Target For Treatment Research Articles

Nudix Hydrolase 13 Impairs the Initiation of Colorectal Cancer by Inhibiting PKM1 ADP-Ribosylation.

Metabolic dysregulation has been implicated as a key factor in colorectal cancer (CRC) initiation, however, the underlying driving forces and mechanisms remain poorly understood. Herein, transcriptome profiling of paired early-stage CRCs and adenomas identifies Nudix hydrolase 13 (NUDT13) as a critical suppressor. Elevated NUDT13 expression impedes the proliferation of CRC cells under hypoxic conditions and markedly inhibits CRC initiation by upregulating PKM1. Mechanistically, NUDT13 directly binds and stabilizes PKM1 protein by reducing its poly ADP-ribosylation (PARylation), which is catalyzed by PARP1 at E275/D281/E282/E285/D296, thereby inducing an oxidative phosphorylation (OXPHOS) phenotype in CRC cells. Moreover, spatiotemporal knockout of Nudt13 enhances intestinal tumorigenesis in mice, which can be significantly suppressed by PARP1 inhibitor Olaparib. Notably, residues E245/E248/E249 within the Nudix box motif of NUDT13 are essential for PKM1 PARylation, and a mimic peptide derived from this motif is sufficient to stabilize PKM1 protein and robustly inhibit CRC tumorigenesis. Collectively, this study reveals a previously unknown PARylation-dependent mechanism that regulates PKM1 protein stability and switches the metabolic pathway of CRC cells, providing a promising target for CRC treatment.

TRIM21 Promotes Endothelial Cell Activation via Accelerating SOCS3 Ubiquitination Degradation in Atherosclerosis.

Activated endothelial cells play an important role in the beginning of atherosclerotic disease by secreting various proteins and inflammatory cytokines. Ubiquitination is one of the most common post-translational changes in cells. However, the role and mechanisms of ubiquitination in endothelial cell activation remain poorly understood. In this study, we identified TRIM21 as an E3 ubiquitin ligase with increased expression in atherosclerotic disease and activated endothelial cells. Knockdown of TRIM21 resulted in reduced secretion of inflammatory factors and attenuated the pyroptosis of endothelial cells, inhibiting the progression of atherosclerosis. Mechanistically, TRIM21 could bind and ubiquitinate SOCS3, thereby enhancing NLRP3-mediated pyroptosis. Taken together, we found that endothelial TRIM21 activated the JAK/STAT3 pathway by degrading SOCS3, which in turn promoted NLRP3-mediated pyroptosis and aggravated atherosclerosis, revealing that TRIM21 may be a promising treatment target for the medical management of atherosclerosis.

Voltage-gated calcium channel α2δ-1 subunit is involved in the regulation of glucose-stimulated GLP-1 secretion in mice.

Glucagon-like peptide-1 (GLP-1) is an incretin produced by enteroendocrine preproglucagon (PPG)-expressing cells in response to nutrient ingestion that potentiates insulin secretion. The voltage-gated Ca2+ channel has been reported previously to be involved in glucose-stimulated GLP-1 secretion; in this study, we show that PPG-cells in upper and lower small intestine substantially express the voltage-gated Ca2+ channel α2δ-1 subunit (CaVα2δ-1). In vitro experiments using NCI-H716 cells demonstrate that inhibition of CaVα2δ-1 by gabapentin, an inhibitory ligand of the α2δ subunit, attenuates glucose-stimulated intracellular calcium elevation and reduces GLP-1 secretion. In addition, systemic administration of gabapentin significantly reduces glucose-stimulated GLP-1 secretion without affecting blood glucose levels in wild-type mice. Furthermore, knockout mice of intestine-specific Cacna2d1, a gene encoding CaVα2δ-1, exhibit reduced GLP-1 secretion in response to oral glucose administration regardless of sex. These results demonstrate that CaVα2δ-1 expressed in PPG-cells plays an important role in glucose-stimulated GLP-1 secretion and represents a potential target in treatment of diabetes and obesity.

Mediating effect of X-26109 on the causal relationship between CD14+ CD16- monocyte activation complex and rheumatoid arthritis in Europe.

The regulation of the immune system is crucial in the pathogenesis of various diseases. The direct involvement of immune cells in the development of rheumatoid arthritis (RA) and the potential mediation by metabolites remains to be elucidated. This study utilized a two-step, two-sample Mendelian randomization (MR) approach employing the inverse variance weighted (IVW) method to investigate the causal role of immune cells in RA and to assess the mediation effect of metabolites on the association between immune cells and RA. MR analyses identified 44 immune cell traits that were suggestively associated with RA. Additionally, five metabolites demonstrated protective effects against RA. Notably, mediation MR indicated that the causal role of CD14+ CD16- monocyte activation complex (AC) on RA (total effect IVW: OR = 0.978, 95% CI [0.959, 0.998], P = 0.028) was significantly mediated by X-26109 levels, accounting for 7.32% of the total effect. This study provides evidence of a causal relationship between immune cells and RA, with metabolites potentially mediating this relationship. Key Points • Mendelian randomization (MR) analysis was used to investigate the causal impact of immune cells on RA progression and the potential mediating role of metabolites, identifying 44 immune cell traits and several metabolites associated with RA risk • The study found that CD14 + CD16 - monocyte activation complex (AC) is associated with a reduced RA risk, with this effect largely mediated by metabolite X-26109 levels, suggesting a potential therapeutic target for RA prevention and treatment.

Potential of lactylation as a therapeutic target in cancer treatment (Review)

Potential of lactylation as a therapeutic target in cancer treatment (Review)

Overexpression of metalloproteinase PAPPA accelerates cancer progression and correlates with immune cell infiltration in gastric cancer: insights from bioinformatics and in vitro investigations

BackgroundGastric cancer (GC) is one of the most common malignant tumors in the digestive system. However, the development of its targeted therapies has been slow. Therefore, exploring the mechanisms of malignant behavior of GC is key to developing their treatment methods. Pregnancy-associated plasma protein-A(PAPPA) is thought to play an important role in the occurrence and progression of cancer, yet its significance in the development of GC has not been reported.MethodsBioinformatics analysis elucidated PAPPA's expression in GC and its prognostic significance. The study correlated PAPPA expression with immune infiltration and signaling pathways. Cellular assays, including CCK-8, Western blotting, and flow cytometry, were utilized to examine PAPPA's role in gastric cancer cell apoptosis, migration, and invasion.ResultsBioinformatics analysis has demonstrated that the expression of PAPPA is upregulated in GC and correlates with poor prognosis. Correlation and Cox regression analyses have revealed that TNM staging, pathological staging, age, outcome assessment, postoperative tumor residue, and PAPPA expression are prognostic determinants in GC. Further analysis indicates that PAPPA is associated with the infiltration of various immune cells and pathways related to GC. Cellular experiments have shown that PAPPA promotes cell proliferation, and its deficiency can inhibit the proliferation of GC cells, inducing cell cycle arrest at the G1/S phase.ConclusionsThe findings of this investigation suggest that PAPPA serves as a crucial modulator of GC, underscoring its potential as a GC treatment target.

Hollow cerium nanoparticles synthesized by one-step method for multienzyme activity to reduce colitis in mice

BACKGROUND Inflammatory bowel disease (IBD) is a common chronic intestinal inflammatory disease. High oxidative stress is a treatment target for IBD. Cerium oxide (CeO2) nanomaterials as nanozymes with antioxidant activity are potential drugs for the treatment of colitis. AIM To synthesize hollow cerium (H-CeO2) nanoparticles by one-step method and to validate the therapeutic efficacy of H-CeO2 in IBD. METHODS H-CeO2 was synthesized by one-step method and examined its characterization and nanoenzymatic activity. Subsequently, we constructed dextran sulfate sodium (DSS)-induced colitis in mice to observe the effects of H-CeO2 on colonic inflammation. The effects of H-CeO2 on colon inflammation and reactive oxygen species (ROS) levels in IBD mice were detected by hematoxylin and eosin staining and dichlorofluorescein diacetate staining, respectively. Finally, the biological safety of H-CeO2 on mice was evaluated by hematoxylin and eosin staining, blood routine, and blood biochemistry. RESULTS H-CeO2 nanoparticles prepared by the one-step method were uniform, monodisperse and hollow. H-CeO2 had a good ability to scavenge ROS, ∙OH and ∙OOH. H-CeO2 reduced DSS-induced decreases in body weight and colon length, colonic epithelial damage, inflammatory infiltration, and ROS accumulation. H-CeO2 administration reduced the disease activity index of DSS-induced animals from about 8 to 5. H-CeO2 had no significant effect on body weight, total platelet count, hemoglobin, white blood cell, and red blood cell counts in healthy mice. No significant damage to major organs was observed in healthy mice following H-CeO2 administration. CONCLUSION The one-step synthesis of H-CeO2 nanomaterials had good antioxidant activity, biosafety, and inhibited development of DSS-induced IBD in mice by scavenging ROS.

Identification of the immune infiltration and biomarkers in ulcerative colitis based on liquid–liquid phase separation-related genes

Liquid–liquid phase separation (LLPS) associates with immune infiltration in multiple diseases. Nonetheless, the role of LLPS-related genes (LLPS-RGs) in immune infiltration of ulcerative colitis (UC) is still elusive. We identified the hub LLPS-RGs (DE-LLPS-RGs) (HSPB3, SLC16A1, TRIM22, SRI, PLEKHG6, GBP1, PADI2) by machine learning algorithms. Hub genes were screened that displayed high prediction accuracy of UC patients. Both the microarray and scRNA-seq datasets showed a strong correlation with immune cell infiltration and cytokines, especially GBP1, TRIM22, SRI. And qRT-PCR analysis showed that GBP1 play a pro-inflammatory role in UC. Two distinct clusters were identified, in which cluster A displayed higher immune infiltration level compared with the cluster B. The top targeted biological pathways of two clusters were distinct, glutamate receptor antagonist ranked top for cluster A while HDAC inhibitor ranked top in cluster B. External cohort and UC cell model validation indicated the similar immune infiltration levels, gene expression and cytokine expression patterns. We determined the seven high accuracy diagnostic genes of UC patients and provide a new perspective on immunoregulation in UC pathogenesis. And suggest patient stratification and candidate targets for precision treatment based on hub genes screened.

A pan-cancer analysis of homeobox family: expression characteristics and latent significance in prognosis and immune microenvironment

BackgroundThe Homeobox (HOX) gene family are conserved transcription factors that are essential for embryonic development, oncogenesis, and cancer suppression in biological beings. Abnormally expressed HOX genes in cancers are directly associated with prognosis.MethodsPublic databases such as TCGA and the R language were used to perform pan-cancer analyses of the HOX family in terms of expression, prognosis, and immune microenvironment. The HOX score was defined, and potential target compounds in cancers were predicted by Connective Map. Immunohistochemistry was employed to validate protein expression levels. Gene knockdowns were used to verify the effects of HOXB7 and HOXC6 on the proliferation and migration of lung adenocarcinoma (LUAD) cells.ResultsHOX genes play different roles in different cancers. Many HOX genes, especially HOXB7 and HOXC6, have higher expression and lower overall survival in specific cancers and are predicted as risk factors. The high expression of most HOX genes is mainly related to immune subtypes C1-C4 and C6. Potential anti-tumor compounds for down-regulating HOX gene expression were identified, such as HDAC inhibitors and tubulin inhibitors. LUAD Cell migration and proliferation were inhibited when HOXB7 or HOXC6 was knocked down.ConclusionsMany HOX genes may act as both oncogenes and tumor suppressor genes, necessitating precision medicine based on specific cancers. The HOX gene family plays a crucial role in the development of certain cancers, and their expression patterns are closely related to cancer prognosis and the tumor microenvironment (TME), which may affect cancer prognosis and response to immunotherapy. Compounds that are negatively correlated with the expression levels of the HOX family in various cancers, such as HDAC inhibitors, are potential anti-cancer drugs. HOXB7 and HOXC6 may serve as potential targets for cancer treatment and the development of targeted compounds in the future.

Impaired hippocampal neurogenesis associated with regulatory ceRNA network in a mouse model of postoperative cognitive dysfunction

BackgroundPostoperative cognitive dysfunction (POCD) represents a post-surgical complication that features progressive cognitive impairment and memory loss, often occurring in elderly patients. This study aimed to investigate the potential biological mechanisms underlying POCD.MethodsMale C57BL/6 mice (2 and 17 months old) were randomly assigned to surgery or control groups. The surgery group underwent laparotomy under 1.5% isoflurane anesthesia, while controls received no intervention. Cognitive function was assessed 7–10 days post-surgery using open field, Y-maze, and novel object recognition tests.Hippocampal mRNA expression was analyzed using Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. A competing endogenous RNA (ceRNA) network was constructed using microRNA (miRNA) target prediction databases (miRanda, miRTarbase, miRcode) and sequencing results. Key findings were validated by RT-qPCR and immunofluorescence. The Connectivity Map (CMap) database was queried to predict potential POCD treatments.ResultsAging significantly affected mice’s spontaneous activity in the open field test (F1, 28 = 8.933, P < 0.01) and the proportion of time spent in the center area (F1, 28 = 5.387, P < 0.05). Surgery significantly reduced the rate of spontaneous alternations in the Y-maze (F1, 28 = 16.94, P < 0.001) and the recognition index in novel object recognition test (F1, 28 = 6.839, P < 0.05) in aging mice, but had no effect on young mice. Transcriptome analysis revealed that aging and surgery downregulated multiple neurogenesis-related genes in the hippocampus. Doublecortin (DCX) immunofluorescence staining confirmed reduced hippocampal neurogenesis in aging mice, which was further decreased after surgery. We identified several key lncRNAs and miRNAs implicated in neurogenesis regulation. Additionally, drugs were predicted as potential therapeutic candidates for POCD treatment.ConclusionBoth aging and surgery have complex effects on the hippocampal transcriptome in mice. The significant decrease in neurogenesis may be a potential reason for the increased susceptibility of aging mice to POCD. The identified key regulatory lncRNAs, miRNAs, and drugs provide potential therapeutic targets for POCD prevention and treatment.

ACSM3 Suppresses Ovarian Cancer Progression by Inactivating the IFN-γ/JAK/STAT3 Signaling Pathway.

This study aimed to investigate the role of Acyl-CoA medium-chain synthetase 3 (ACSM3) in ovarian cancer (OC) progression. ACSM3 expression in OC tissues and cells is detected by real-time quantitative polymerase chain reaction, immunohistochemistry, or western blot. The influences of ACSM3 on OC progression are assessed in vitro and in vivo experiments. Gene set enrichment analysis is performed to find significantly enriched pathways related to ACSM3. In this study, ACSM3 expression in OC tissues and cells is downregulated. ACSM3 inhibited tumor growth in vivo. Knockdown of ACSM3 promoted cell proliferation, migration, and invasion, inhibited cell apoptosis, and activated JAK/STAT3 signaling pathway in SKOV3 cells, while overexpression of ACSM3 in A2780 cells led to the opposite results. Moreover, treatment with interferon-gamma (IFN-γ) in A2780 cells reversed the effects of ACSM3 on cell proliferation, migration, invasion, and apoptosis, but IFN-γ further enhanced the effects of ACSM3 knockdown on SKOV3 cell proliferation, migration, invasion, and apoptosis. In conclusion, ACSM3 inhibited OC cell proliferation, migration, and invasion, and promoted cell apoptosis by suppressing the IFN-γ/JAK/STAT3 signaling pathway, which might provide a promising therapeutic target for OC treatment.

E2F1-Dependent CDCA5 overexpression drives cervical cancer progression and correlates with poor prognosis.

Cervical cancer (CC) remains a leading cause of cancer-related mortality in women worldwide, highlighting the urgent need for novel therapeutic strategies. This study investigates the molecular mechanisms and clinical significance of Cell Division Cycle Associated 5 (CDCA5) in cervical cancer progression. We performed comprehensive analyses of CDCA5 expression in cervical cancer and normal tissues, correlating expression levels with clinicopathological features and patient outcomes. Functional studies using CC cell lines (SiHa, HeLa, and CaSki) examined the effects of CDCA5 manipulation on tumor cell behavior. We identified E2F1 as a key transcriptional regulator of CDCA5 and validated our findings using in vivo xenograft models. CDCA5 was significantly upregulated in CC tissues and correlated with advanced disease stages and poor survival outcomes. Mechanistically, CDCA5 depletion in SiHa and HeLa cells suppressed proliferation, migration, and invasion, while its overexpression in CaSki cells enhanced these malignant properties. We identified E2F1 as a transcriptional activator of CDCA5. Importantly, CDCA5 knockdown significantly inhibited tumor growth in nude mouse models. Our findings establish CDCA5 as a critical E2F1-regulated oncogenic factor in cervical cancer progression. The strong correlation between CDCA5 expression and poor clinical outcomes suggests its potential as both a prognostic biomarker and therapeutic target in cervical cancer treatment.

Ubiquitin-specific peptidase 14 promotes neuron injury by stabilizing acyl-CoA synthetase long-chain family member 4 through deubiquitination

Objective: Ubiquitin-specific peptidase 14 (USP14) may be a target for stroke treatment. Our study aims to explore the molecular mechanism of USP14 in the stroke process. Material and Methods: A stroke cell model was constructed using oxygen–glucose deprivation/reoxygenation (OGD/R)-induced SK-N-SH cells, and cell growth was assessed using cell counting kit 8 assay, EdU assay, and flow cytometry. Proinflammatory cytokine levels were tested through an enzyme-linked immunosorbent assay. The levels of USP14 and acyl-CoA synthetase long-chain family member 4 (ACSL4) were determined through Western blot and quantitative real-time polymerase chain reaction, whereas the interaction of USP14 and ACS14 was evaluated by co-immunoprecipitation assay. Results: OGD/R-induced SK-N-SH cell injury by enhancing ferroptosis and the knockdown of USP14 inhibited OGD/R-induced cell inflammation, apoptosis, and ferroptosis. Moreover, USP14 enhanced ACSL4 protein expression through deubiquitination. ACSL4 silencing mitigated neuron injury, and ACSL4 upregulation abolished USP14 knockdown-mediated inhibition of neuron injury. Conclusion: USP14 can enhance neuron injury through stabilizing ACSL4 protein expression.

Home Environment as a Therapeutic Target for Prevention and Treatment of Chronic Diseases: Delivering Restorative Living Spaces, Patient Education and Self-Care by Bridging Biophilic Design, E-Commerce and Digital Health Technologies

A high prevalence of chronic diseases exposes diverse healthcare pain points due to the limited effectiveness of pharmaceutical drugs and biologics, sedentary lifestyles, insufficient health literacy, chronic stress, unsatisfactory patient experience, environmental pollution and competition with commercial determinants of health. To improve patient care and long-term outcomes, the impact of the home environment is overlooked and underutilized by healthcare. This cross-disciplinary work describes perspectives on (1) the home environment as a therapeutic target for the prevention and treatment of chronic diseases and (2) transforming health-centric household goods e-commerce platforms into digital health interventions. We provide a rationale for creating therapeutic home environments grounded in biophilic design (multisensory, environmental enrichment) and supporting physical activities, quality sleep, nutrition, music, stress reduction, self-efficacy, social support and health education, hence providing clinical benefits through the modulation of the autonomic nervous system, neuroplasticity and behavior change. These pleiotropic “active non-pharmacological ingredients” can be personalized for people living with depression, anxiety, migraine, chronic pain, cancer, cardiovascular and other conditions. We discuss prospects for integrating e-commerce with digital health platforms to create “therapeutic home environment” interventions delivered through digital therapeutics and their combinations with prescription drugs. This multimodal approach can enhance patient engagement while bridging consumer spending with healthcare outcomes.

Chronic asymptomatic orchitis in dogs alters Sertoli cell number and maturation status

Infertility due to non-obstructive azoospermia is a common diagnosis in infertile male dogs. Chronic asymptomatic orchitis (CAO) has been postulated as a significant cause of non-obstructive azoospermia in acquired male canine infertility. Despite severe microenvironmental changes, some resilient spermatogonial stem cells persist in CAO-affected testes. As Sertoli cells play an essential role in spermatogenesis and the testicular micromilieu, they represent a new target for CAO potential treatment and consequently deserve further investigation. To investigate Sertoli cell number and maturational status, different markers [Vimentin, anti-Müllerian hormone (AMH), and cytokeratin-18 (CK18)] were evaluated in healthy and CAO-affected testes at mRNA and protein levels. Sertoli cell number was reduced in CAO-affected dogs. Sertoli cells also partly returned to an immature status, as indicated by the expression of AMH and CK18 at mRNA and protein levels. The degree of spermatogenesis disruption matched with the degree of Sertoli cell alterations. The investigation of CAO in this study is limited by the number of samples and the lack of testicular volume measurements, but this does not diminish its importance in new findings. In conclusion, this study identifies alterations in Sertoli cell number and maturation status as a cause or consequence of CAO. The results indicate the need to restore Sertoli cell function as a potential therapeutic target for a successful restart of spermatogenesis.

Identifying common pathways for doxorubicin and carfilzomib-induced cardiotoxicities: transcriptomic and epigenetic profiling

Cancer therapy-related cardiovascular toxicity (CTR-CVT) is now recognised as one of the leading causes of long-term morbidity and mortality in cancer patients. To date, potential overlapping cardiotoxicity mechanism(s) across different chemotherapeutic classes have not been elucidated. Doxorubicin, an anthracycline, and Carfilzomib, a proteasome inhibitor, are both known to cause heart failure in some patients. Given this common cardiotoxic effect of these chemotherapies, we aimed to investigate differential and common mechanism(s) associated with Doxorubicin and Carfilzomib-induced cardiac dysfunction. Primary human cardiomyocyte-like cells (HCM-ls) were treated with 1 µM of either Doxorubicin or Carfilzomib for 72 h. Both Doxorubicin and Carfilzomib induced a significant reduction in HCM cell viability and cell damage. DNA methylation analysis performed using MethylationEPIC array showed distinct and common changes induced by Doxorubicin and Carfilzomib (10,270 or approximately 12.9% of the DMPs for either treatment overlapped). RNA-seq analyses identified 5,643 differentially expressed genes (DEGs) that were commonly dysregulated for both treatments. Pathway analysis revealed that the PI3K-Akt signalling pathway was the most significantly enriched pathway with common DEGs, shared between Doxorubicin and Carfilzomib. We identified that there are shared cardiotoxicity mechanisms for Doxorubicin and Carfilzomib pathways that can be potential therapeutic targets for treatments across 2 classes of anti-cancer agents.

SOX9: a key transcriptional regulator in organ fibrosis

The SOX9 gene locus is not only extensive but also intricate, and it could promote fibrosis in different organs or tissues, including cardiac fibrosis, liver fibrosis, kidney fibrosis, pulmonary fibrosis, as well as other organ fibrosis. Many disorders are associated with the process of fibrosis; moreover, fibrosis is a common symptom of chronic inflammatory diseases, characterized by the accumulation of excessive components in the extracellular matrix through different signaling pathways. The advanced stage of the fibrotic process leads to organ dysfunction and, ultimately, death. In this review, we first give an overview of the original structure and functions of SOX9. Second, we will discuss the role of SOX9 in fibrosis in various organs or tissues. Third, we describe and reveal the possibility of SOX9 as an antifibrotic treatment target. Finally, we will focus on the application of novel technologies for SOX9 and the subsequent investigation of fibrosis.

Deconstructing the nature of emotion regulation impairments at the identification, selection, and implementation stages in individuals at clinical high-risk for psychosis.

Psychotic disorders are characterized by emotion regulation abnormalities that predict greater symptom severity and poor functional outcomes. However, it is unclear whether these abnormalities also occur in individuals at clinically high risk for psychosis (CHR). The current study used ecological momentary assessment (EMA) to address this question and examined the nature of abnormalities at three stages of emotion regulation (identification, selection, implementation). Participants included 120 CHR and 59 CN who completed 1week of EMA surveys evaluating emotional experience, emotion regulation, context, and symptoms. Multi-level models examined concurrent and time-lagged effects. CHR evidenced elevated state negative affect and abnormalities at all three stages of emotion regulation. At the identification stage (i.e., determining the need to regulate), regulatory attempts were made too frequently and with too much effort at low levels of negative affect and not frequently enough and with insufficient effort at high levels of negative affect. Selection stage abnormalities (i.e., choosing the exact strategy to attempt based on context) were characterized by increased frequency of selecting individual strategies and greater polyregulation (i.e., use of multiple strategies concurrently). Implementation stage (i.e., executing the selected strategy) abnormalities were indicated by being less effective at decreasing the intensity of negative affect from time t to t+1. It is not only heightened stress reactivity that confers risk for psychosis, but also abnormalities in applying emotion regulation strategies to control the stress response. The profile of abnormalities observed in CHR is similar to schizophrenia, suggesting treatment targets that transcend phases of psychotic illness.

Blood pressure and in-hospital outcomes in patients hospitalized with atrial fibrillation: findings from the CCC-AF project.

The relationship between blood pressure (BP) levels and adverse outcomes in patients with atrial fibrillation (AF) is incompletely understood. Our study aims to elucidate the relationship between BP levels upon admission and in-hospital outcomes in patients hospitalized with AF. Based on the Improving Care for Cardiovascular Disease in China-AF (CCC-AF) project, patients hospitalized with AF collected from 236 hospitals in China from 2015 to 2019 were included in current analysis. A total of 60 390 patients hospitalized with AF were included. Using systolic BP (SBP)/diastolic BP (DBP) of 130-139/80-89 mmHg upon admission as the reference, SBP/DBP ≥160/100 mmHg was associated with an increased risk of stroke/transient ischemic attack (TIA) (adjusted OR, 1.65; 95% CI, 1.27-2.15; P < 0.001) and heart failure (HF) (adjusted OR, 1.29; 95% CI, 1.18-1.41; P < 0.001). SBP/DBP < 120/ < 80 mmHg was associated with an increased risk of HF (adjusted OR, 1.24; 95% CI, 1.14-1.34; P < 0.001), and all-cause death (adjusted OR, 1.90; 95% CI, 1.90-3.86; P < 0.001). A similar pattern was observed in the analysis of the relationship between SBP and DBP levels and in-hospital outcomes, respectively. Among patients hospitalized with AF, higher BP levels upon admission are associated with an increased risk of stroke/TIA and HF, and lower BP levels are associated with an increased risk of HF and all-cause death. Hence, physicians should pay attention to higher and lower BP levels. Randomized trials to identify the optimal treatment target for AF patients are warranted.

Improvements in Exercise for Alzheimer's Disease: Highlighting FGF21-Induced Cerebrovascular Protection.

Alzheimer's disease (AD) is the most common neurodegenerative disease. Currently, it has shown a trend of earlier onset, with most patients experiencing a progressive decline in cognitive function following the disease's onset, which places a heavy burden on society and family. Since no drug cure for AD exists, exploring new ways for its treatment and prevention has become critical. Early vascular damage is an initial trigger for neuronal injury in AD, underscoring the importance of vascular health in the early stages of the disease. Patients with early AD experience abnormal blood-brain barrier transport of amyloid-β (Aβ) peptides, with excess Aβ being deposited in the cerebral vasculature. The toxic effects of Aβ lead to abnormalities in cerebrovascular structure and function. Fibroblast growth factor21 (FGF21) is an endocrine factor that positively regulates energy homeostasis and glucose-lipid metabolism. Notably, it is one of the effective targets for metabolic disease prevention and treatment. Recent studies have found that FGF21 has anti-aging and vasoprotective effects, with receptors for FGF21 present in the brain. Exercise stimulates the liver to produce large amounts of FGF21, which enters the blood-brain barrier with the blood to exert neurovascular protection. Therefore, we review the biological properties of FGF21, its role in the cerebrovascular structure and function in AD, and the mechanism of exercise-regulated FGF21 action on AD-related cerebrovascular changes, aiming to provide a new theoretical basis for using exercise to ameliorate degenerative neurological diseases.