Receptor Expression Research Articles

Differential Alterations in the Expression of AMPA Receptor and Its Trafficking Proteins in the Hippocampus Are Associated with Recognition Memory Impairment in the Rotenone-Parkinson's Disease Mouse Model: Neuroprotective Role of Bacopa monnieri Extract CDRI 08.

Parkinson's disease (PD), an age-associated neurodegenerative motor disorder, is associated with dementia and cognitive decline. However, the precise molecular insight into PD-induced cognitive decline is not fully understood. Here, we have investigated the possible alterations in the expression of glutamate receptor and its trafficking/scaffolding/regulatory proteins underlying the memory formation and neuroprotective effects of a specialized Bacopa monnieri extract, CDRI-08 (BME) in the hippocampus of the rotenone-induced PD mouse model. Our Western blotting and qRT-PCR data reveal that the PD-induced recognition memory decline is associated with significant upregulation of the AMPA receptor subunit GluR1 and downregulation of GluR2 subunit genes in the hippocampus of rotenone-affected mice as compared to the vehicle control. Further, expressions of thetrafficking proteins are significantly upregulated in the hippocampus of rotenone-affected mice compared to the vehicle control. Our results also reveal that the above alterations in the hippocampus are associated with similar expression patterns of total CREB, pCREB, and BDNF. BME (CDRI-08, 200mg/kg BW) reverses the expression of AMPA receptor subunits, their trafficking proteins differentially, and the transcriptional modulatory proteins depending on whether the BME treatment was given before or after the rotenone treatment. Our data suggest that expression of the above genes is significantly reversed in the BME pre-treated mice subjected to rotenone treatment towards their levels in the control mice compared to its treatment after rotenone administration. Our results provide the possible molecular basis underlying the rotenone-induced recognition memory decline, conditions mimicking the PD symptoms in mouse model and neuroprotective action of bacoside A and bacoside B (58%)-enriched Bacopa monnieri extract (BME) in the hippocampus.

Kidney outcomes are altered by preconception weight modulation in rodent mothers with obesity

Obesity increases the risk of chronic kidney disease. We have previously demonstrated the benefits of preconception maternal weight loss on fertility and pregnancy outcomes in a mouse model of maternal obesity. Here, we elucidate if preconception weight loss, either by diet modification or the glucose-like peptide 1 agonist liraglutide, used in the treatment of diabetes and obesity, improves maternal kidney outcomes in late gestation. C57BL/6 female mice were fed either a high-fat-diet (HFD) or a chow (control) diet for 8 weeks. To induce pre-pregnancy weight loss, HFD-fed dams were switched to chow diet (HFD-C) or administered liraglutide (0.3 mg/kg subcutaneous) whilst continuing on HFD (HFD-L). Liraglutide was discontinued one week prior to mating. HFD-V mice continued on HFD, with saline injections. A group of HFD-fed dams were ‘diet switched’ to chow after conception (post-conception, HFD-PC). Maternal body weight and glucose tolerance were measured: (1) preconception and (2) during late gestation followed by blood, urine and kidney collection. Serum creatinine, urinary creatinine and albumin, kidney tissue gene expression and protein were measured. In the preconception period, HFD-L and HFD-C mothers have lower urine albumin:creatinine ratios (UACR) and fatty acid synthase (FAS) protein expression (P < 0.005 vs. HFD-V). At late gestation, kidneys of HFD-V and HFD-PC dams have increased gene expression of insulin receptor and FAS (P < 0.05) and higher UACR compared to controls (P < 0.01). In the HFD-PC group, kidneys show increased mRNA and protein expression of metabolic and oxidative stress markers (FAS, 8-OHdG vs. control, P < 0.05, P < 0.0001 respectively). The preconception intervention groups with liraglutide, or diet change show reduced oxidative stress (protein expression of 8-OHdG, P < 0.05 vs. HFD), mRNA and protein expression of FAS (P < 0.05 vs. HFD), protein expression of fibrosis markers (collagen IV, fibronectin vs. HFD, P < 0.05), and UACR (P < 0.05 vs. HFD). This study suggests that preconception weight loss benefits maternal kidney health during pregnancy, superior to diet intervention once already pregnant.

Sepsis shapes the human γδ TCR repertoire in an age- and pathogen-dependent manner.

Sepsis affects 25 million children per year globally, leading to 2.9 million deaths and substantial disability in survivors. Extensive characterization of interactions between the host and bacteria in children is required to design novel preventive and therapeutic strategies tailored to this age group. Vγ9Vδ2 T cells are the first T cells generated in humans. These cells are defined by the expression of Vγ9Vδ2 T-cell receptors (TCRs, using the TRGV9 and TRDV2 gene segments), which react strongly against the prototypical bacterial phosphoantigen HMBPP. We investigated this reactivity by analyzing the TCR δ (TRD) repertoire in the blood of 76 children (0-16 years) with blood culture-proven bacterial sepsis caused by HMBPP-positive Escherichia coli or by HMBPP-negative Staphylococcus aureus or by HMBPP-negative Streptococcus pneumoniae. Strikingly, we found that S. aureus, and to a lesser extent E. coli but not S. pneumoniae, shaped the TRDV2 repertoire in young children (<2 years) but not in older children or adults. This dichotomy was due to the selective expansion of a fetal TRDV2 repertoire. Thus, young children possess fetal-derived Vγ9Vδ2 T cells that are highly responsive toward specific bacterial pathogens.

Epidermal growth factor receptor and programmed cell death-1 expression levels in peripheral T cell subsets of patients with non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths, in part due to its late diagnosis. Increased epidermal growth factor receptor (EGFR) expression in cancer cells is associated with a poor prognosis, and EGFR tyrosine kinase inhibitors are widely used in cancer treatment. This study aimed to clarify the relationship between EGFR expression on T cells and cancer prognosis in patients with non-small cell lung cancer (NSCLC). Forty patients with NSCLC and 40 healthy volunteers were included in this study. Peripheral CD4+T helper (Th1, Th2, Th9, Th17, Th1Th17, follicular and peripheral Th) and cytotoxic T lymphocyte (CD8+follicular and peripheral T) subsets were identified with flow cytometry according to their chemokine receptors. EGFR expression on T lymphocytes in relation to overall survival (OS) was investigated in patients with NSCLC. The patients [mean age (min-max) = 64.03 (45-83); 20 stage I-III and 20 stage IV] had increased EGFR expression on CD3+T, CD4+Th, Th1, Th2, and Th17 cells compared to the controls (p < 0.05). High EGFR expression on CD3+T, CD4+Th, Th1, and Th2 cells was associated with poor OS. Also, PD-1 expression on lymphocytes, CD3+T, and Th cells was increased in patients with NSCLC compared to controls. The high expression of EGFR and PD-1 on Th cells and the reduced percentage of lymphocytes and Th cells, especially in stage IV patients with NSCLC, revealed that increased EGFR activity may trigger apoptosis of Th cells and promote the development of metastases, while high EGFR expression on CD3+T, CD4+Th, Th1, and Th2 cells may be an independent poor prognostic marker in NSCLC.

Developmental exposure to arsenic reduces anxiety levels and leads to a depressive-like behavior in female offspring rats: Molecular changes in the prefrontal cortex

Exposure to inorganic arsenic (iAs) detrimentally affects the structure and function of the central nervous system. In-utero and postnatal exposure to iAs has been connected to adverse effects on cognitive development. Therefore, this investigation explores neurobehavioral and neurochemical effects of 0.05 and 0.10 mg/L iAs exposure during gestation and lactation periods on 90-day-old female offspring rats. The assessment of anxiety- and depressive-like behaviors was conducted through the application of an elevated plus maze and a forced swim test. The neurochemical changes were evaluated in the prefrontal cortex (PFC) through the determination of enzyme activities and α1 GABAA subunit expression levels. Our findings revealed a notable impact of iAs exposure on anxiety and the induction of depressive-like behavior in 90-day-old female offspring. Furthermore, the antioxidant status within the PFC exhibited discernible alterations in exposed rats. Notably, the activities of acetylcholinesterase and glutamate pyruvate transaminase demonstrated an increase, while glutamate oxaloacetate transaminase activity displayed a decrease within the PFC due to the iAs treatment. Additionally, a distinct downregulation in the mRNA expression of the α1GABAA receptor was observed in this neuronal region. These findings strongly suggest that iAs exposure during early stages of rat development causes significant modifications in brain oxidative stress markers and perturbs the activity of enzymes associated with cholinergic and glutamatergic systems. In parallel, it elicits a discernible reduction in the level of GABA receptors within the PFC. These molecular alterations may play a role in the diminished anxiety levels and the depressive-like behavior outlined in the current investigation.

Evaluation of granulocyte colony-stimulating factor effect on the expression of inhibitory receptors by T cells in multiple myeloma

Evaluation of granulocyte colony-stimulating factor effect on the expression of inhibitory receptors by T cells in multiple myeloma

Bioactive alkaloids from Nepalese Corydalis chaerophylla D.C. acting on the regulation of PCSK9 and LDL-R in vitro.

Four new alkaloids Chaeronepaline-A (1), Chaeronepaline-B (2), Chaeronepaline-C (3), and Chaeronepaline-D (4) were isolated from Corydalis chaerophylla D.C. collected from Nepal and their structures were elucidated by spectroscopic data, 1D, 2D NMR and mass spectrometry. The structures were established as 3,12- Dimethoxy-5,6-dihydroisoquinolino [2,1-b] isoquinolin- 7- ium- 2, 9- diol (1), 7-methyl-5, 6, 7, 8-tetrahydroisoquinoline- 2, 3- methylenedioxy- (8-> 9)- 10, 12- methylenedioxy- benzoic-16-acid (2), 7- methyl-5, 6, 7, 8- tetrahydro- 8H-spiro-9,14-dihydroxy-11,12-methylenedioxy-indane-isoquinoline (3) and 7- methyl-5, 6, 7, 8- tetrahydro- 8H-spiro-9,14-dihydroxy-11,12-methylenedioxy-indane-isoquinoline-N-oxide (4). The new alkaloids were tested in human hepatoma cell line to assess their ability to modulate the expression of low-density lipoprotein receptor (LDL-R), of proprotein convertase subtilisin/kexin 9 (PCSK9) and to affect cellular cholesterol biosynthesis with the aim to evaluate their potential hypocholesterolemic effect. Results indicated that compounds 2 and 3 upregulate the LDLR, and inhibited the cholesterol biosynthesis with compound 2, which also reduced the secretion of PCSK9 by Huh7 cells. These in vitro data indicated a potential hypocholesterolemic effect of compound 2 that requires further in vivo validation.

Characterization of IL-6R-expressing monocytes in the lung of patients with chronic obstructive pulmonary disease

BackgroundMonocytes play a crucial role in innate immune responses for host defense, however, their involvement in chronic obstructive pulmonary disease (COPD) remains poorly understood. We previously identified a subset of monocytes in COPD lung tissues characterized by high interleukin-6 receptor (IL-6R) expression. This study aimed to characterize the phenotypes of IL-6Rhi monocytes in the lungs of COPD patients. MethodsUsing flow cytometry, we assessed the abundance of pulmonary CD14+IL-6Rhi cells in never smokers (CNS), control ex-smokers (CES) and COPD patients. IL-6 expression in CD14+ monocytes isolated from the peripheral blood of patients with COPD was also examined. CD45+CD206–CD14+IL-6Rhi and CD45+CD206–CD14+IL-6R–/lo cells were isolated from COPD lung tissues for transcriptome analysis. A monocyte line THP1 cell with constitutive IL-6R expression was stimulated with recombinant IL-6, followed by RNA sequencing to evaluate the IL-6 responsiveness of IL-6R+ monocytes. ResultsThe number of pulmonary CD14+IL-6Rhi monocytes was elevated in COPD patients compared to CNS, whereas CD14+ monocytes in the peripheral blood of COPD patients did not express IL-6R. Upregulated mRNA expression in CD14+IL-6Rhi monocytes was associated with chemotaxis, monocyte differentiation, fatty acid metabolism and integrin-mediated signaling pathway. Stimulation of THP1 cells with recombinant IL-6 induced changes in the expression of genes linked to chemotaxis and organism development. ConclusionIn patients with COPD, CD14+IL-6Rhi monocytes are increased in lung tissues compared to those in CNS. They exhibit a transcriptome profile different from that of CD14+IL-6R–/lo monocytes.

Repetitive Administration of Low-Dose Lipopolysaccharide Improves Repeated Social Defeat Stress-Induced Behavioral Abnormalities and Aberrant Immune Response.

Repetitive exposure of innate immune cells to a subthreshold dosage of endotoxin components may modulate inflammatory responses. However, the regulatory mechanisms in the interactions between the central nervous system (CNS) and the immune system remain unclear. This study aimed to investigate the effects of lipopolysaccharide (LPS) preconditioning in repeated social defeat stress (RSDS)-induced abnormal immune responses and behavioral impairments. This study aimed to elucidate the mechanisms that underlie the protective effects of repeated administration of a subthreshold dose LPS on behavioral impairments using the RSDS paradigm. LPS preconditioning improved abnormal behaviors in RSDS-defeated mice, accompanied by decreased monoamine oxidases and increased glucocorticoid receptor expression in the hippocampus. In addition, pre-treated with LPS significantly decreased the recruited peripheral myeloid cells (CD11b+CD45hi), mainly circulating inflammatory monocytes (CD11b+CD45hiLy6ChiCCR2+) into the brain in response to RSDS challenge. Importantly, we found that LPS preconditioning exerts its protective properties by regulating lipocalin-2 (LCN2) expression in microglia, which subsequently induces expressions of chemokine CCL2 and pro-inflammatory cytokine. Subsequently, LPS-preconditioning lessened the resident microglia population (CD11b+CD45intCCL2+) in the brains of the RSDS-defeated mice. Moreover, RSDS-associated expressions of leukocytes (CD11b+CD45+CCR2+) and neutrophils (CD11b+CD45+Ly6G+) in the bone marrow, spleen, and blood were also attenuated by LPS-preconditioning. In particular, LPS preconditioning also promoted the expression of endogenous antioxidants and anti-inflammatory proteins in the hippocampus. Our results demonstrate that LPS preconditioning ameliorates lipocalin 2-associated microglial activation and aberrant immune response and promotes the expression of endogenous antioxidants and anti-inflammatory protein, thereby maintaining the homeostasis of pro-inflammation/anti-inflammation in both the brain and immune system, ultimately protecting the mice from RSDS-induced aberrant immune response and behavioral changes.

Dupilumab Reduces Urticaria Activity, Itch, and Hives in Patients with Chronic Spontaneous Urticaria Regardless of Baseline Serum Immunoglobulin E Levels.

In chronic spontaneous urticaria (CSU), interleukin (IL)-4 and IL-13 may promote mast cell activation directly via IL-4 receptor expression, or indirectly via upregulated immunoglobulin E (IgE) production. Dupilumab significantly improved CSU signs and symptoms in the phase 3, randomized, placebo-controlled LIBERTY-CSU CUPID Study A. This analysis explores the impact of dupilumab on CSU signs and symptoms and serum IgE levels in patients from LIBERTY-CSU CUPID Study A with serum total IgE above and below 100IU/mL at baseline. Patients with H1-antihistamine-refractory CSU received dupilumab (n = 70) or placebo (n = 68) for 24 weeks. Efficacy endpoints were change from baseline to weeks 12 and 24 in serum total IgE levels, Itch Severity Score over 7 days (ISS7), Urticaria Activity Score over 7 days (UAS7), and Hives Severity Score over 7days (HSS7) in dupilumab- or placebo-treated patients with serum total IgE above and below 100IU/mL at baseline. Dupilumab treatment significantly reduced median (interquartile range) IgE levels at week 12 [dupilumab: -31.9% (-41.9; -22.6); placebo: -6.3% (-21.3; 14.9)] and week 24 [dupilumab: -48.2% (-56.8; - 39.5); placebo: - 6.3% (-34.5; 14.8)]. Similar IgE reductions relative to baseline were observed in dupilumab-treated patients regardless of baseline IgE level. Dupilumab treatment improved ISS7, UAS7, and HSS7 over 12 and 24 weeks, regardless of baseline serum IgE level (interaction p ≥ 0.59 for all treatment by subgroup comparisons), with weak correlations (r < 0.2) observed between IgE level changes and ISS7, UAS7, and HSS7 outcomes. Dupilumab significantly improved CSU signs and symptoms and reduced serum IgE, regardless of baseline IgE levels. In the current analysis, baseline total IgE had no predictive value as a dupilumab treatment response biomarker in CSU. Downregulation of IgE, a key mediator of mast cell activation and histamine release, may at least partially explain the effectiveness of dupilumab in reducing CSU signs and symptoms. ClinicalTrials.gov Identifier: NCT04180488.

Ki-67 expression and its correlation with clinicopathological parameters in Iraqi breast cancer patients

Breast cancer is the most common cancer worldwide and the major cause of cancer-related death among women in both developed and developing countries. In Iraq, breast cancer accounted for 37.9% of all malignant cases in 2020 and 15.3% of cancer-related fatalities. Relevant biomarkers play an important role in predicting prognosis and deciding the most effective therapy for each patient to delay metastases and reduce mortality. Objective: This study aimed to assess the significance of Ki-67 expression as a prognostic biomarker in breast cancer patients as well as investigate the correlations between Ki-67 and their clinicopathological features. Methods: The case-control study comprised sixty newly diagnosed breast cancer patients and ten women with benign breast tumors who served as controls. We assessed the tissue expression level of Ki-67 protein using the immunohistochemistry technique. Results: Our results showed that the median immunohistochemical expression scores of Ki-67 in the newly diagnosed breast cancer group were higher than those of the control group; the difference was significant (p &lt; 0.001). The Ki-67 expression score in breast cancer cells increases with tumor size and grade. Ki-67 expression showed a substantial negative correlation with estrogen receptor expression and a significant positive correlation with HER2 expression.

D2 dopamine receptor expression, reactivity to rewards, and reinforcement learning in a complex value-based decision-making task.

Different dopamine (DA) subtypes have opposing dynamics at postsynaptic receptors, with the ratio of D1 to D2 receptors determining the relative sensitivity to gains and losses, respectively, during value-based learning. This effective sensitivity to different reward feedback interacts with phasic DA levels to determine the effectiveness of learning, particularly in dynamic feedback situations where the frequency and magnitude of rewards need to be integrated over time to make optimal decisions. We modeled this effect in simulations of the underlying basal ganglia pathways and then tested the predictions in individuals with a variant of the human dopamine receptor D2 (DRD2; -141C Ins/Del and Del/Del) gene that associates with lower levels of D2 receptor expression (N = 119) and compared their performance in the Iowa Gambling Task to noncarrier controls (N = 319). Ventral striatal (VS) reactivity to rewards was measured in the Cards task with fMRI. DRD2 variant carriers made less effective decisions than noncarriers, but this effect was not moderated by VS reward reactivity as is hypothesized by our model. These results suggest that the interaction between DA receptor subtypes and reactivity to rewards during learning may be more complex than originally thought.

Efficacy of GluN2B-Containing NMDA receptor antagonist for antitumor and antidepressant therapy in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancer. Evidence suggests that the ionotropic glutamate receptor N-methyl-D-aspartate (NMDA) receptor, a critical molecule in the central nervous system, is expressed in NSCLC. However, the specific expression patterns, subcellular localization, functional modulation, and pathological implications of NMDA receptor subtypes in NSCLC have not been fully elucidated. In this study, we employed a multi-disciplinary approach, combining biochemical and molecular biology with electrophysiological recordings and behavioral assays, to investigate these aspects. We reveal the expression of GluN2B-containing NMDA receptors in A549 and H460 NSCLC cell lines and the induction of NMDA receptor-mediated currents by glutamate in A549 cells. Furthermore, the GluN2B-specific inhibitors ifenprodil and Ro 25–6981 significantly reduced cell viability and migration, while promoting apoptosis. Importantly, intraperitoneal administration of ifenprodil in nude mice inhibited the growth of subcutaneous tumors derived from A549 and H460 cells and ameliorated depression-like behaviors. These findings underscore the potential antiproliferative effects of ifenprodil and Ro 25–6981 and suggest that GluN2B-containing NMDA receptors may represent novel therapeutic targets for NSCLC, with the added benefit of potential antidepressant action.

The beneficial effects of lupeol on particulate matter–mediated pulmonary inflammation

Particulate matter (PM) poses significant health risks, especially fine particles (PM2.5) that can cause severe lung injuries. Lupeol, a phytosterol from medicinal plants, has potential anti-cancer properties. This study investigated lupeol's protective effects against PM2.5-induced lung damage. Mice received lupeol following intratracheal PM2.5 exposure. Results showed lupeol reduced lung damage, lowered wet/dry (W/D) weight ratio, and suppressed increased permeability caused by PM2.5. Additionally, lupeol decreased plasma inflammatory cytokines, total protein concentration in bronchoalveolar lavage fluid (BALF), and PM2.5-induced lymphocyte proliferation. Lupeol also reduced expression of toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), and autophagy-related proteins microtubule-associated protein 1 A/1 B-light chain 3 (LC3) II and Beclin 1, while increasing phosphorylated mammalian target of rapamycin (mTOR) phosphorylation. These findings suggest lupeol's potential as a therapeutic agent for PM2.5-induced lung damage via modulation of the TLR4-MyD88 and mTOR-autophagy pathways.

The CCL2-CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop through glomerular macrophage and neutrophil infiltration in lupus nephritis.

The CCL2-CCR2 axis is involved in lupus nephritis, however the precise roles in the mechanisms by which different pathological lesions develop after glomerular immune complex deposition remain elusive. Previously, we demonstrated that genetic CCR2 inhibition induced a histological switch from glomerular endocapillary hypercellularity to wire-loop lesions in murine lupus nephritis. This study aimed to clarify the CCL2-CCR2 axis-mediated cellular mechanism in the formation of these different pathological lesions. We injected MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 or B1, into wild-type (WT) mice to selectively induce glomerular endocapillary hypercellularity or wire-loop lesions. The expression of chemokine and chemokine receptors was analyzed using RT-quantitative PCR and/or immunofluorescence. We found 2B11.3 caused glomerular endocapillary hypercellularity in WT mice with glomerular infiltration of larger numbers of CCR2-expressing macrophages and neutrophils phagocyting immune complex, whereas B1 induced wire-loop lesions. In glomerular endocapillary hypercellularity, CCL2 was identified as the ligand involved in the CCR2-positive cell infiltration; it was expressed by glomerular endothelial cells and macrophages. Notably, 2B11.3-induced glomerular endocapillary hypercellularity converted to wire-loop lesions with reduced glomerular macrophage and neutrophil infiltration in CCL2-deficient (Ccl2-/-) mice similarly observed in Ccr2-/- mice. Moreover, this histological conversion was also observed when both glomerular macrophage and neutrophil infiltration were inhibited in anti-Ly6G antibody-treated Ccr5-/- mice but not when only glomerular macrophage infiltration was inhibited in Ccr5-/- mice or when only glomerular neutrophil infiltration was inhibited in anti-Ly6G antibody-treated WT mice. In contrast, B1 injection caused wire-loop lesions in Ccl2-/- and Ccr2-/- mice, as observed in WT mice. Moreover, 2B11.3 induced CCL2 from glomerular endothelial cells to a larger extent than B1 when injected into Ccr2-/- mice. In conclusion, the CCL2-CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop by regulating glomerular infiltration of phagocytic cells: macrophages and neutrophils. © 2024 The Pathological Society of Great Britain and Ireland.

The impact of human epidermal growth factor receptor-2 (low) status on the efficacy of first line cyclin-dependent kinase 4/6 inhibitors in advanced breast cancer.

The fact that the human epidermal growth factor receptor 2 (HER2)-low group, historically classified as HER2 negative in breast cancer histology, benefited from HER2-targeted treatments similarly to the HER2-positive group indicates that this group has a distinct histology from the HER2-0 group. The effectiveness of cyclin-dependent kinase 4/6 inhibitors, which are the standard first-line treatment for hormone receptor-positive, HER2-negative advanced breast cancer, in this newly defined histological subgroup remains a topic of debate. In our study, we examined the impact of HER2 status on the efficacy of CDK4/6 inhibitors. Our study is a retrospective, multicenter, real-world data analysis. One hundred sixty patients were included in the study. The relationship between HER2 status and other clinical-pathological features, as well as progression-free survival, was examined. Median follow-up was 20.33 ± 0.98 months. The mPFS could not be reached. All patients exhibited positive estrogen receptor expression. Among the patients, 111 (69.4%) were categorized as HER2-0, and 49 (30.6%) as HER2-low. The 24-month progression-free survival rates were similar between HER2-0 and HER2-low patients (60.6% vs 65.3%, hormone receptor: 1.18, CI: 0.67-2.20, P = .554). We established that the mPFS achieved with cyclin-dependent kinase 4/6 inhibitors as a first-line therapy for patients with advanced breast cancer is unaffected by HER2 status.

Hormone receptor expression in low-grade adenosquamous carcinoma of the breast progressing to high-grade metaplastic carcinoma: A case report.

Breast low-grade adenosquamous carcinoma is an uncommon cancer that has been neglected in genetic and pathophysiological research. Consequently, medical practitioners face challenges in the effective diagnosis and treatment of this condition. We present the case of a 57-year-old Asian female patient who presented with bilateral breast masses on physical examination. Ultrasound and an MRI revealed a highly suspicious malignant mass in her right breast that was completely removed surgically. After pathological analysis, the diagnosis was low-grade adenosquamous carcinoma with local high-grade transformation, and some of the tumor components were estrogen receptor positive. The patient underwent appropriate postoperative chemotherapy and achieved a favorable outcome. During the follow-up period after surgical resection, the patient did not experience any local recurrence or distant metastasis. Owing to the rare combination of estrogen receptor positivity and high-grade progression, this patient also required adjuvant chemotherapy. This enhances the essential foundation for diagnosing and treating this rare disease, and facilitates the implementation of treatment plans.

Hypertension disrupts the vascular clock in both sexes.

Blood pressure (BP) displays a circadian rhythm and disruptions in this pattern elevate cardiovascular risk. While both central and peripheral clock genes are implicated in these processes, the importance of vascular clock genes is not fully understood. BP, vascular reactivity, and the renin-angiotensin-aldosterone system display overt sex differences, but whether changes in circadian patterns underlie these differences is unknown. Therefore, we hypothesized that circadian rhythms and vascular clock genes would differ across sex and would be blunted by Ang II-induced hypertension. Ang II infusion elevated BP and disrupted circadian patterns similarly in both males and females. In females, an impact on heart rate and locomotor activity was revealed, while in males hypertension suppressed baroreflex sensitivity. A marked disruption in the vascular expression patterns of Per1 and Bmal1 were noted in both sexes. Vascular expression of the G protein-coupled estrogen receptor (Gper1) also showed diurnal synchronization in both sexes that was similar to that of Per1 and Per2 and disrupted by hypertension. In contrast, vascular expression of Esr1 showed a diurnal rhythm and hypertension-induced disruption only in females. This study shows a strikingly similar impact of hypertension on BP rhythmicity, vascular clock genes, and vascular estrogen receptor expression in both sexes. We identified a greater impact of hypertension on locomotor activity and heart rate in females and on baroreflex sensitivity in males and also revealed a diurnal regulation of vascular estrogen receptors. These insights highlight the intricate ties between circadian biology, sex differences, and cardiovascular regulation.

Neuropeptide Y receptor activation preserves inner retinal integrity through PI3K/Akt signaling in a glaucoma mouse model.

Neuropeptide Y (NPY), an endogenous peptide composed of 36 amino acids, has been investigated as a potential therapeutic agent for neurodegenerative diseases due to its neuroprotective attributes. This study investigated the neuroprotective effects of NPY in a mouse model of glaucoma characterized by elevated intraocular pressure (IOP) and progressive retinal ganglion cell degeneration. Elevated IOP in mice was induced through intracameral microbead injections, accompanied by intravitreal administration of NPY peptide. The results demonstrated that NPY treatment preserved both the structural and functional integrity of the inner retina and mitigated axonal damage and degenerative changes in the optic nerve under high IOP conditions. Further, NPY treatment effectively reduced inflammatory glial cell activation, as evidenced by decreased expression of glial fibrillary acidic protein and Iba-1. Notably, endogenous NPY expression and its receptors (NPY-Y1R and NPY-Y4R) levels were negatively affected in the retina under elevated IOP conditions. NPY treatment restored these changes to a significant extent. Molecular analysis revealed that NPY mediates its protective effects through the mitogen-activated protein kinase (MAPK) and PI3K/Akt signaling pathways. These findings highlight the therapeutic potential of NPY in glaucoma treatment, underscoring its capacity to preserve retinal health, modulate receptor expression under stress, reduce neuroinflammation, and impart protection against axonal impairment.

Hyperandrogenism Decreases Seizure Threshold in A Rat Model of Polycystic Ovary Syndrome.

In women of childbearing age with epilepsy, 40% experience the comorbidity of polycystic ovary syndrome (PCOS), which is marked by a higher prevalence of hyperandrogenism. Our recent clinical observations indicate the potential contribution of hyperandrogenism-induced PCOS to epilepsy susceptibility, and this study aimed to unravel the underlying factors that increase the susceptibility of females to epilepsy. A letrozole-induced PCOS rat model was employed to simulate endogenous hyperandrogenism. Susceptibility was assessed through seizure kindling rates using pentetrazol and electroencephalogram recordings. Additionally, the role of androgens in epilepsy was verified through interventions using Diane-35. This study revealed that letrozole induced elevated testosterone levels and PCOS-related changes in female rats. PCOS rats, through pentetrazol-kindling, exhibited a reduced seizure threshold compared with controls. Elevated testosterone levels were observed in both the hippocampal and frontal brain tissues, accompanied by changes in circulation. Two weeks of Diane-35 intervention showed a tendency to alleviate these changes, modifying testosterone levels in both the plasma and brain tissue. Western blotting and immunohistochemistry revealed increased expression of GABA-A receptor in the hippocampus and decreased AMPA receptor expression in the frontal cortex, correlating with anti-epileptic status in PCOS rats. This study delves into the impact of elevated androgen levels on seizure threshold, providing crucial insights into the underpinnings of the comorbidity between PCOS and epilepsy. These findings significantly contribute to the evolving field of epilepsy research, emphasizing the imperative consideration of hormonal influences for the development of targeted therapeutic interventions in individuals with epilepsy and PCOS.