in MCs. OBJECTIVE:The aim of this study was to examine the influence of CaV1.2 on MCs' activation and its role in the onset and progression of FA. METHODS:The inhibitory effect of nimodipine (Nim) on MCs activation in vitro was evaluated by detecting LAD2 degranulation and cytokine release; the anti-food allergy effect of Nim was examined by the establishment of an IgE-mediated FA model; the effect of CaV1.2 on the occurrence of FA was investigated using conditional knockout of CaV1.2 in MCs (CKO) mice. RESULTS:Nim inhibited MCs activation in vitro and alleviated ovalbumin (OVA)-induced FA in vivo. The expression of CaV1.2 in MCs exhibited detrimental effects, whereas its deficiency ameliorated local and systemic allergy and significantly alleviated FA in mice. When CaV1.2 was replenished in CKO mice by BMMC injection, such supplementation exacerbated FA symptoms. CONCLUSION:Depression of CaV1.2 in MCs attenuates the activation of MCs and alleviates the symptoms of FA. These results suggest that CaV1.2 could be a new target for FA.
Thalassaemia is a hereditary haemoglobinopathy characterised by impaired globin synthesis, resulting in ineffective erythropoiesis and systemic iron overload. While current management relies on blood transfusions and chelation, these often fail to address the underlying molecular signalling dysregulation that contributes to the disease's progression, such as the imbalance in erythropoietin production and the activation of inflammatory pathways. Brazilin, the primary homoisoflavonoid from Biancaea sappan L., presents a multifaceted therapeutic profile. This review synthesises evidence of brazilin's activity as a potent iron chelator and reactive oxygen species (ROS) scavenger and anti-inflammatory agent, while evaluating its potential as a novel JAK2 inhibitor. Molecular docking suggests brazilin may bind to the JAK2 ATP-binding pocket, though functional validation is still required. By modulating the erythroferrone (ERFE)-hepcidin (HAMP) axis, brazilin potentially restores iron homeostasis and mitigates splenomegaly. We further evaluate its pharmacokinetics and safety profile, highlighting low toxicity and high oral bioavailability. This positions brazilin as a promising lead candidate for thalassaemia adjunct treatment, warranting further in vivo validation.
Pentraxin 3 (PTX3) responds rapidly to inflammatory signals. This study investigated the functional involvement of PTX3 in angiotensin II (Ang II)-mediated cardiac hypertrophy pathogenesis, with particular focus on its potential regulation through inflammatory pathways and oxidative stress mechanisms. In vivo, chronic Ang II infusion over 4 weeks was used to induce hypertrophic cardiomyopathy in mice. In parallel, an in vitro model of cardiomyocyte hypertrophy was established by treating neonatal rat cardiomyocytes (NRCMs) with Ang II for 24 h. Ang II treatment significantly increased PTX3 expression, an effect observed in both mouse heart tissue and NRCMs. The cardiac hypertrophy and fibrosis in mice treated with Ang II were alleviated by PTX3 knockout. Genetic ablation of PTX3 attenuated Ang II-induced upregulation of cardiac hypertrophy markers in mice hearts, including atrial natriuretic peptide, brain natriuretic peptide, and beta-myosin heavy chain. Additionally, PTX3 knockout suppressed the elevation of pro-inflammatory cytokines, including tumour necrosis factor-alpha and interleukin-1beta, following Ang II stimulation. Genetic deficiency of PTX3 significantly ameliorated cardiac oxidative stress potentiated by Ang II infusion. These outcomes showed that targeting of PTX3 could ameliorate hypertrophic cardiomyopathy via attenuation of inflammatory response and oxidative stress. PTX3 may be a target for therapy of hypertrophic cardiomyopathy in the future.
BACKGROUND:Hepatocellular Carcinoma (HCC) is a matter of great global public health importance; however, its current therapeutic effectiveness is deemed inadequate, and the range of therapeutic targets is limited. This study aimed to explore the efficacy of Bosutinib (BOS) in HCC and the underlying molecular mechanism. METHODS:Bioinformatic analysis, machine learning, and online databases were used for screening targets and molecular docking studies. The mRNA level of mammalian polo-like kinase 1 (PLK1) was identified via real-time quantitative PCR. The protein expression of PLK1, PTK2, and USP9X was detected using western blot. Cell viability, apoptosis, and migration were evaluated by MTT, flow cytometry, and transwell assay. The angiogenesis capacity was determined using tube formation assay. The glucose consumption, lactate production, and ATP/ADP ratios were analysed using commercial kits. CO-IP assay was used to confirm the interaction between PLK1 and USP9X. A mouse model was used for exploring BOS in vivo. Immunochemistry was used to examine PLK1 and USP9X expression in tumours. RESULTS:This study illustrated that BOS inhibited proliferation, migration, angiogenesis, and glycolysis of HCC cells. Bioinformatic analysis and machine learning identified PLK1 as a core gene related to the glycolysis of HCC. PLK1 was upregulated in HCC and correlated with an unfavourable prognosis. Further evaluation showed that the anti-tumour effects of BOS were impaired by PLK1 overexpression. In addition, BOS treatment inhibited PLK1 protein level, while its mRNA level was not affected. Moreover, Bosutinib inhibited USP9X to reduce the deubiquitination of PLK1. CO-IP assay indicated that reduced USP9X could enhance the ubiquitination of PLK1 and reduce protein stability. Finally, BOS showed anti-tumour effects in a mouse model. CONCLUSION:This study revealed that BOS inhibited cell proliferation, migration, angiogenesis, and glycolysis via suppressing USP9X, thus reducing deubiquitination of PLK1 in HCC, demonstrating the potential of BOS for the treatment of HCC.
OBJECTIVES:Borderline personality disorder (BPD) is associated with psychosocial dysfunction and has a number of untoward public health associations. There is no established first-line pharmacological treatment for BPD, and available options are not suitable for all individuals. The aim of this study was to evaluate the safety and efficacy of lumateperone in adults with BPD. METHODS:Sixty adults with BPD were recruited for a randomized, double-blind, placebo-controlled study. Participants received 8-week treatment with lumateperone (42 mg/day) or identical placebo in a parallel design. The primary efficacy outcome measure was the clinician-rated Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD). Safety data were collected. Effects of active versus placebo treatment were analyzed using a linear mixed-effects regression model that included terms for treatment group, time, and treatment-by-time interaction. RESULTS:There was no significant interaction between treatment and time on the ZAN-BPD scale at week 8. Lumateperone was generally well tolerated. Secondary measures did not result in statistically significant differences from placebo. CONCLUSIONS:Lumateperone did not appear to reduce BPD symptoms compared with placebo. These findings also need to be viewed cautiously given the small sample size, large drop-out rate, and robust placebo response.
OBJECTIVES:Catatonia in older adults is often under-recognized, particularly when it occurs in the setting of acute medical illness or neurological disease. Benzodiazepines are first-line therapy, yet geriatric prescribing frameworks such as the American Geriatrics Society Beers Criteria discourage benzodiazepine use in older adults, which can contribute to delays in treatment. METHODS:We report a 71-year-old woman with prior ischemic stroke and major depressive disorder who presented with failure to thrive, behavioral withdrawal, and motor findings consistent with catatonia. Catatonia severity was assessed with the Bush-Francis Catatonia Rating Scale (BFCRS) and the KANNER scale, and she was treated with lorazepam. RESULTS:BFCRS total score improved from 21 at baseline to 11 following lorazepam titration (0.5 mg three times daily increased to 1 mg three times daily). The KANNER Part II score improved from 18 to 10. Clinically, nursing and therapy documentation noted improved engagement, resumption of oral intake, acceptance of medications and hygiene, and participation in physical therapy. At 1- and 5-month follow-up visits, she had no recurrence of catatonic signs by clinical assessment. CONCLUSIONS:This case highlights the need for routine screening for catatonia in medically ill older adults, including those with cerebrovascular disease. When catatonia is present, the risk-benefit balance may favor benzodiazepines despite general geriatric cautions. Explicitly listing catatonia among appropriate indications for benzodiazepines in geriatric prescribing frameworks may reduce treatment delays.
OBJECTIVES:Elevated intracranial pressure (ICP) remains a challenge and immediate danger in patients with acute brain injury. Current literature supports the use of a single hyperosmolar agent to reduce ICP. However, the efficacy and safety of overlapping hyperosmolar agents have not been evaluated. The objectives of this study are to analyze the ICP lowering effects and evaluate the safety profile of overlapping hyperosmolar therapy. MATERIALS AND METHODS:This single-center, retrospective study included adults (≥18 y) admitted to the Neurosciences Intensive Care Unit between May 2018 and September 2024 with acute brain injury leading to intracranial hypertension refractory to a single hyperosmolar agent and an ICP monitor. They received overlapping doses of mannitol and hypertonic sodium approximately every 3 hours. We evaluated the impact of overlapping hyperosmolar therapy on ICP. Safety outcomes included acute kidney injury incidence, electrolyte disturbances, and volume status changes. RESULTS:Forty-six patients were included in this study with a median (IQR) age of 46.5 (35.9, 62.4) years. Median (IQR) dose of mannitol was 40.1 (34.6, 50.0) g, while median (IQR) dose of hypertonic sodium was 120 (90, 125) mEq. About 86% of patients experienced a decrease in ICP after initiation of overlapping hyperosmolar therapy. Six acute kidney injuries occurred, and 7 patients experienced pulmonary edema. Median (IQR) peak sodium, chloride, and osmolar gap values were 149 (144, 155) mEq/L, 115 (111, 119) mEq/L, and 5.7 (0.7, 9.0) mOsm/kg. CONCLUSIONS:Overlapping hyperosmolar therapy may provide a transient ICP reduction without excessive adverse effects in patients with refractory ICP to a single hyperosmolar agent.
OBJECTIVES:A ropinirole patch provides continuous dopaminergic stimulation, permitting its increasing use in clinical practice. Inappropriate dose conversion after switching from other dopamine agonists may cause insufficient efficacy or dose-limiting adverse effects. Moreover, factors influencing dose modification remain unclear. Thus, this study aimed to identify factors associated with the need for dose modification in patients with Parkinson disease who switched from another dopamine agonist to a ropinirole patch. METHODS:In this multicenter, retrospective study, dose trajectories over 3 months were categorized as dose reduction, maintenance, or escalation. Clinical characteristics associated with dose changes were assessed using univariate analyses, followed by ordinal logistic regression to identify independent predictors. Correlations among candidate variables were examined for potential dependency. RESULTS:Of the 110 patients screened, 95 were analyzed. Twenty-two patients required dose reduction or discontinuation, primarily because of dyskinesia, hallucinations, or somnolence, whereas 19 required dose escalation because of insufficient efficacy. Univariate analysis identified female sex, lower body weight, and pre-existing peak-dose dyskinesia as significant factors. In multivariate analysis, lower body weight [odds ratio (OR)=1.04; 95% CI=1.00-1.09] and pre-existing peak-dose dyskinesia (OR=0.38; 95% CI=0.15-0.94) independently predicted dose modification. Model comparisons suggested potential dependency between body weight and female sex. CONCLUSIONS:Pre-existing peak-dose dyskinesia and lower body weight independently influence the need for ropinirole patch dose modification after switching. Individualized dose titration is recommended, particularly in light-weight patients or those with dyskinesia, and prospective studies are warranted to refine dose conversion strategies.
BACKGROUND:Intrinsic capacity (IC), proposed by the World Health Organization, reflects the composite of an individual's physical and mental capacities and is considered a key indicator of healthy aging. Although air pollution has been associated with multiple adverse health outcomes, evidence on its relationship with IC-a multidimensional indicator of overall functional ability-remains limited. OBJECTIVE:This study aimed to examine the longitudinal associations between long-term exposure to particulate matter of different sizes (PM1, PM2.5 and PM10) and declines in intrinsic capacity among middle-aged and older adults in mainland China. METHODS:Data were obtained from the nationally representative longitudinal cohort of the China Health and Retirement Longitudinal Study (CHARLS), including adults aged ≥ 45 years. Annual average concentrations of PM1, PM2.5 and PM10 were estimated using satellite-based models based on participants' residential locations. A composite IC score was constructed according to the WHO intrinsic capacity framework. Multivariable logistic regression models were used to evaluate associations between particulate matter exposure and IC decline. Restricted cubic spline models were applied to assess nonlinear dose-response relationships. Mixed-exposure effects were further evaluated using weighted quantile sum regression, Bayesian kernel machine regression and quantile g-computation. RESULTS:Long-term exposure to PM1, PM2.5 and PM10 was significantly associated with a higher risk of IC decline and lower composite IC scores. Nonlinear dose-response relationships were observed between particulate matter exposure and IC decline. In mixed-exposure analyses, PM10 and PM2.5 showed the strongest contributions to the joint effects, with PM10 having the highest weight and posterior inclusion probability. Each one-quantile increase in the overall pollutant mixture was significantly associated with a decline in composite IC scores.
OBJECTIVES:The Eastern Association for the Surgery of Trauma guidelines conditionally recommend beta blockers for adults with traumatic brain injury (TBI); however, real-world utilization varies widely. This study describes critically ill patients with TBI who received propranolol during their hospitalization. METHODS:This was a retrospective study evaluating patients 18 years or older admitted with TBI to the intensive care unit (ICU) at a level 1 trauma center between January 1, 2015, and April 30, 2023. Patients were identified using the institution's trauma registry and propranolol administration records. The primary outcome was to describe propranolol use in patients admitted with TBI. Secondary outcomes included in-hospital mortality, 28-day mortality, ICU and hospital length of stay, and discharge disposition. Safety outcomes included bradycardia, hypotension, or vasopressor use within 12 hours following propranolol administration. RESULTS:A total of 217 patients were included. Most patients (95.9%) sustained blunt TBI, and the most common bleeding site was mixed (39.6%), followed by subdural (20.7%) and subarachnoid (20.7%). Beta blockers were initiated on average by day 8 with a mean duration of 22.9 days. In-hospital mortality was 18.9%, and 27.2% of patients were discharged to home or with home health. Bradycardia was observed in 40.1% of patients and hypotension or vasopressor use in 14.7%. CONCLUSIONS:In a predominantly severe TBI patient population, most patients received propranolol after 1 week of admission for an average of 3 weeks. Mortality was close to 20% and approximately a quarter of patients were discharged home on a BB.
BACKGROUND:Traumatic brain injury is a leading cause of death and disability worldwide, yet no single drug has proven effective in improving long-term neurological recovery. Understanding the pharmacological efforts made so far is essential for guiding future research and treatment strategies. PURPOSE:This narrative review aimed to summarize current evidence on medications that reduce neurological deficits in TBI and to highlight emerging therapeutic directions toward neural restoration. METHODS:A comprehensive literature search was conducted using MEDLINE, Embase, and ClinicalTrials.gov up to May 2025. Studies in English focusing on human trials, meta-analyses, and relevant translational research were included. Articles were appraised for quality using the GRADE and Cochrane risk-of-bias tools, and findings were summarized thematically. RESULTS:Tranexamic acid given early after injury, nimodipine for traumatic subarachnoid hemorrhage, and short-term anticonvulsants for seizure prevention showed the strongest evidence. Adjunctive drugs such as statins, β-blockers, and SSRIs demonstrated potential benefits in improving vascular, inflammatory, and cognitive outcomes. Newer agents, including minocycline, anakinra, cyclosporine A, and N-acetylcysteine, showed encouraging results in phase II studies. Advances in biomarkers, imaging, and adaptive trials are improving patient selection and precision dosing. CONCLUSION:Progress in TBI pharmacotherapy is shifting from symptom control toward neurorepair. Continued research integrating biomarkers, affordable therapies, and personalized approaches holds promise for reducing disability and improving recovery after TBI.
BACKGROUND:Type 2 Diabetes Mellitus (T2DM) and AF (Atrial Fibrillation) frequently coexist, amplifying cardiovascular risks via shared mitochondrial dysfunction involving metabolic dysregulation, oxidative stress, and inflammation. While the SGLT2 inhibitor dapagliflozin (DAPA) demonstrates cardiorenal protection through mitochondrial improvement, its direct mechanistic actions in T2DM-AF patients remain unknown. Our study aimed to elucidate DAPA's mitochondrial regulatory mechanisms in T2DM-AF to break the vicious cycle of mitochondrial dysfunction remodelling, addressing an unmet clinical need in this high-risk population. METHODS:The high-glucose atrial fibrillation (HG-AF) model was established using 30 mM glucose combined with 10 Hz electrical stimulation, followed by validation through glucose uptake assay, electrophysiology, and fibrosis-related protein and calcium transient analysis. Mitochondrial function was evaluated using ROS/JC-1 probes, ATP quantification, and mitochondrial-related protein expression. To investigate the role of DAPA, we assessed its activation of the AMPK/PGC-1α/SIRT3 signalling pathway via western blot and further confirmed the mechanism using the AMPKα inhibitor Compound C. In addition, a mouse model of HG-AF was established to further validate the in vitro results. RESULTS:Cell experiments showed that after treatment with 30 mM glucose and 10 Hz electrical stimulation, HL-1 cells exhibited increased 2-NBDG uptake, decreased Fluo-4 AM intensity, upregulation of glucose transporters and fibrosis-related proteins, and disrupted electrophysiological protein expression, confirming the successful establishment of the HG-AF model. DAPA treatment attenuated fibrosis, restored electrophysiological protein expression, decreased Drp1, and increased OPA1 and SOD2 levels. It also enhanced Fluo-4 AM intensity, reduced ROS, improved JC-1 aggregates, and boosted ATP production. In vivo experiments further confirmed that in HG-AF mice, the duration of AF and the RR interval were significantly prolonged, and there was upregulation of CaMKII/ox-CaMKII, downregulation of ion channel proteins, and elevated levels of fibronectin in cardiac tissue. DAPA treatment activated the AMPK/PGC-1α/SIRT3 pathway, reduced the acetylation levels of OPA1 and SOD2, increased ATP levels, and decreased MDA levels. Pretreatment with Compound C abolished the DAPA-induced activation of the aforementioned pathway and the improvement in mitochondrial function. CONCLUSION:In the HG-AF setting, DAPA attenuated cardiomyocyte damage by enhancing mitochondrial function through activation of the AMPK/PGC-1α/SIRT3 signalling pathway.
OBJECTIVES:This systematic review aims to assess the efficacy and tolerability of ketamine in the treatment of obsessive-compulsive disorder. BACKGROUND:Obsessive-compulsive disorder is a chronic and severe disorder characterized by intrusive thoughts and repetitive behaviours that can cause significant distress. Notwithstanding current treatments and interventions for obsessive-compulsive disorder, some individuals still do not adequately respond to conventional pharmacotherapeutic and/or psychotherapeutic interventions. Emerging evidence indicates that ketamine, an N-methyl-D-aspartate receptor antagonist, could have potential rapid-acting and enduring efficacy in the treatment of obsessive-compulsive disorder. METHODS:A systematic search was conducted with OVID, PubMed, and Scopus from database inception to July 2025. Two independent reviewers (I.H. and M.C.S.) screened the studies, assessed methodological quality, and extracted pertinent data. Five studies (3 randomized controlled trials and 2 open-label trials) were deemed eligible for inclusion and included variable routes of administration (intravenous, intramuscular, and oral) and dosing frequencies. RESULTS:Across studies, ketamine consistently and significantly improved overall obsessive-compulsive disorder symptom severity, with reductions up to 50% to 60%; however, the duration of effects varied from a few hours postinfusion to 6 weeks. Overall, ketamine was generally well tolerated. CONCLUSIONS:Further research should focus on optimizing ketamine treatment (ie, dosing regimens, routes of administration) for sustained symptom reduction.
OBJECTIVES:Clozapine is regarded as the gold standard pharmacotherapy agent for treatment-resistant schizophrenia patients. However, myocarditis and pericarditis, which are significant life-threatening side effects of clozapine, should be closely monitored. These side effects frequently manifest with subtle and insidious symptoms that can be easily misinterpreted as psychiatric symptoms, thereby complicating their identification. Consequently, a high level of clinical awareness and suspicion is imperative. METHODS:Cases of clozapine-associated myocarditis and pericarditis are presented in this study. Following a detailed examination of the electronic records, the patient data are presented. RESULTS:In the first case, tachycardia, hypertension, elevated C-reactive protein (CRP) and troponin T levels, and echocardiographic findings indicative of myocarditis led to a diagnosis of myocarditis. In the second patient, flu-like symptoms, electrocardiogram changes, elevated CRP levels on day 10, and the presence of effusion on echocardiography, but without troponin elevation, led to a diagnosis of pericarditis. In both cases, due to early suspicion, a cardiology consultation was requested, followed by further investigations as recommended, resulting in the diagnoses. Immediate discontinuation of clozapine resulted in rapid resolution of systemic inflammation and normalization of vital signs. CONCLUSIONS:These cases emphasize the dual necessity of clozapine monitoring: early identification and management of cardiac complications, and the judicious approach to discontinuation, avoiding premature cessation based on nonspecific findings. Timely, multidisciplinary evaluation is integral to ensuring cardiac safety and uninterrupted psychiatric treatment.
BACKGROUND:Atherosclerosis (AS) is a major cause of cardiovascular diseases, with OX-LDL-induced VSMC dysfunction being a critical pathogenic driver of AS development. Saikosaponin D (SSD), a bioactive compound, shows therapeutic potential, but its mechanism in AS is unclear. METHODS:An atherosclerotic cell model was established by treating hVSMCs with OX-LDL. Intracellular ROS was detected via a fluorescent probe, MDA content and SOD activity via biochemical kits. Inflammatory cytokines (IL-6, IL-8 and TNF-α) were quantified by ELISA. Lipid parameters (TG, LDL and HDL) were analysed biochemically, and intracellular lipid accumulation was assessed via Oil Red O staining. Autophagy (LC3B and p62) and senescence-related (p16 and p21) protein expression was detected by WB, with cellular senescence further assessed via SA-β-gal staining. SSD's potential targets were predicted via bioinformatics (CTD, SwissTargetPrediction and GeneCards). SSD-EPHB2 interaction was predicted by AutoDock Vina docking (visualised by PyMOL), and its stability was evaluated by using iMODS-based NMA. EPHB2's functional role was confirmed via its overexpression in hVSMCs. RESULTS:SSD significantly attenuated OX-LDL-induced oxidative stress, inflammation, lipid accumulation, autophagic flux impairment and cellular senescence in hVSMCs. Bioinformatics analysis pinpointed EPHB2 as a hub gene. Molecular studies confirmed that SSD directly binds to EPHB2 and downregulates its expression. Crucially, overexpressing EPHB2 abolished all the protective effects of SSD. CONCLUSION:SSD alleviates OX-LDL-induced hVSMC dysfunction by inhibiting EPHB2, highlighting the SSD-EPHB2 pathway as a potential therapeutic target for AS.
PURPOSE:To explore the feasibility of phase contrast (PC) MRI and three-dimensional pulsed arterial spin labelling (3D PASL)-MRI in assessing cerebrovascular blood flow changes after surgical revascularization in patients with moyamoya disease (MMD). METHODS:This study was a prospective study and comprised two sections. In the first section, 43 patients with MMD who never underwent any revascularization surgery and 19 healthy control volunteers were enrolled. In the second section, 51 patients with MMD who underwent revascularization surgery were included. PC-MRI and 3D PASL-MRI were performed. The average blood flow in the internal carotid (ICA), basilar (BA), superficial temporal (STA) arteries and cerebral blood flow (CBF) were compared between the MMD patients and control volunteers (first section) as well as before and after surgery (second section). Then, MMD patients were divided into haemorrhage and non-haemorrhage subgroups and the average blood flow and CBF before and after surgery were compared between the subgroups. RESULTS:The average flow in the ICA, BA, STA was lower in the MMD patients than in the healthy control group (p = 0.000, p = 0.001, p = 0.001). The CBF of the seven clusters was higher in the healthy controls than in the MMD patients' groups. The average flow in the ICA, BA and STA was increased in MMD patients after combined surgery (p = 0.000, p = 0.002, p = 0.000). Fifteen clusters of elevated CBF and one of reduced CBF were postoperatively evident. Eight clusters of elevated CBF were compared with the preoperative status in the patients without haemorrhage. In the haemorrhage group, postoperative CBF did not significantly change after combined surgery (p > 0.05). CONCLUSION:Both 3D PASL-MRI and PC-MRI can noninvasively evaluate CBF changes in patients with MMD after surgery. The CBF of the cerebral was significantly improved after surgery. Moreover, the improvement of CBF was more obvious in patients with non-hemorrhagic rather than hemorrhagic MMD.
