Background: Parkinson's disease (PD) is a neurodegenerative disorder with established sex differences in incidence and progression. Epidemiological evidence suggests nicotine may confer protection against PD, but its mechanisms, particularly regarding sex-specific effects, remain unclear. This study investigated the neuroprotective mechanisms of nicotine in a rotenone-induced PD rat model, with a specific focus on evaluating sex-dependent modulation across behavioral, pathological, and gut-related outcomes.
Methods: Male and female Sprague-Dawley rats were administered rotenone (2 mg/kg/day, s.c.) for four weeks to induce PD. Nicotine (0.5 mg/kg/day, s.c.) was administered 30 min after rotenone. Motor function was assessed using rotarod and CatWalk XT gait analysis. Neuropathology in the substantia nigra was evaluated via immunofluorescence for α-synuclein and tyrosine hydroxylase (TH). Gut pathology was analyzed through colon histopathology (H&E staining) and ELISA for IL-6 and α-synuclein. Gut microbiota composition was assessed by 16 S rDNA sequencing, and serum metabolomics was performed using UPLC-MS/MS. Data were analyzed by two-way ANOVA with Tukey's post-hoc test.
Results: Nicotine significantly attenuated rotenone-induced motor impairments: males showed a superior response in balance-related parameters, while females exhibited enhanced efficacy in dynamic gait metrics. Pathologically, nicotine reduced nigral α-synuclein accumulation and TH depletion in both sexes, with males showing greater α-synuclein accumulation following rotenone exposure. Crucially, nicotine exclusively ameliorated colon histopathology, reduced plasma α-synuclein, and suppressed colon IL-6 in females, while attenuating intestinal α-synuclein accumulation in both sexes. Microbiota analysis revealed sex-divergent taxonomic shifts with nicotine treatment. Metabolomics showed significantly more extensive metabolic reprogramming in females, particularly affecting indole derivatives. Pearson correlations revealed significant sex-specific associations between altered serum indole derivatives and gut microbiota genera.
Conclusions: Nicotine exerts neuroprotection in PD through sex-dependent modulation of multiple pathological pathways, primarily involving the gut-microbiota-metabolite axis. Females benefit from enhanced gastrointestinal protection and metabolic reprogramming, while males show preferential motor balance restoration. These findings underscore the critical importance of sex-stratified therapeutic strategies for PD.
{"title":"Sex-specific metabolic and microbial remodeling in a rotenone-induced rat model of Parkinson's disease following nicotine administration.","authors":"Zhen Ni, Gaoge Wang, Qian Li, Xiaqing Wu, Zheng Song, Hao Yu, Pengpeng Yu, Yibo Chen, Lixiang Li, Huan Chen, Hongwei Hou, Qingyuan Hu","doi":"10.1186/s13293-026-00865-1","DOIUrl":"https://doi.org/10.1186/s13293-026-00865-1","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is a neurodegenerative disorder with established sex differences in incidence and progression. Epidemiological evidence suggests nicotine may confer protection against PD, but its mechanisms, particularly regarding sex-specific effects, remain unclear. This study investigated the neuroprotective mechanisms of nicotine in a rotenone-induced PD rat model, with a specific focus on evaluating sex-dependent modulation across behavioral, pathological, and gut-related outcomes.</p><p><strong>Methods: </strong>Male and female Sprague-Dawley rats were administered rotenone (2 mg/kg/day, s.c.) for four weeks to induce PD. Nicotine (0.5 mg/kg/day, s.c.) was administered 30 min after rotenone. Motor function was assessed using rotarod and CatWalk XT gait analysis. Neuropathology in the substantia nigra was evaluated via immunofluorescence for α-synuclein and tyrosine hydroxylase (TH). Gut pathology was analyzed through colon histopathology (H&E staining) and ELISA for IL-6 and α-synuclein. Gut microbiota composition was assessed by 16 S rDNA sequencing, and serum metabolomics was performed using UPLC-MS/MS. Data were analyzed by two-way ANOVA with Tukey's post-hoc test.</p><p><strong>Results: </strong>Nicotine significantly attenuated rotenone-induced motor impairments: males showed a superior response in balance-related parameters, while females exhibited enhanced efficacy in dynamic gait metrics. Pathologically, nicotine reduced nigral α-synuclein accumulation and TH depletion in both sexes, with males showing greater α-synuclein accumulation following rotenone exposure. Crucially, nicotine exclusively ameliorated colon histopathology, reduced plasma α-synuclein, and suppressed colon IL-6 in females, while attenuating intestinal α-synuclein accumulation in both sexes. Microbiota analysis revealed sex-divergent taxonomic shifts with nicotine treatment. Metabolomics showed significantly more extensive metabolic reprogramming in females, particularly affecting indole derivatives. Pearson correlations revealed significant sex-specific associations between altered serum indole derivatives and gut microbiota genera.</p><p><strong>Conclusions: </strong>Nicotine exerts neuroprotection in PD through sex-dependent modulation of multiple pathological pathways, primarily involving the gut-microbiota-metabolite axis. Females benefit from enhanced gastrointestinal protection and metabolic reprogramming, while males show preferential motor balance restoration. These findings underscore the critical importance of sex-stratified therapeutic strategies for PD.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147347245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-02DOI: 10.1186/s13293-026-00867-z
Xiao Huang, Darui Gao, Wenya Zhang, Mengmeng Ji, Yang Pan, Yanyu Zhang, Yiwen Dai, Anshi Wu, Fanfan Zheng, Wuxiang Xie
Background: Cancer patients face a markedly elevated risk of thromboembolism (TE), including both venous thromboembolism (VTE) and arterial thromboembolism (ATE), which contribute substantially to morbidity and mortality in this population.
Objective: This study examined sex disparities in associations between sleep, sedentary behavior (SB), light physical activity (LPA), moderate-to-vigorous physical activity (MVPA), and TE risk, in cancer patients using data from the UK Biobank.
Methods: A longitudinal cohort analysis of 6,765 cancer patients (2,774 men and 3,991 women) from the accelerometry subsample was conducted using Cox proportional hazards and isotemporal substitution models stratified by sex.
Results: The incidence of VTE was 3.0% in men versus 2.2% in women, while ATE incidence was 5.0% versus 2.2%, respectively. Compared with high LPA, medium and low durations were associated with 2.75- and 2.88-fold higher VTE risk only in men. Reallocating 1 h per day from sleep or SB to LPA reduced VTE risk by 24% and 19% in men. Low MVPA was associated with 3.35- and 1.59-fold higher ATE risk in women and men, respectively. Reallocating 1 h per day from sleep, SB, or LPA to MVPA reduced ATE risk by 71%, 70%, and 66%, respectively, only in women.
Conclusions: LPA was associated with a lower risk of VTE only in male cancer patients, whereas MVPA was linked to a lower risk of ATE in female patients, indicating sex-specific associations between movement behaviors and TE risk.
{"title":"Sex disparities in the associations between accelerometer-measured movement behaviors and subsequent thromboembolism risk in cancer patients.","authors":"Xiao Huang, Darui Gao, Wenya Zhang, Mengmeng Ji, Yang Pan, Yanyu Zhang, Yiwen Dai, Anshi Wu, Fanfan Zheng, Wuxiang Xie","doi":"10.1186/s13293-026-00867-z","DOIUrl":"https://doi.org/10.1186/s13293-026-00867-z","url":null,"abstract":"<p><strong>Background: </strong>Cancer patients face a markedly elevated risk of thromboembolism (TE), including both venous thromboembolism (VTE) and arterial thromboembolism (ATE), which contribute substantially to morbidity and mortality in this population.</p><p><strong>Objective: </strong>This study examined sex disparities in associations between sleep, sedentary behavior (SB), light physical activity (LPA), moderate-to-vigorous physical activity (MVPA), and TE risk, in cancer patients using data from the UK Biobank.</p><p><strong>Methods: </strong>A longitudinal cohort analysis of 6,765 cancer patients (2,774 men and 3,991 women) from the accelerometry subsample was conducted using Cox proportional hazards and isotemporal substitution models stratified by sex.</p><p><strong>Results: </strong>The incidence of VTE was 3.0% in men versus 2.2% in women, while ATE incidence was 5.0% versus 2.2%, respectively. Compared with high LPA, medium and low durations were associated with 2.75- and 2.88-fold higher VTE risk only in men. Reallocating 1 h per day from sleep or SB to LPA reduced VTE risk by 24% and 19% in men. Low MVPA was associated with 3.35- and 1.59-fold higher ATE risk in women and men, respectively. Reallocating 1 h per day from sleep, SB, or LPA to MVPA reduced ATE risk by 71%, 70%, and 66%, respectively, only in women.</p><p><strong>Conclusions: </strong>LPA was associated with a lower risk of VTE only in male cancer patients, whereas MVPA was linked to a lower risk of ATE in female patients, indicating sex-specific associations between movement behaviors and TE risk.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147343590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01DOI: 10.1186/s13293-026-00856-2
Mateja Perović, Jianqi Hou, Michael L Mack
Background: Both brain-derived neurotrophic factor (BDNF) and ovarian hormones are powerful neuromodulators, yet evidence of their impact on human cognition remains mixed. As prior work has studied them in isolation, examining their interacting effects presents a key empirical opportunity for explicating their effects on cognition.
Methods: We genotyped participants for the BDNF Val66Met single nucleotide polymorphism, which is associated with less efficient activity-dependent BDNF secretion and altered hippocampal function, and examined their performance on a complex learning task at two points in the menstrual cycle: early follicular (characterized by low levels of ovarian hormones) and late follicular (characterized by high estradiol).
Results: While met carriers showed advantages during the early follicular timepoint, val homozygotes outperformed them at the late follicular timepoint. Furthermore, effects in met carriers were largely driven by increased sensitivity to both absolute levels and changes in levels of estradiol.
Conclusions: The current findings provide the first evidence of BDNF Val66Met interacting with the menstrual cycle to predict cognition, demonstrate nuanced genotype- and hormone-specific outcomes, and underscore the importance of studying effects of interacting biological systems on human cognition.
{"title":"Menstrual cycle modulates the effect of BDNF Val66Met variant on category learning.","authors":"Mateja Perović, Jianqi Hou, Michael L Mack","doi":"10.1186/s13293-026-00856-2","DOIUrl":"https://doi.org/10.1186/s13293-026-00856-2","url":null,"abstract":"<p><strong>Background: </strong>Both brain-derived neurotrophic factor (BDNF) and ovarian hormones are powerful neuromodulators, yet evidence of their impact on human cognition remains mixed. As prior work has studied them in isolation, examining their interacting effects presents a key empirical opportunity for explicating their effects on cognition.</p><p><strong>Methods: </strong>We genotyped participants for the BDNF Val66Met single nucleotide polymorphism, which is associated with less efficient activity-dependent BDNF secretion and altered hippocampal function, and examined their performance on a complex learning task at two points in the menstrual cycle: early follicular (characterized by low levels of ovarian hormones) and late follicular (characterized by high estradiol).</p><p><strong>Results: </strong>While met carriers showed advantages during the early follicular timepoint, val homozygotes outperformed them at the late follicular timepoint. Furthermore, effects in met carriers were largely driven by increased sensitivity to both absolute levels and changes in levels of estradiol.</p><p><strong>Conclusions: </strong>The current findings provide the first evidence of BDNF Val66Met interacting with the menstrual cycle to predict cognition, demonstrate nuanced genotype- and hormone-specific outcomes, and underscore the importance of studying effects of interacting biological systems on human cognition.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01DOI: 10.1186/s13293-026-00862-4
Lama Al-Qusairi
Men and women exhibit well-established differences in electrolyte regulation, susceptibility to hypertension, kidney disease prevalence, and response to therapies for cardiovascular and renal disorders. Among these, plasma potassium regulation emerges as a key area of sex-specific divergence. Clinical and experimental studies consistently show that women are more susceptible to hypokalemia, while men are more prone to hyperkalemia, a pattern most evident during physiological or pathological stressors such as specific dietary patterns, exercise, medication use, and diseases like chronic kidney disease or cardiorenal syndrome. In this review, we synthesize current evidence from both human and animal studies on sex differences in potassium homeostasis and discuss their clinical implications. We also explore the physiological and molecular mechanisms underlying these differences, and highlight critical knowledge gaps. Advancing our understanding of these biological differences and their underlying mechanisms is essential to move beyond one-size-fits-all nutritional recommendations and disease management strategies.
{"title":"Sex differences in potassium regulation: evidence, molecular mechanisms and clinical implications.","authors":"Lama Al-Qusairi","doi":"10.1186/s13293-026-00862-4","DOIUrl":"https://doi.org/10.1186/s13293-026-00862-4","url":null,"abstract":"<p><p>Men and women exhibit well-established differences in electrolyte regulation, susceptibility to hypertension, kidney disease prevalence, and response to therapies for cardiovascular and renal disorders. Among these, plasma potassium regulation emerges as a key area of sex-specific divergence. Clinical and experimental studies consistently show that women are more susceptible to hypokalemia, while men are more prone to hyperkalemia, a pattern most evident during physiological or pathological stressors such as specific dietary patterns, exercise, medication use, and diseases like chronic kidney disease or cardiorenal syndrome. In this review, we synthesize current evidence from both human and animal studies on sex differences in potassium homeostasis and discuss their clinical implications. We also explore the physiological and molecular mechanisms underlying these differences, and highlight critical knowledge gaps. Advancing our understanding of these biological differences and their underlying mechanisms is essential to move beyond one-size-fits-all nutritional recommendations and disease management strategies.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01DOI: 10.1186/s13293-026-00852-6
Lejla Medzikovic, Grégoire Ruffenach, Ateyeh Dehghanitafti, Brenda Wong, Ashley Ryder, Mohammad Reza Hatamnejad, Wasila Sun, Leana Esdin, Joshua Eghbali, Adam Brownstein, Asif Razee, Soban Umar, Jason Hong, Mansoureh Eghbali
Background: Pulmonary arterial hypertension (PAH) presents as increased pressure in the pulmonary arteries (PA) leading to cardiac right ventricular (RV) failure and death. Pulmonary arterial (PA) remodeling characterized by enhanced proliferation of pulmonary arterial smooth muscle cells (PASMC) and fibroblasts (PAFB) underlies PAH. There are currently no cures and PAH mortality remains high. PAH has a striking female-predominant incidence - 4:1 ratio - indicating that males may have a protective factor. However, to date only a few sex-biased factors in PAH have been investigated.
Methods: Analyses were performed on a publicly available microarray dataset (GSE117261), comprising human lung tissues from PAH patients and healthy controls, as well as publicly available single-cell lung atlases of humans and mice. Lung tissue, plasma, PASMC and PAFB were collected from male and female PAH patients. Cell proliferation was assessed after recombinant HGF protein stimulation. PH was induced in male and female rats by monocrotaline (MCT). Lung-specific knockdown was performed by intratracheal siRNA instillation the first two weeks after MCT injection. PA and RV function were assessed by echocardiography, RV systolic pressure by catheterization, and PA remodeling by histology.
Results: HGF was only upregulated in lungs of male PAH patients compared to male control lungs, but not in female PAH patients vs. female controls. Elevated plasma HGF correlated with favorable clinical characteristics only in male PAH patients. HGF is highly expressed in vascular SMC and FB in the lung and recombinant HGF inhibited PASMC and PAFB proliferation to a greater extent in cells isolated from male PAH patients compared to female. Lung HGF expression is increased to a higher extent and longer duration at early stage of PH in male rats in MCT model vs. female rats. Finally, knockdown of HGF in the lungs in early disease stage exacerbated PH in male rats characterized by higher mortality, worsened RV and PA function as well as enhanced PA medial thickening and adventitial fibrosis.
Conclusions: Lung HGF expression may be upregulated to counteract PAH disease progression by inhibiting proliferation of PASMC and PAFB. Elevated HGF in males might at least partially account for the lower incidence of male PAH patients.
{"title":"Hepatocyte growth factor may contribute to male protection against pulmonary arterial hypertension.","authors":"Lejla Medzikovic, Grégoire Ruffenach, Ateyeh Dehghanitafti, Brenda Wong, Ashley Ryder, Mohammad Reza Hatamnejad, Wasila Sun, Leana Esdin, Joshua Eghbali, Adam Brownstein, Asif Razee, Soban Umar, Jason Hong, Mansoureh Eghbali","doi":"10.1186/s13293-026-00852-6","DOIUrl":"https://doi.org/10.1186/s13293-026-00852-6","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary arterial hypertension (PAH) presents as increased pressure in the pulmonary arteries (PA) leading to cardiac right ventricular (RV) failure and death. Pulmonary arterial (PA) remodeling characterized by enhanced proliferation of pulmonary arterial smooth muscle cells (PASMC) and fibroblasts (PAFB) underlies PAH. There are currently no cures and PAH mortality remains high. PAH has a striking female-predominant incidence - 4:1 ratio - indicating that males may have a protective factor. However, to date only a few sex-biased factors in PAH have been investigated.</p><p><strong>Methods: </strong>Analyses were performed on a publicly available microarray dataset (GSE117261), comprising human lung tissues from PAH patients and healthy controls, as well as publicly available single-cell lung atlases of humans and mice. Lung tissue, plasma, PASMC and PAFB were collected from male and female PAH patients. Cell proliferation was assessed after recombinant HGF protein stimulation. PH was induced in male and female rats by monocrotaline (MCT). Lung-specific knockdown was performed by intratracheal siRNA instillation the first two weeks after MCT injection. PA and RV function were assessed by echocardiography, RV systolic pressure by catheterization, and PA remodeling by histology.</p><p><strong>Results: </strong>HGF was only upregulated in lungs of male PAH patients compared to male control lungs, but not in female PAH patients vs. female controls. Elevated plasma HGF correlated with favorable clinical characteristics only in male PAH patients. HGF is highly expressed in vascular SMC and FB in the lung and recombinant HGF inhibited PASMC and PAFB proliferation to a greater extent in cells isolated from male PAH patients compared to female. Lung HGF expression is increased to a higher extent and longer duration at early stage of PH in male rats in MCT model vs. female rats. Finally, knockdown of HGF in the lungs in early disease stage exacerbated PH in male rats characterized by higher mortality, worsened RV and PA function as well as enhanced PA medial thickening and adventitial fibrosis.</p><p><strong>Conclusions: </strong>Lung HGF expression may be upregulated to counteract PAH disease progression by inhibiting proliferation of PASMC and PAFB. Elevated HGF in males might at least partially account for the lower incidence of male PAH patients.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-26DOI: 10.1186/s13293-026-00861-5
Xi Chen, Yueqi Lu, You Duan, Yongfeng Bai, Weidong Ye, Sijia Chen, Hang Zhou, Heng Xu, Le Xu, Cheng Guo
Alternative splicing (AS) significantly enhances transcriptomic diversity, and its dysregulation is implicated in numerous human diseases. However, no public database systematically compiles sex-related AS events across human tissues. We developed SASdb (http://www.gdbioinfo.top/sasdb), a comprehensive database contains 2,951,059 AS events and 46,418 sex-biased alternative splicing (SAS) events, covering 22 human tissues. SASdb reveals extensive sex-specific splicing patterns, offering new insights into molecular sex differences. A case study on NSCLC-specific SAS events, absent in healthy tissues, highlights their enrichment in cancer-related pathways like autophagy, GPI-anchor biosynthesis, and AMPK/mTOR signaling. SASdb's intuitive visualization supports research in sex biology and precision medicine.
{"title":"SASdb: a comprehensive database for sex-biased alternative splicing profiles in human tissues.","authors":"Xi Chen, Yueqi Lu, You Duan, Yongfeng Bai, Weidong Ye, Sijia Chen, Hang Zhou, Heng Xu, Le Xu, Cheng Guo","doi":"10.1186/s13293-026-00861-5","DOIUrl":"https://doi.org/10.1186/s13293-026-00861-5","url":null,"abstract":"<p><p>Alternative splicing (AS) significantly enhances transcriptomic diversity, and its dysregulation is implicated in numerous human diseases. However, no public database systematically compiles sex-related AS events across human tissues. We developed SASdb (http://www.gdbioinfo.top/sasdb), a comprehensive database contains 2,951,059 AS events and 46,418 sex-biased alternative splicing (SAS) events, covering 22 human tissues. SASdb reveals extensive sex-specific splicing patterns, offering new insights into molecular sex differences. A case study on NSCLC-specific SAS events, absent in healthy tissues, highlights their enrichment in cancer-related pathways like autophagy, GPI-anchor biosynthesis, and AMPK/mTOR signaling. SASdb's intuitive visualization supports research in sex biology and precision medicine.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147301585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-23DOI: 10.1186/s13293-026-00859-z
Yutian Zhao, Ruoshui Liu, Jonathan P Ng, Sophia Yu, In Sook Ahn, Graciel Diamante, Guanglin Zhang, Ariel Thorson, Kelsey P Schaefers, John M Stafford, Xia Yang
{"title":"Estradiol treatment induces both shared and unique gene regulation and networks in adipose cell types of gonadectomized obese XX and XY mice.","authors":"Yutian Zhao, Ruoshui Liu, Jonathan P Ng, Sophia Yu, In Sook Ahn, Graciel Diamante, Guanglin Zhang, Ariel Thorson, Kelsey P Schaefers, John M Stafford, Xia Yang","doi":"10.1186/s13293-026-00859-z","DOIUrl":"10.1186/s13293-026-00859-z","url":null,"abstract":"","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12930959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-22DOI: 10.1186/s13293-026-00863-3
D M Mens, V M T van Verschuer, J M van Rees, R R J Coebergh van den Braak, C Verhoef, D E Hilling
Objective: Limited literature is available comparing sexes in rectal cancer. This nationwide study using real-world data was performed to evaluate sex-based differences in diagnosis, treatment and survival outcomes in rectal cancer.
Methods: Data from the Netherlands Cancer Registry were analyzed for patients diagnosed with rectal adenocarcinoma between 2015 and 2019. Patient and tumor characteristics, treatment strategies, response to neoadjuvant therapy, and survival outcomes were compared between sexes.
Results: The cohort consisted of 22251 patients (37.1% women, 62.9% men). Women more frequently presented with cT4 tumors (16% vs. 11%, P < 0.001) but no differences were observed in nodal status, distant metastases, use of neoadjuvant (chemo) radiotherapy and radicality in resections between sexes. In the total study population, 5-year survival did not differ significantly (63.6% in women vs. 61.6% in men, P=0.23). However, in surgically treated patients, survival was higher in women (77.4% vs. 75.0%, P=0.019). Female sex was an independent predictor for survival in surgically treated patients (HR 0.90; 95% CI 0.82-0.98). In the subgroup of patients who were asymptomatic at the time of diagnosis [n=1320], there were no sex-based differences in presentation, treatment, or survival (5-year overall survival: 78.8% vs. 80.4%, P=0.45).
Conclusion: Sex-based differences exist in rectal cancer presentation and outcome. Women are more likely to present a more advanced T-stage. Despite this, women have a better overall survival after surgical treatment. In contrast, men and women undergoing treatment for asymptomatic rectal cancer have comparable outcomes.
目的:比较直肠癌性别的文献有限。这项使用真实世界数据的全国性研究旨在评估基于性别的直肠癌诊断、治疗和生存结果的差异。方法:分析荷兰癌症登记处2015年至2019年诊断为直肠腺癌的患者的数据。患者和肿瘤特征、治疗策略、对新辅助治疗的反应和生存结果在性别之间进行了比较。结果:该队列包括22251例患者(女性37.1%,男性62.9%)。女性更常出现cT4肿瘤(16% vs. 11%)。结论:直肠癌的表现和预后存在性别差异。女性更有可能出现更晚期的t期。尽管如此,女性在手术治疗后总体生存率更高。相比之下,接受无症状直肠癌治疗的男性和女性有相当的结果。
{"title":"Nationwide analysis on sex differences in diagnosis, treatment and survival of rectal cancer.","authors":"D M Mens, V M T van Verschuer, J M van Rees, R R J Coebergh van den Braak, C Verhoef, D E Hilling","doi":"10.1186/s13293-026-00863-3","DOIUrl":"https://doi.org/10.1186/s13293-026-00863-3","url":null,"abstract":"<p><strong>Objective: </strong>Limited literature is available comparing sexes in rectal cancer. This nationwide study using real-world data was performed to evaluate sex-based differences in diagnosis, treatment and survival outcomes in rectal cancer.</p><p><strong>Methods: </strong>Data from the Netherlands Cancer Registry were analyzed for patients diagnosed with rectal adenocarcinoma between 2015 and 2019. Patient and tumor characteristics, treatment strategies, response to neoadjuvant therapy, and survival outcomes were compared between sexes.</p><p><strong>Results: </strong>The cohort consisted of 22251 patients (37.1% women, 62.9% men). Women more frequently presented with cT4 tumors (16% vs. 11%, P < 0.001) but no differences were observed in nodal status, distant metastases, use of neoadjuvant (chemo) radiotherapy and radicality in resections between sexes. In the total study population, 5-year survival did not differ significantly (63.6% in women vs. 61.6% in men, P=0.23). However, in surgically treated patients, survival was higher in women (77.4% vs. 75.0%, P=0.019). Female sex was an independent predictor for survival in surgically treated patients (HR 0.90; 95% CI 0.82-0.98). In the subgroup of patients who were asymptomatic at the time of diagnosis [n=1320], there were no sex-based differences in presentation, treatment, or survival (5-year overall survival: 78.8% vs. 80.4%, P=0.45).</p><p><strong>Conclusion: </strong>Sex-based differences exist in rectal cancer presentation and outcome. Women are more likely to present a more advanced T-stage. Despite this, women have a better overall survival after surgical treatment. In contrast, men and women undergoing treatment for asymptomatic rectal cancer have comparable outcomes.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-21DOI: 10.1186/s13293-026-00837-5
Arthur P Arnold, Xuqi Chen, Michael N Grzybowski, Janelle M Ryan, Dale R Sengelaub, Tara Mohanroy, V Andree Furlan, Helen R Schmidtke, Jeremy W Prokop, Monika Tutaj, Julia L Ciosek, Theodore S Kalbfleisch, Liza O'Donnell, William Grisham, Shanie Landen, Lynn Malloy, Akiko Takizawa, Kai Li, Hayk Barseghyan, Carrie B Wiese, Laurent Vergnes, Karen Reue, Jonathan Wanagat, Helen Skaletsky, David C Page, Vincent R Harley, Melinda R Dwinell, Aron M Geurts
Background: Previous research on Four Core Genotypes and XY* mice has been instrumental in establishing important effects of sex-chromosome complement that cause sex differences in physiology and disease. We have generated rat models using similar modifications of the testis-determining gene Sry, to produce XX and XY rats with the same type of gonad, as well as XO, XXY and XYY rats with varying gonads. The models permit discovery of novel sex-chromosome effects (XX vs. XY) that contribute to sex differences in any rat phenotype, and test for effects of different numbers of X or Y chromosomes.
Methods: XY rats were created with an autosomal transgene of Sry, producing XX and XY progeny with testes. In other rats, CRISPR-Cas9 technology was used to remove Y chromosome factors that initiate testis differentiation, producing fertile XY gonadal females. Interbreeding of these lines produced rats with interesting combinations of sex chromosomes and gonads: XO, XX, XY, XXY rats with ovaries; and XO, XX, XY, XXY, and XYY rats with testes. These groups can be compared to detect sex differences caused by sex-chromosome complement (XX vs. XY) and/or by gonadal hormones (rats with testes vs. ovaries). Other comparisons detect the effects of X or Y chromosome number (in gonadal females: XO vs. XX, XX vs. XXY, XO vs. XY, XY vs. XXY; in gonadal males: XY vs. XXY, XY vs. XYY; XX vs. XXY, XO vs. XX, XO vs. XY).
Results: We measured numerous phenotypes to characterize these models, including gonadal histology, breeding performance, anogenital distance, levels of reproductive hormones, body and organ weights, and central nervous system sexual dimorphisms. Serum testosterone levels were comparable in adult XX and XY gonadal males. Phenotypes previously known to be sexually differentiated by the action of gonadal hormones were found to be similar in XX and XY rats with the same type of gonad, suggesting that XX and XY rats with the same type of gonad have comparable levels of gonadal hormones at various stages of development.
Conclusion: The results establish powerful new models to discriminate sex-chromosome and gonadal hormone effects that cause sex differences in rat physiology and disease.
背景:以往对四种核心基因型和XY*小鼠的研究有助于确立性染色体补体在生理和疾病中引起性别差异的重要作用。我们对睾丸决定基因Sry进行了类似的修饰,产生了具有相同性腺类型的XX和XY大鼠,以及具有不同性腺类型的XO、XXY和XYY大鼠。这些模型允许发现新的性染色体效应(XX vs. XY),这些效应导致了任何大鼠表型的性别差异,并测试了不同数量的X或Y染色体的影响。方法:用常染色体基因Sry克隆XY大鼠,产生具有睾丸的XX和XY后代。在其他大鼠中,使用CRISPR-Cas9技术去除启动睾丸分化的Y染色体因子,产生可生育的XY性腺雌性。这些系杂交产生的大鼠具有有趣的性染色体和性腺组合:XO、XX、XY、XXY大鼠有卵巢;睾丸大鼠XO、XX、XY、XXY、XYY。这些组可以进行比较,以检测由性染色体补体(XX vs XY)和/或性腺激素(有睾丸的大鼠vs有卵巢的大鼠)引起的性别差异。其他比较检测X或Y染色体数目的影响(在生殖期女性中:XO vs. XX, XX vs. XXY, XO vs. XY, XY vs. XXY;在生殖期男性中:XY vs. XXY, XY vs. XYY; XX vs. XXY, XO vs. XX, XO vs. XY)。结果:我们测量了许多表型来表征这些模型,包括性腺组织学、繁殖性能、肛门生殖器距离、生殖激素水平、身体和器官重量以及中枢神经系统性别二态性。血清睾酮水平在成年XX和XY性腺男性中是相当的。我们发现,在具有相同性腺类型的XX大鼠和XY大鼠中,先前已知的通过性腺激素作用进行性别分化的表型是相似的,这表明具有相同性腺类型的XX大鼠和XY大鼠在不同发育阶段的性腺激素水平相当。结论:该结果为鉴别大鼠生理和疾病中性别差异的性染色体和性腺激素效应建立了强有力的新模型。
{"title":"Sry-modified laboratory rat lines to study sex-chromosome effects underlying sex differences in physiology and disease: four core genotypes and more.","authors":"Arthur P Arnold, Xuqi Chen, Michael N Grzybowski, Janelle M Ryan, Dale R Sengelaub, Tara Mohanroy, V Andree Furlan, Helen R Schmidtke, Jeremy W Prokop, Monika Tutaj, Julia L Ciosek, Theodore S Kalbfleisch, Liza O'Donnell, William Grisham, Shanie Landen, Lynn Malloy, Akiko Takizawa, Kai Li, Hayk Barseghyan, Carrie B Wiese, Laurent Vergnes, Karen Reue, Jonathan Wanagat, Helen Skaletsky, David C Page, Vincent R Harley, Melinda R Dwinell, Aron M Geurts","doi":"10.1186/s13293-026-00837-5","DOIUrl":"10.1186/s13293-026-00837-5","url":null,"abstract":"<p><strong>Background: </strong>Previous research on Four Core Genotypes and XY* mice has been instrumental in establishing important effects of sex-chromosome complement that cause sex differences in physiology and disease. We have generated rat models using similar modifications of the testis-determining gene Sry, to produce XX and XY rats with the same type of gonad, as well as XO, XXY and XYY rats with varying gonads. The models permit discovery of novel sex-chromosome effects (XX vs. XY) that contribute to sex differences in any rat phenotype, and test for effects of different numbers of X or Y chromosomes.</p><p><strong>Methods: </strong>XY rats were created with an autosomal transgene of Sry, producing XX and XY progeny with testes. In other rats, CRISPR-Cas9 technology was used to remove Y chromosome factors that initiate testis differentiation, producing fertile XY gonadal females. Interbreeding of these lines produced rats with interesting combinations of sex chromosomes and gonads: XO, XX, XY, XXY rats with ovaries; and XO, XX, XY, XXY, and XYY rats with testes. These groups can be compared to detect sex differences caused by sex-chromosome complement (XX vs. XY) and/or by gonadal hormones (rats with testes vs. ovaries). Other comparisons detect the effects of X or Y chromosome number (in gonadal females: XO vs. XX, XX vs. XXY, XO vs. XY, XY vs. XXY; in gonadal males: XY vs. XXY, XY vs. XYY; XX vs. XXY, XO vs. XX, XO vs. XY).</p><p><strong>Results: </strong>We measured numerous phenotypes to characterize these models, including gonadal histology, breeding performance, anogenital distance, levels of reproductive hormones, body and organ weights, and central nervous system sexual dimorphisms. Serum testosterone levels were comparable in adult XX and XY gonadal males. Phenotypes previously known to be sexually differentiated by the action of gonadal hormones were found to be similar in XX and XY rats with the same type of gonad, suggesting that XX and XY rats with the same type of gonad have comparable levels of gonadal hormones at various stages of development.</p><p><strong>Conclusion: </strong>The results establish powerful new models to discriminate sex-chromosome and gonadal hormone effects that cause sex differences in rat physiology and disease.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-21DOI: 10.1186/s13293-026-00855-3
V J Duque, J V Nani, M Jovanovic, M Lozić, O Šarenac, A G Pauža, D M Murphy, N Z Japundžić-Žigon, A S Mecawi
Introduction: Hypertension is a multifactorial condition of unknown cause that affects more than 1.28 billion adults worldwide and impacts the sexes differently. The hypothalamic paraventricular nucleus (PVN) plays a central role in blood pressure (BP) regulation by modulating sympathetic tone and releasing neuropeptides that affect the cardiovascular function. In this study, we investigated the transcriptomic profile of the PVN in hypertensive strains and across sexes, aiming to identify novel sex-specific molecular pathways involved in the regulation of BP.
Methods: To accomplish this goal, we sequenced RNA from the PVNs of normotensive Wistar rats and Spontaneously Hypertensive Rats (SHR), both male and female. We also performed a cardiovascular assessment based on blood pressure (BP) measurements and their variability.
Results: Cardiovascular assessment revealed higher SBP in SHRs than in Wistar rats; while males exhibited greater autonomic regulation associated with vasomotor and neurohumoral mechanisms, while females maintained comparable SBP levels primarily through an increase in heart rate, reflecting distinct autonomic adaptations. Hypertension also impacted gene expression, with influences from both the hypertensive state and sex. Compared with female SHRs, male SHRs presented a marked increase in differentially expressed genes (DEGs). Key upregulated genes in males, including Brain-Derived Neurotrophic Factor (Bdnf) and Hypocretin (Hcrt), have already been linked to elevated BP, and Angiotensin II Receptor Type 1 (Agtr1a) is possibly associated with increased SBP-VLF variability, which serves as an indirect measure of enhanced sympathetic tone. In contrast, the female transcriptomic signature was characterized by the upregulation of anti-inflammatory pathways, with upregulation of NLR Family CARD Domain Containing 3 (Nlrc3) and Paired Ig-like Receptor B (Pirb), and downregulation of Absent in Melanoma 2 (Aim2), and S100 Calcium Binding Protein B (S100b). Notably, genes associated with neuroinflammation, such as the downregulation of Annexin A1 (Anxa1) and the upregulation of Solute Carrier Family 11 Member 1 (Slc11a1), were consistently altered in both sexes.
Conclusion: These results provide new insights into the cardiovascular and molecular basis of sex differences in hypertension, suggesting distinct neurohumoral autonomic profile in males, whereas in females a greater anti-inflammatory component. These findings offer a valuable framework for developing future sex-specific therapeutic strategies.
{"title":"Sex-specific hypothalamic PVN transcriptomic signatures of blood pressure autonomic regulation and neuroinflammation in hypertension.","authors":"V J Duque, J V Nani, M Jovanovic, M Lozić, O Šarenac, A G Pauža, D M Murphy, N Z Japundžić-Žigon, A S Mecawi","doi":"10.1186/s13293-026-00855-3","DOIUrl":"10.1186/s13293-026-00855-3","url":null,"abstract":"<p><strong>Introduction: </strong>Hypertension is a multifactorial condition of unknown cause that affects more than 1.28 billion adults worldwide and impacts the sexes differently. The hypothalamic paraventricular nucleus (PVN) plays a central role in blood pressure (BP) regulation by modulating sympathetic tone and releasing neuropeptides that affect the cardiovascular function. In this study, we investigated the transcriptomic profile of the PVN in hypertensive strains and across sexes, aiming to identify novel sex-specific molecular pathways involved in the regulation of BP.</p><p><strong>Methods: </strong>To accomplish this goal, we sequenced RNA from the PVNs of normotensive Wistar rats and Spontaneously Hypertensive Rats (SHR), both male and female. We also performed a cardiovascular assessment based on blood pressure (BP) measurements and their variability.</p><p><strong>Results: </strong>Cardiovascular assessment revealed higher SBP in SHRs than in Wistar rats; while males exhibited greater autonomic regulation associated with vasomotor and neurohumoral mechanisms, while females maintained comparable SBP levels primarily through an increase in heart rate, reflecting distinct autonomic adaptations. Hypertension also impacted gene expression, with influences from both the hypertensive state and sex. Compared with female SHRs, male SHRs presented a marked increase in differentially expressed genes (DEGs). Key upregulated genes in males, including Brain-Derived Neurotrophic Factor (Bdnf) and Hypocretin (Hcrt), have already been linked to elevated BP, and Angiotensin II Receptor Type 1 (Agtr1a) is possibly associated with increased SBP-VLF variability, which serves as an indirect measure of enhanced sympathetic tone. In contrast, the female transcriptomic signature was characterized by the upregulation of anti-inflammatory pathways, with upregulation of NLR Family CARD Domain Containing 3 (Nlrc3) and Paired Ig-like Receptor B (Pirb), and downregulation of Absent in Melanoma 2 (Aim2), and S100 Calcium Binding Protein B (S100b). Notably, genes associated with neuroinflammation, such as the downregulation of Annexin A1 (Anxa1) and the upregulation of Solute Carrier Family 11 Member 1 (Slc11a1), were consistently altered in both sexes.</p><p><strong>Conclusion: </strong>These results provide new insights into the cardiovascular and molecular basis of sex differences in hypertension, suggesting distinct neurohumoral autonomic profile in males, whereas in females a greater anti-inflammatory component. These findings offer a valuable framework for developing future sex-specific therapeutic strategies.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12964816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}