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Longer-term effects of chiropractic care on neuroplasticity, stress, and immune biomarkers remain unclear. This study evaluates the effects of chiropractic care on physiological biomarkers, including brain-derived neurotrophic factor (BDNF), cortisol (saliva, blood, hair), and inflammatory cytokines [interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), C-reactive protein (CRP), B-lymphocytes (CD19), T-helper cells (CD4), cytotoxic T cells (CD8), and natural killer cells (CD56)] in subclinical spinal pain patients. Parallel-group, pragmatic randomized controlled trial conducted at the Rehabilitation Center of Railway General Hospital, Rawalpindi, Pakistan. Intervention: 12 weeks; follow-up: 16 weeks (May-December 2022). Participants with subclinical spinal pain were randomly assigned by using simple lottery method to either 12 weeks of chiropractic or sham care. We aimed to recruit up to 150 participants over three months; however, given the pragmatic nature of the trial and logistical constraints, including the availability of chiropractors, the final number enrolled was determined by how many eligible participants could be recruited during this time. Adults aged 20-60 years with subclinical spinal pain (n = 106 randomized; 88 completed 12-week measures; 73 completed 16-week follow-up). Among those who finished 12 weeks: chiropractic, 26 males/15 females, mean age 37.49 ± 12.39 years; sham, 24 males/23 females, mean age 26.85 ± 7.13 years. The primary outcome blood BDNF and secondary outcome, including saliva, blood and hair cortisol, IL-6, TNF-α, IFN-γ, CRP, CD19, CD4, CD8, and CD56 levels were measured at baseline, after 12 weeks of intervention, and at a 16-week follow-up. Linear and linear mixed-effects regression models were used to assess the effect of care and time on biological measures. Significant between-group differences were observed after 12 weeks of intervention, with higher salivary cortisol 5 ± 2 [0, 10], p = 0.045 and blood BDNF150 ± 60 (40, 270), p = 0.009 and IL-6 1.0 ± 0.3 [0.5, 1.5], p < 0.001 levels in the chiropractic care group. At the 16-week follow-up, blood cortisol -9 ± 4 [-17, -1], p = 0.024, IFN-γ - 22 ± 7 [-35, -9], and TNF-α -2 ± 1 [-5, 0], p = 0.028 levels increased in the sham group. Within-group comparisons showed a non-significant 10 ± 20 [-20, 50], p = 0.439 reduction in hair cortisol levels in the chiropractic group at 12 weeks, along with increased levels of blood cortisol, BDNF, CD8, CD4, IL-6, and CD19. 12 weeks of Chiropractic care modulates biomarkers linked to neuroplasticity, inflammation, and stress. Increases in brain-derived neurotrophic factor and interleukin-6 suggest enhanced neuroplasticity and inflammatory responses, while decreases in tumor necrosis factor-alpha indicate a regulatory effect on systemic inflammation. These findings support the notion that chiropractic care modulates physiological systemic biomarkers, which may underscore its benefits on clinical outcomes. ClinicalTrials.gov NCT05369156. Show less

This review aims to evaluate the efficacy and safety of olezarsen (Tryngolza) in treating familial chylomicronemia syndrome (FCS), a rare genetic disorder characterized by severe hypertriglyceridemia. A comprehensive literature search was conducted via PubMed from January 2022 to mid-March 2025, using keywords such as olezarsen, antisense oligonucleotide, triglyceride, hypertriglyceridemia, apolipoprotein C3 (APOC3), and cardiovascular. Relevant English-language studies assessing the pharmacokinetics, pharmacology, efficacy, or safety of olezarsen were included. Data from the US Food and Drug Administration (FDA)-approved package insert were also reviewed. Olezarsen is an antisense oligonucleotide targeting APOC3 mRNA, a key regulator of plasma triglyceride levels. It has been shown to significantly reduce triglyceride levels via APOC3 protein degradation. Clinical trials have demonstrated substantial reductions in triglyceride levels and APOC3, with minimal adverse events. Phase 2 and 3 trials showed consistent efficacy and safety profiles, with common adverse events including COVID-19 infection, abdominal pain, and diarrhea.Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs:Olezarsen offers a targeted and effective treatment for FCS, addressing limitations of traditional therapies such as fibrates, omega-3 fatty acids, and statins. Its novel mechanism of action and once-monthly dosing regimen may improve patient adherence, providing significant advancement in FCS management. Olezarsen represents a new treatment for FCS, offering a targeted approach to significantly reduce triglyceride levels. Its integration into clinical practice has the potential to transform the management of FCS; however, more studies are needed to firmly establish its role. Show less

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition marked by inattention, hyperactivity, and impulsivity. This narrative review examines the effects of various exercise modalities on ADHD symptoms, based on recent meta-analyses and randomized controlled trials with a focus on children and adolescents published between 2015 and 2025. Exercise modalities categorized as aerobic, open-skill, closed-skill, high-intensity interval training (HIIT), and cognitively demanding activities were examined in recent meta-analyses and clinical trials. Closed-skill exercises like swimming and yoga reduced hyperactivity and impulsivity, while open-skill sports improved attention. HIIT and cognitively engaging tasks enhanced executive function and increased neurochemicals such as BDNF and catecholamines. HIIT shows promise when intensity is individualized and recovery is adequate. Preliminary mechanistic links include catecholamine and BDNF modulation; PI3K-pathways remain hypothesis-generating. Although optimal exercise parameters remain to be determined, accumulating evidence supports the role of structured physical activity as a feasible and effective adjunct to conventional treatment. While many programs involved ~2-3 sessions/week for ≥30 min, heterogeneity in protocols and study quality precludes universal prescriptions. Future trials should report adherence, ADHD-specific outcomes, and risk-of-bias controls. Show less

The Tibetan sheep is a typical hypoxia-tolerant mammal, which lives on the plateau, at an altitude of between 2500 and 5000 m above sea level; the study of its hypoxic adaptation mechanism provides a reference for exploring the hypoxic adaptation mechanism of other animals. To grope for the genetic mechanism of adaptation to the hypoxic environment at the transcriptional level in Tibetan sheep testicular tissue, and to identify candidate genes and key pathways related to sheep adaptation, histological observation of testicular tissues from two sheep breeds was carried out using haematoxylin-eosin (HE) conventional staining. A total of 103 differentially expressed genes (DEGs) were authenticated in high altitude Tibetan sheep (ZYH) and low altitude Tibetan sheep (ZYM) by RNA sequencing technology (RNA-Seq), which included 50 up-regulated genes and 53 down-regulated genes. Functional analyses revealed several terms and pathways that were closely related to testis adaptation to the plateau. Several genes (including GGT5, AGTR2, EDN1, LPAR3, CYP2C19, IGFBP3, APOC3 and PKC1) were remarkably enriched in several pathways and terms, which may impact the Plateau adaptability of sheep by adjusting its reproductive activity and sexual maturation, and protecting Sertoli cells, various spermatocytes, and spermatogenesis processes. The results make a reasonable case for a better understanding of the molecular mechanisms of adaptation to altitude in sheep. Show less

Hypertriglyceridemia is an independent risk factor for cardiovascular diseases. In previous trials, apolipoprotein C-III (APOC3) inhibition through the antisense oligonucleotides volanesorsen, olezarsen, and plozasiran reduced triglyceride levels. However, the three medications' safety and efficacy have yet to be compared. A network meta-analysis was performed to compare multiple doses of the three medications to each other through the placebo. Randomized controlled trials (RCTs) were retrieved by searching PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane until November 22nd, 2024. The mean difference (MD) and 95% confidence interval (CI) were used for continuous outcomes. The risk ratio (RR) and 95% CI were used for dichotomous outcomes. Ten RCTs with a total of 1,129 patients were included. volanesorsen 300 mg once weekly showed the most significant percent reduction in triglyceride levels (MD = -91.0%, 95% CI: (-109.2%; -72.8%); P < 0.01). Only plozasiran once monthly, regardless of the dose, showed a non-significant percent reduction in triglycerides. This finding should be taken cautiously as the data were derived from a phase 1 trial with a small sample size. All the regimens significantly reduced APOC3 levels compared to placebo, with plozasiran 100 mg monthly and volanesorsen 300 mg once weekly showing the most significant reduction (MD range: -92.8% to -88.5%; P < 0.01). None of the treatments showed a statistically significant difference in overall adverse events rate compared to the placebo. APOC3 antisense oligonucleotide inhibitors effectively reduced triglyceride and APOC3 levels in hypertriglyceridemia with an acceptable safety profile. However, the results should be interpreted cautiously due to the small sample size. Further research is needed to confirm the beneficial effects of APOC3 inhibitors and show strong evidence of the impact of each regimen. Show less

This study aimed to elucidate the psychological mechanisms underlying the relationship between alexithymia and problematic eating behaviors (EB) among older adults. Specifically, we examined whether physical activity (PA) mediated this association, and we further explored the heterogeneity of alexithymia using Latent Profile Analysis (LPA). A cross-sectional survey was conducted among 1,773 community-dwelling older adults in China. Participants completed validated questionnaires assessing alexithymia, PA, and EB. Mediation analysis tested the indirect effect of PA on the alexithymia-EB relationship, while LPA identified subgroups of individuals with distinct alexithymia profiles. Mediation analysis revealed that PA significantly mediated the relationship between alexithymia and maladaptive EB, accounting for 18% of the total effect. LPA supported a three-profile solution: pervasive alexithymia (21.15%), adaptive (72.81%), and affective-cognitive dissociation (6.04%). Profile membership was differentially associated with health behaviors, with the pervasive group showing the most unfavorable outcomes (high EB, low PA), and the adaptive group demonstrating the most favorable pattern. These findings highlight PA as a key behavioral pathway through which alexithymia contributes to maladaptive eating in older adults. Moreover, alexithymia is not uniform but heterogeneous, with distinct profiles that confer varied health behavior risks. Interventions to improve eating habits in elderly populations may benefit from tailoring strategies to alexithymia subtypes and systematically promoting PA as an adaptive regulatory mechanism. Show less

The human brain functions as a highly integrated system. Interconnected cellular and molecular networks within this system process sensory information, cognitive functions, and motor responses. The brain also exhibits a remarkable potential for plasticity-driven adaptive learning and memory. Importantly, neuroplasticity serves as a key mechanism of neuroprotection while also enabling the brain to compensate for injury through adaptive structural remodeling. Understanding the brain as a dynamic system requires examining how its components interact to produce adaptive physiological responses and complex behaviors, such as social interactions. Key molecules, such as brain-derived neurotrophic factor (BDNF) and oxytocin (OT), play pivotal roles in maintaining the brain's dynamic complexity and integrative functioning. In this review, we introduce the concept of "neurosocial plasticity", which refers to the brain's ability to adapt both neural circuitry and social behavior through the dynamic interaction between BDNF and OT. This concept highlights how BDNF-OT interactions may support both neural plasticity and the capacity for adaptive social functioning. We then explore how their co-localization, co-expression, and co-regulation may regulate neural and social plasticity, ultimately shaping the brain's adaptability and the development of social behaviors across various contexts. Show less

Osteosarcoma is a primary bone malignancy in which outcomes for patients with metastatic or relapsed disease remain unsatisfactory despite optimized surgery-chemotherapy backbones. Recently, advances in cancer neuroscience have highlighted neurotrophins-nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)-and their Trk/p75 Show less

Three single component Dy(iii) complexes featuring β-diketone ligand TTBD (4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione) were studied for their potential as white-light emitters. The complexes include a water-containing species (DyA) and two anhydrous species (DyM and DyD) incorporating the auxiliary bidentate ligand pyrazine (pyz). The coordination geometry and ligand environment, particularly the nuclearity and presence of sensitizing co-ligands, significantly influence the relative intensities of the characteristic Dy(iii) yellow Show less

Genetic polymorphisms play a crucial role in regulating the physiological mechanisms underlying athletic performance, including muscle structure, energy metabolism, and cognitive functions. In recent years, increasing attention has been directed toward genetic variants that may influence cognitive traits such as motivation, stress tolerance, and attention, which are critical for optimal athletic performance. The present study aimed to provide the first preliminary meta-analysis of the association between athlete status and specific candidate polymorphisms related to cognitive processes (COMT rs4680, BDNF rs6265, OPRM1 rs1799971, and APOE rs7412/rs429358). A total of 17 case-control studies meeting the inclusion criteria were retrieved from relevant databases and included in the analysis. Statistical evaluations were performed using random- and fixed-effects models with a 95% confidence interval. The results indicated a potential association between the COMT Val158Met polymorphism and athlete status in both the overall and power athlete subgroups (p < 0.05). In contrast, no significant associations were observed for BDNF rs6265, OPRM1 rs1799971, or APOE rs7412/rs429358. However, this finding is based on a small number of studies and must be interpreted as exploratory. While this preliminary meta-analysis highlights a significant evidence gap, it also underscores, due to methodological limitations, the need for further empirical studies to understand the potential role of these polymorphisms in athlete status. Show less

Excessive hepatic lipid accumulation is the hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), yet its underlying mechanisms still not fully understood. In this study, we identified RNA binding motif protein 39 (Rbm39) as a key modulator of hepatic lipid homeostasis during MASLD progression. To establish in vivo MASLD model, mice were fed either a high-fat diet (HFD) or a Gubra-Amylin NASH (GAN) diet. We employed adeno-associated virus to manipulate Rbm39 expression levels to assess its role in MASLD. Transcriptome analysis was conducted to pinpoint the genes targeted by Rbm39. Western blot, RT-PCR, dual-luciferase reporter gene assays, and alternative splicing analysis were utilized to delve into the molecular mechanisms. Our results showed that Rbm39 expression was notably decreased in the livers of MASLD mice. Knockdown of hepatic Rbm39 aggravated HFD-induced hepatic steatosis and GAN diet-induced MASH, along with a notable decrease in serum lipid levels. Conversely, overexpression of Rbm39 attenuated MASLD development and progression. RNA sequencing data analysis indicated that Rbm39 regulated the expression of apolipoprotein B (Apob) and fatty acid-binding protein 4 (Fabp4), both of which are crucial for lipid transport. Mechanistically, Rbm39 enhanced the transcription of Apob by upregulating hepatocyte nuclear factor 4α (Hnf4α), while it suppressed Fabp4 transcription by regulating alternative splicing of hypoxia inducible factor-1α (Hif-1α). These findings highlight the pivotal role of Rbm39 in maintaining hepatic lipid homeostasis and suggest its potential as a therapeutic target for MASLD. Show less

The liver plays a crucial role in maintaining lipid homeostasis by converting toxic free fatty acids into VLDL, which the body uses for energy. Even minor changes in VLDL formation and secretion can result in serious health conditions such as atherosclerosis and non-alcoholic fatty liver disease. Despite the importance of VLDL, the proteins and signaling pathways involved in its regulation remain largely unknown. This study aims to develop a novel methodology to study intracellular VLDL transport events and explore the role of liver fatty acid-binding protein (LFABP) in VLDL transport and secretion. Current methods to study VLDL are often tedious, time-consuming, and expensive, underscoring the need for an alternative approach. We designed a new immunofluorescence-based assay to track the formation and secretion of VLDL in cells over time using fluorescently tagged TopFluor oleic acid. Confocal microscopy confirmed that TopFluor oleic acid enters hepatocytes and colocalizes with the ER, Golgi, and plasma membrane. Additionally, the collection of cell culture media revealed that TopFluor was incorporated into VLDL particles, as confirmed by fluorescence readings and ApoB100 immunoblots. This novel assay provides a valuable tool for further research into the mechanisms of VLDL regulation and the development of potential therapeutic targets for related diseases. Utilizing this assay, we identified LFABP as a key regulatory protein in post-Golgi VLDL trafficking. Our data suggest that LFABP plays a crucial role in this process, and its functional impairment leads to reduced VLDL secretion. Show less

This review explores the roles of interleukin-30 (IL-30) and interleukin-27 (IL-27) in inflammation and autoimmune diseases, with a focus on psoriasis. The two coexisting cytokines should be analysed in conjunction as their actions are antagonistic Show less

The opioid epidemic continues to grow, placing a significant strain on Emergency Departments (EDs), resulting in patients presenting daily with opioid-related concerns including intoxication, withdrawal, infections, injury, and death. Consequently, in recent years many EDs, including our own, have utilized Emergency Department Observation Units (EDOU) to not only manage withdrawal and overdose, but also initiate long-term treatment. This study aims to evaluate the outcomes of patients with opioid use disorder (OUD) who were managed in our EDOU. This was a retrospective study of patients placed in an EDOU who had the primary diagnosis of OUD in a single large, urban, tertiary academic hospital from May to November 2021. Demographic data and factors related to the ED visit and EDOU actions (e.g., use of peer navigator services, buprenorphine dose and prescription, distribution of naloxone discharge kits, and addiction clinic referral) were analyzed. The primary outcome variables were complications after buprenorphine use (e.g., precipitated withdrawal), the number of repeat ED visits or subsequent hospitalizations within 30 days for both all causes and opioid-related causes, and fatalities within 30 days of EDOU discharge. Twenty-nine patients were identified for chart review. Of these, 59 % were male. The median age was 55 years. Additionally, 93 % of the patients were insured, 66 % had housing, 72 % possessed a phone, and none were employed. During EDOU stays, 48 % [95 % CI 0.2989, 0.6711] of patients received buprenorphine with a total mean dose of 19 mg (SD, 10.6 mg). Upon discharge from the EDOU, 48 % [95 % CI 0.2989, 0.6711] were prescribed buprenorphine, 14 % [95 % CI 0.0451, 0.3257] received a naloxone discharge kit, and 45 % [95 % CI 0.2696, 0.6402] received an addiction clinic appointment. No patients had precipitated withdrawal, serious adverse events, or upgrades to inpatient care. Within 30-days of EDOU discharge, 38 % [95 % CI 0.213, 0.5764] of patients had a subsequent ED visit for any cause, and 6.9 % [95 % CI 1.2, 2.2] had a subsequent hospitalization for any cause. There were no fatalities within 30 days of EDOU discharge. The EDOU can serve as a promising location to provide quality care for patients presenting to the ED with OUD, with minimal adverse effects. There were few subsequent hospitalizations following discharge from the EDOU. Further non-observational studies regarding OUD management in an EDOU setting should be performed to optimize care and improve clinical outcomes and healthcare utilization. Show less

Understanding the liver stem cells (LSCs) holds great promise for new insights into liver diseases and liver regeneration. However, the heterogenicity and plasticity of liver cells have made it controversial. Here, by employing single-cell RNA-sequencing technology, transcriptome features of Krt19 Show less

Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques and disrupted axonal lysosome transport has been implicated in worsening Alzheimer's pathology. Our prior studies have revealed that loss of Adaptor protein-4 (AP-4) complex function, linked primarily to Spastic Paraplegia (HSP), leads to a similar build of lysosomes in structures we term "AP-4 dystrophies". Surprisingly, these AP-4 dystrophies were also characterized by enrichment of components of APP processing machinery, β-site cleaving enzyme 1 (BACE1) and Presenilin 2. Our studies examining whether the abnormal axonal lysosome build up resulting from AP-4 loss could lead to amyloidogenesis revealed that the loss of AP-4 complex function in an Alzheimer's disease model resulted in a strong increase in size and abundance of amyloid plaques in the hippocampus and corpus callosum as well as increased microglial association with the plaques. Interestingly, we found a further increase in enrichment of the secretase, BACE1, in the axonal swellings of the plaques of Alzheimer model mice lacking AP-4 complex compared to those having normal AP-4 complex function, suggestive of increased amyloidogenic processing under this condition. Additionally, the exacerbation of plaque pathology was region-specific as it did not increase in the cortex. The burden of the AP-4 linked axonal dystrophies/AP-4 dystrophies was higher in the corpus callosum and hippocampus compared to the cortex, establishing the critical role of AP-4 -dependent axonal lysosome transport and maturation in regulating amyloidogenic amyloid precursor protein processing. Show less

To provide a comprehensive overview of hypertriglyceridemia (HTG) in youth, identifying gaps in categorizing triglyceride (TG) levels and management strategies, and exploring new therapies for TG reduction. Non-fasting TG levels as important cardiovascular (CV) risk indicators, with HTG's pathophysiology involving genetic and secondary factors affecting TG metabolism. Emerging treatments, including those affecting the lipoprotein lipase complex and inhibiting proteins like apoC3 and ANGPTL3, show promise. The review highlights the need for specific management approaches for youth, the significance of non-fasting TG levels, and the potential of new therapies in reducing CV and pancreatitis risks, advocating for further research on these treatments' efficacy and safety. Show less

The significant progress has been made in targeted therapy for lung adenocarcinoma (LUAD) in the past decade. Only few targeted therapeutics have yet been approved for the treatment of lung squamous cell carcinoma (LUSC). Several higher frequency of gene alterations are identified as potentially actionable in LUSC. Our work aimed to explore the complex interplay of multiple genetic alterations and pathways contributing to the pathogenesis of LUSC, with a very low frequency of a single driver molecular alterations to develop more effective therapeutic strategies in the future. We retrospectively analyzed the targeted next-generation sequencing (NGS) data (approximately 600 genes) of 335 patients initially diagnosed with non-small cell lung cancer (NSCLC) at our institution between January 2019 and March 2023 and explored the somatic genome alteration difference between LUSC and LUAD. We analyzed that the presence of loss-of-function (LoF) mutations (nonsense, frameshift, and splice-site variants) in histone-lysine N-methyltransferase 2D ( Our results prompted that somatic LoF mutations of Show less

The accumulation and aggregation of beta-amyloid (Aβ) peptides contributes to neuronal dysfunction and death. These Aβ peptides originate from a transmembrane protein known as amyloid precursor protein (APP), which can be processed via two competing pathways. Alpha-secretase (ADAM10) cleavage is thought to be neuroprotective while beta-secretase (BACE1) cleavage results in the production of Aβ. Aerobic exercise reduces BACE1 activity, but the mechanisms involved are unknown though several exercise-induced mediators such as lactate may be involved. The current study examined whether systemic lactate can alter APP processing and BACE1 and ADAM10 activity. Mice were randomly assigned to one of four groups (n = 10 per group): (1) sedentary; (2) lactate-injection (1.0 g kg Show less

Alzheimer's disease (AD) is a significant global healthcare challenge, particularly in the elderly population. This neurodegenerative disorder is characterized by impaired memory and progressive decline in cognitive function. BACE1, a transmembrane protein found in neurons, oligodendrocytes, and astrocytes, exhibits varying levels across different neural subtypes. Abnormal BACE1 activity in the brains of individuals with AD leads to the formation of beta-amyloid proteins. The complex interplay between myelin sheath formation, BACE1 activity, and beta-amyloid accumulation suggests a critical role in understanding the pathological mechanisms of AD. The primary objective of this study was to identify molecular inhibitors that target Aβ. Structure-based virtual screening (SBVS) was employed using the MCULE database, which houses over 2 million chemical compounds. A total of 59 molecules were selected after the toxicity profiling. Subsequently, five compounds conforming to the Egan-Egg permeation predictive model of the ADME rules were selected and subjected to molecular docking using AutoDock Vina on the Mcule drug discovery platform. The top two ligands and the positive control, 5HA, were subjected to molecular dynamics simulation for five nanoseconds. Toxicity profiling, physiochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, average potential energy, RMSD, RMSF, and Rg analyses were conducted to identify the ligand MCULE-9199128437-0-2 as a promising inhibitor of BACE1. Show less

Inherited retinal disorders (IRDs) are a complex group of heritable diseases which are characterized by rod, cone, retinal pigment epithelium, or optic nerve dysfunction. Recently, mutations in An observational, prospective, case report on a hispanic female with A female, aged 24, affected by We reported a patient with a novel Show less

Sepsis is a leading cause of mortality worldwide, and pneumonia is the most common cause of sepsis in humans. Low levels of high-density lipoprotein cholesterol (HDL-C) levels are associated with an increased risk of death from sepsis, and increasing levels of HDL-C by inhibition of cholesteryl ester transfer protein (CETP) decreases mortality from intraabdominal polymicrobial sepsis in APOE*3-Leiden.CETP mice. Here, we show that treatment with the CETP inhibitor (CETPi) anacetrapib reduced mortality from Streptococcus pneumoniae-induced sepsis in APOE*3-Leiden.CETP and APOA1.CETP mice. Mechanistically, CETP inhibition reduced the host proinflammatory response via attenuation of proinflammatory cytokine transcription and release. This effect was dependent on the presence of HDL, leading to attenuation of immune-mediated organ damage. In addition, CETP inhibition promoted monocyte activation in the blood prior to the onset of sepsis, resulting in accelerated macrophage recruitment to the lung and liver. In vitro experiments demonstrated that CETP inhibition significantly promoted the activation of proinflammatory signaling in peripheral blood mononuclear cells and THP1 cells in the absence of HDL; this may represent a mechanism responsible for improved bacterial clearance during sepsis. These findings provide evidence that CETP inhibition represents a potential approach to reduce mortality from pneumosepsis. Show less

Breast cancer (BC) is the most common and fatal cancer among women, yet the causal relationship between circulating lipids, lipid-lowering drugs, and BC remains unclear. Mendelian randomization (MR) and summary data-based MR (SMR) analysis are used to explore the causal relationship between plasma lipids, lipid-lowering drug targets, and BC. The result of MR suggested that per mg/dL higher levels of LDL-C (OR = 1.045, FDR = 0.023), HDL-C (OR = 1.079, FDR = 0.003), TC (OR = 1.043, FDR = 0.026), and APOA-I (OR = 1.085, FDR = 2.64E-04) were associated with increased BC risk, while TG was associated with reduced BC risk (OR = 0.926, FDR = 0.003). Per mg/dL higher levels of HDL-C (OR = 1.080, FDR = 0.011) and APOA-I (OR = 1.083, FDR = 0.002) were associated with increased ER+BC risk, while TG was associated with reduced ER+BC risk (OR = 0.909, FDR = 0.002). For every per 1 mg/dL decrease in LDL, HMGCR (OR: 0.839; FDR = 0.016), NPC1L1 (OR: 0.702; FDR = 0.004), and PCSK9 (OR: 0.916; FDR = 0.026) inhibition were associated with reduced BC risk, whereas CETP inhibition (OR: 1.194; FDR = 0.026) was associated with increased BC risk. For every per 1 mg/dL decrease in LDL, HMGCR (OR: 0.822; FDR = 0.023), NPC1L1 (OR: 0.633; FDR = 2.37E-03), and APOB inhibition (OR: 0.816; FDR = 1.98E-03) were associated with decreased ER-BC risk, while CETP inhibition (OR: 1.465; FDR = 0.011) was associated with increased ER-BC risk. SMR analysis indicated that HMGCR was associated with increased BC risk (OR: 1.112; p = 0.044). Lipids are associated with the BC risk, and lipid-lowering drugs targets HMGCR, NPC1L1, PCSK9, and APOB may be effective strategies for preventing BC. However, lipid-lowering drugs target CETP may potentially increase BC risk. Show less

Tanshinone I (Tan I) has been proven to exert an anti-inflammatory effect, but the complete mechanism remains unclear. In this study, Tan I was described to have no effect on Syk expression in resting or LPS-stimulated macrophages ex vivo, but dramatically suppressed Syk phosphorylation and CD80, CD86, and IL-1β expression of macrophages. The inflammatory activity of macrophages in ApoC3-transgenic (ApoC3 Show less

Obstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Thus, we aimed to investigate the genetic association of lipid-modifying therapy with risk of OSA. A drug-target mendelian randomization (MR) study using both cis-variants and cis-expression quantitative trait loci (eQTLs) of lipid-modifying drug targets was performed. The MR analyses used summary-level data of genome wide association studies (GWAS). Primary MR analysis was conducted using inverse-variance-weighted (IVW) method. Sensitivity analysis was performed using weighted median (WM) and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Genetically proxied low-density lipoprotein cholesterol (LDL-C)-lowering effect of cholesteryl ester transfer protein (CETP) was associated with reduced risk of OSA (odds ratio [OR] =0.75, 95% confidence interval [CI]: 0.60-0.94, false discovery rate [FDR] q value = 0.046). A significant MR association with risk of OSA was observed for CETP expression in subcutaneous adipose tissue (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049), lung (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049) and small intestine (OR = 0.96, 95%CI: 0.93-1.00, FDR q value = 0.049). No significant effects of high-density lipoprotein cholesterol (HDL-C)-raising effect of CETP inhibition, LDL-C-lowering and triglycerides-lowering effect of other drug targets on OSA risk were observed. The present study presented genetic evidence supporting the association of LDL-C-lowering therapy by CETP inhibition with reduced risk of OSA. These findings provided novel insights into the role of lipid management in patients with OSA and encouraged further clinical validations and mechanistic investigations. Show less

Whether apolipoproteins (apolipoprotein A1, apolipoprotein B, apolipoprotein B/apolipoprotein A1 [ApoB/ApoA1] ratio) or very-low-density lipoprotein (VLDL) cholesterol are better risk predictors than established lipid risk markers, and whether there are sex differences, is uncertain, both in general populations and in patients with diabetes. The aim of this study was to assess the association between established risk markers, apolipoproteins and the risk of macro- and microvascular disease and death in a large study of women and men with diabetes and to assess the potential sex differences in the associations. Established lipid risk markers were studied in 11 140 individuals with type 2 diabetes from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial, and apolipoproteins (A1, B, ApoB/ApoA1 ratio) and VLDL cholesterol from nuclear magnetic resonance (NMR) lipid analyses in biobanked samples from 3586 individuals included in the ADVANCE case-cohort study (ADVANCE CC). Primary outcomes were major macro- and microvascular events and death. Cox proportional hazards models adjusted for confounders were used to quantify the associations (hazard ratio [HR] and 95% confidence intervals [CIs]) between established lipid risk markers and apolipoproteins with study outcomes. To address potential effect modification by sex, we investigated the association between the lipid risk markers and outcomes in subgroup analyses by sex. There was a lower risk of macrovascular complications for high-density lipoprotein (HDL) cholesterol (HR [95%CI] 0.88 [0.82-0.95]), a higher risk for total cholesterol (1.10 [1.04-1.17]), low-density lipoprotein (LDL) cholesterol (1.15 [1.08-1.22]), non-HDL cholesterol (1.13 [1.07-1.20]) and the total cholesterol/HDL ratio (1.20 [1.14-1.27]) but no significant associations with triglycerides from ADVANCE. There was a higher risk of macrovascular complications for the ApoB/ApoA1 ratio (1.13 [1.03-1.24]) from the ADVANCE CC. Only the ApoB/ApoA1 ratio (1.19 [1.06-1.34]), but none of the established lipid risk markers, was associated with a higher risk of microvascular complications. There were no statistically significant sex differences for any of the established lipid risk markers or apolipoproteins with any outcome. Using C-statistics and net reclassification improvement (NRI) did not detect significant improvement in predicting all outcomes by adding lipids or apolipoproteins to the models with confounding factors only. All established lipid risk markers, except triglycerides, were predictors of macrovascular complications, but not microvascular complications, in patients with type 2 diabetes. The ApoB/ApoA1 ratio was associated with major macro- and microvascular complications, but there was no evidence that apolipoproteins are better than established lipid risk markers in predicting cardiovascular complications in patients with type 2 diabetes. Show less

Non-obstructive azoospermia (NOA) is a major contributor of male infertility. Herein, we used existing datasets to identify novel biomarkers for the diagnosis and prognosis of NOA, which could have great significance in the field of male infertility. NOA datasets were obtained from the Gene Expression Omnibus (GEO) database. CIBERSORT was utilized to analyze the distributions of 22 immune cell populations. Hub genes were identified by applying weighted gene co-expression network analysis (WGCNA), machine learning methods, and protein-protein interaction (PPI) network analysis. The expression of hub genes was verified in external datasets and was assessed by receiver operating characteristic (ROC) curve analysis. Gene set enrichment analysis (GSEA) was applied to explore the important functions and pathways of hub genes. The mRNA-microRNA (miRNA)-transcription factors (TFs) regulatory network and potential drugs were predicted based on hub genes. Single-cell RNA sequencing data from the testes of patients with NOA were applied for analyzing the distribution of hub genes in single-cell clusters. Furthermore, testis tissue samples were obtained from patients with NOA and obstructive azoospermia (OA) who underwent testicular biopsy. RT-PCR and Western blot were used to validate hub gene expression. Two immune-related oxidative stress hub genes ( It appears that Show less

Fibroblast growth factor receptor 1 ( The current study examined 50 out of 67 pediatric patients with low-grade gliomas (LGGs) who had genomic testing between 2011 and 2022 at our institution to determine whether a correlation exists between We found that of the 50 patients with genomic data, 7 (14%) experienced ICH, and an additional spontaneous hemorrhage was recorded; however, no genomic testing was performed for this case. Five of the seven patients (71.4%) had an Our case series highlights this link between the FGFR1 mutation and spontaneous intracranial hemorrhage in pediatric LGGs. Show less