Associations between smoking, sex steroid hormones, trouble sleeping, and depression among U.S. adults: a cross-sectional study from NHANES (2013-2016).

BACKGROUND: Dose-response and nonlinear relationships of cigarette exposure with sleep disturbances and depression are warranted, and the potential mechanism of sex hormones in such associations remains unclear. METHODS: Cigarette exposure, trouble sleeping, and depression were assessed by standard questionnaires, and the levels of cotinine and sex steroid hormones were determined among 9900 adults from the National Health and Nutrition Examination Survey (NHANES). Multiple linear regression, logistic regression, and mediation models were conducted to evaluate the associations between smoking, sex steroid hormones, trouble sleeping, and depression. RESULTS: With never smokers as a reference, current smokers had a higher prevalence of trouble sleeping (OR = 1.931, 95% CI: 1.680, 2.219) and depression (OR = 2.525, 95% CI: 1.936, 3.293) as well as testosterone level (ß = 0.083, 95% CI: 0.028, 0.140). Pack-years of smoking and cigarettes per day were positively associated with the prevalence of trouble sleeping and depression as well as testosterone level (Ptrend <0.05). The restricted cubic spline model showed linear relationships of cotinine with trouble sleeping, depression, and testosterone. The positive associations of cigarettes per day with trouble sleeping and depression were greater in females than that in males (Pmodification <0.05). However, the potential role of sex hormones was not observed in the association of cotinine with trouble sleeping or depression (Pmediation >0.05). CONCLUSION: Smoking may induce sex hormone disturbance and increase the risk of sleep problems and depression symptoms, and ceasing smoking may reduce the risk of such complications.

Ultrasensitive DNA Methylation Ratio Detection Based on the Target-Induced Nanoparticle-Coupling and Site-Specific Base Oxidation Damage for Colorectal Cancer.

DNA methylation analysis holds great promise in the whole process management of cancer early screening, diagnosis, and prognosis monitoring. Nevertheless, accurate detection of target methylated DNA, especially its methylation ratio in the genome, remains challenging. Herein, we report for the first time an integrated strategy of target-induced nanoparticle-coupling and site-specific base oxidation damage for DNA methylation analysis with the assistance of well-designed nanosensors. The ultrahigh sensitivity for detecting target methylated DNA as low as 32 × 10-17 M and high specificity for distinguishing 0.001% methylation ratio are achieved by this proposed strategy without amplification operations. Notably, the precise quantification of target DNA methylation ratio has been achieved for the first time. Through quantitative detection of target methylated DNA and methylation ratio, this proposed strategy could reliably diagnose and monitor cancer progression and treatment responses for colorectal cancer, which is superior to the clinical Septin 9 kit. It is anticipated that the proposed strategy has attractive application prospects in early diagnosis and monitoring for colorectal cancer and other various diseases.

Activation of G protein-coupled receptor 30 protects neurons by regulating autophagy in astrocytes.

Ischemic stroke leads to neuronal damage induced by excitotoxicity, inflammation, and oxidative stress. Astrocytes play diverse roles in stroke and ischemia-induced inflammation, and autophagy is critical for maintaining astrocytic functions. Our previous studies showed that the activation of G protein-coupled receptor 30 (GPR30), an estrogen membrane receptor, protected neurons from excitotoxicity. However, the role of astrocytic GPR30 in maintaining autophagy and neuroprotection remained unclear. In this study, we found that the neuroprotection induced by G1 (GPR30 agonist) in wild-type mice after a middle cerebral artery occlusion was completely blocked in GPR30 conventional knockout (KO) mice but partially attenuated in astrocytic or neuronal GPR30 KO mice. In cultured primary astrocytes, glutamate exposure induced astrocyte proliferation and decreased astrocyte autophagy by activating mammalian target of rapamycin (mTOR) and c-Jun N-terminal kinase (JNK) and inhibiting p38 mitogen-activated protein kinase (MAPK) pathway. G1 treatment restored autophagy to its basal level by regulating the p38 pathway but not the mTOR and JNK signaling pathways. Our findings revealed a key role of GPR30 in neuroprotection via the regulation of astrocyte autophagy and support astrocytic GPR30 as a potential drug target against ischemic brain damage.

Activation of Paraventricular Melatonin Receptor 2 Mediates Melatonin-Conferred Cardioprotection Against Myocardial Ischemia/Reperfusion Injury.

Previous studies have shown that melatonin (Mel) can effectively ameliorate myocardial ischemia/reperfusion (MI/R) injury, but the mechanism is yet to be fully elucidated. Mel receptors are expressed in the paraventricular nucleus (PVN), which is also involved in regulating cardiac sympathetic nerve activity. The aim of this study was to examine whether Mel receptors in the PVN are involved in the protective effects of Mel against MI/R injury. The results of quantitative polymerase chain reaction, western blot, and immunofluorescence assays indicated that Mel receptor 2 (MT2) expression in the PVN was upregulated after MI/R. Intraperitoneal administration of Mel significantly improved post-MI/R cardiac function and reduced the infarct size, whereas shRNA silencing of MT2 in the PVN partially blocked this effect. Intraperitoneal administration of Mel reduced sympathetic nerve overexcitation caused by MI/R, whereas shRNA silencing of MT2 in the PVN partially diminished this effect. Furthermore, enzyme-linked immunosorbent assay and western blot results indicated that intraperitoneal administration of Mel lowered the levels of inflammatory cytokines in the PVN after MI/R injury, whereas the application of sh-MT2 in the PVN reduced this effect of Mel. Mel significantly reduced the levels of NF-κB after astrocyte oxygen and glucose deprivation/reoxygenation injury, and this effect was offset when MT2 was silenced. The above experimental results suggest that MT2 in the PVN partially mediated the protective effects of Mel against MI/R injury, and its underlying mechanisms may be related to postactivation amelioration of PVN inflammation and reduction of cardiac sympathetic nerve overexcitation.

Inhibition of RhoA/ROCK signaling pathway ameliorates hypoxic pulmonary hypertension via HIF-1α-dependent functional TRPC channels.

Hypoxic pulmonary vasoconstriction (HPV) can be modulated by Rho/Rho kinase signaling, which can alter HPV vascular function via regulating myosin light chain phosphorylation, in a manner generally believed to be Ca2+-independent. We hypothesized that the RhoA/ROCK signaling pathway also can regulate HPV vascular function via a Ca2+-dependent mechanism, signaling through the functional transient receptor potential canonical (TRPC) channels. In this study, male BALB/c mice were exposed to normoxic or 10% oxygen (hypoxic) conditions for six weeks, after which systolic pressure and right ventricular hypertrophy were assessed. Transient intracellular calcium was monitored using a fluorescence imaging system. Muscle tension was measured with a contractile force recording system, and protein expression was assessed by immunoblotting. We found that the expressions of RhoA and ROCK were increased in mouse pulmonary arteries (PAs) under conditions of chronic hypoxia. Inhibition of the RhoA/ROCK signaling pathway prevented the development of hypoxic pulmonary hypertension (HPH), as evidenced by significantly reduced PA remodeling and pulmonary vasoconstriction. Immunoblotting results revealed that inhibition of the RhoA/ROCK signaling pathway significantly decreased the expression of HIF-1α. Knockdown of HIF-1α down-regulated the expression and function of the TRPC1 and TRPC6 channels in PASMCs under conditions of hypoxia. Contraction of the PAs and a Ca2+ influx into PASMCs through either receptor- or store-operated Ca2+ channels were also increased after hypoxia. However, RhoA/ROCK inhibitors markedly attenuated these changes. These results indicate that inhibition of the RhoA/ROCK signaling pathway ameliorates HPH via HIF-1α-dependent functional TRPCs.

PFKFB3 promotes endotoxemia-induced myocardial dysfunction through inflammatory signaling and apoptotic induction.

Cardiac dysfunction is a vital complication during endotoxemia (ETM). Accumulating evidence suggests that enhanced glycolytic metabolism promotes inflammatory and myocardial diseases. In this study, we performed deep mRNA sequencing analysis on the hearts of control and lipopolysaccharide (LPS)-challenged mice (40 mg/kg, i.p.) and identified that the glycolytic enzyme, 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase 3 (PFKFB3) might play an indispensable role in ETM-induced cardiac damage. Quantitative real-time PCR validated the transcriptional upregulation of PFKFB3 in the myocardium of LPS-challenged mice and immunoblotting and immunostaining assays confirmed that LPS stimulation markedly increased the expression of PFKFB3 at the protein level both in vivo and in vitro. The potent antagonist 3-(3pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) was used to block PFKFB3 activity in vivo (50 mg/kg, i.p.) and in vitro (10 µM). Echocardiographic analysis and TUNEL staining showed that 3PO significantly alleviated LPS-induced cardiac dysfunction and apoptotic injury in vivo. 3PO also suppressed the LPS-induced secretion of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6 and lactate in the serum, in addition to lactate in the myocardium. PFKFB3 inhibition also diminished the nuclear translocation and phosphorylation of transcription factor nuclear factor-κB (NF-κB) in both adult cardiomyocytes and HL-1 cells. Furthermore, immunoblotting analysis showed that 3PO inhibited LPS-induced apoptotic induction in cardiomyocytes. Taken together, these findings demonstrate that PFKFB3 participates in LPS-induced cardiac dysfunction via mediating inflammatory and apoptotic signaling pathway.

Exendin-4 Induces Bone Marrow Stromal Cells Migration Through Bone Marrow-Derived Macrophages Polarization via PKA-STAT3 Signaling Pathway.

BACKGROUND/AIMS: The synthesis and degradation processes involved in bone remodeling are critically regulated by osteoblasts and osteoclasts. The GLP-1 receptor agonist Exendin-4 is beneficial for osteoblast differentiation and increases the number of osteoblasts. METHODS: We constructed an ovariectomized model to evaluate the impact of Exendin-4 on bone formation in osteoporosis. A macrophage-depleted model was also created to investigate the effect of macrophages on bone formation. Thirty-two female WT C57BL/6 mice (aged 3 months) were randomly assigned to a normal control group and four ovariectomized (OVX) subgroups: OVX + vehicle group, OVX + Exendin-4 (4.2 µg/kg/day) group, OVX + chloride phosphate liposome group and OVX + chloride phosphate liposome + Exendin-4 group. RESULTS: In this study, we found that Exendin-4 not only increased the number of osteoblasts and decreased the number of osteoclasts, but also increased the number of bone marrow stromal cells (BMSCs) at the bone surface. Moreover, we found that OVX mice treated with Exendin-4 increased TGF-ß1 levels at the bone surface compared with that in OVX mice. Besides, Exendin-4 promoted the polarization of bone marrow-derived macrophages into M2 subtype and increased TGF-ß1 secretion by the M2 subtype. Finally, we found that Exendin-4 induced macrophage polarization via the cAMP-PKA-STAT3 signaling pathway. CONCLUSION: Exendin-4 promotes bone marrow-derived macrophage polarization to the M2 subtype and induces BMSC migration to the bone surface via PKA-STAT3 signaling.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-Glucoside Attenuates Ischemia/Reperfusion-Induced Brain Injury in Rats by Promoting Angiogenesis.

Cerebral ischemia can cause brain infarcts, which are difficult to recover due to poor angiogenesis. 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside is a natural polyphenol, has antioxidant and anti-inflammatory activity, and can protect from ischemic neuronal injury. However, little is known about the effect of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside on brain microcirculation after stroke. This study aimed at investigating the influence of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside on brain lesions and angiogenesis after stroke. Sprague-Dawley rats were subjected to right middle cerebral artery occlusion and treated with vehicle, nimodipine, or different doses of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside daily beginning at 6 h post-middle cerebral artery occlusion for 14 days. The volume of cerebral infarcts, degree of neurological dysfunction, and level of microvessel density were determined longitudinally. The levels of vascular endothelial growth factor, angiopoietin 1, and angiopoietin receptor-2 expression in the brain lesions were characterized by immunohistochemistry and Western blot assays at 14 days post-middle cerebral artery occlusion. We found that 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside significantly promoted postoperative recovery in rats by minimizing the volume of cerebral infarcts and improving neurological dysfunction in a dose- and time-dependent manner. Additionally, 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside significantly increased the microvessel density in the brain and upregulated CD31 expression in ischemic penumbra, relative to that in the control. Finally, treatment with 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside significantly upregulated the relative levels of vascular endothelial growth factor, angiopoietin 1, and angiopoietin receptor-2 expression in the brain lesions of rats. Therefore, these data indicated that 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside treatment promoted angiogenesis and recovery from ischemia/reperfusion-induced brain injury in rats.

[Self-assembling peptide GFS-4 nanofiber scaffolds for three-dimensional cell cultures and myocardial infarction repair].

The purpose of this study is to investigate the effects of self-assembling peptide GFS-4 on three-dimen-sional myocardial cell culture and tissue repair of myocardial infarction. The circular dichroism (CD) spectrum was used to detect secondary structure of GFS-4, and atomic force microscope (AFM) was used to analyze the microstructure of self-assembly. The nanofiber scaffolds self-assembled by GFS-4 were used as the three-dimensional culture material to observe the growth effect of cardiomyocytes. The model of myocardial infarction was established and the effect of GFS-4 on myocardial infarction was studied. The results indicated that self-assembling peptide GFS-4 could form mainly ß-sheet structure that can form dense nanofiber scaffolds after 24 hours' self-assembling. The myocardial cells had a favorable growth status in GFS-4 nanofiber scaffold hydrogel when cells treated in three-dimen-sional cell culture. The experiment of repairing myocardial infarction in vitro proved that peptide GFS-4 hydrogel scaffold could alleviate tissue necrosis in a myocardial infarction area. As a new nanofiber scaffold material, self-assembling peptide GFS-4 can be used for three-dimensional cell culture and tissue repairing in myocardial infarction area.

Antisense growth inhibition of methicillin-resistant Staphylococcus aureus by locked nucleic acid conjugated with cell-penetrating peptide as a novel FtsZ inhibitor.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are becoming increasingly difficult to treat, owing to acquired antibiotic resistance. The emergence and spread of MRSA limit therapeutic options and require new therapeutic strategies, including novel MRSA-active antibiotics. Filamentous temperature-sensitive protein Z (FtsZ) is a highly conserved bacterial tubulin homologue that is essential for controlling the bacterial cell division process in different species of S. aureus. We conjugated a locked nucleic acid (LNA) that targeted ftsZ mRNA with the peptide (KFF)3K, to generate peptide-LNA (PLNA). The present study aimed to investigate whether PLNA could be used as a novel antibacterial agent. PLNA787, the most active agent synthesized, exhibited promising inhibitory effects on four pathogenic S. aureus strains in vitro. PLNA787 inhibited bacterial growth and resolved lethal Mu50 infections in epithelial cell cultures. PLNA787 also improved the survival rates of Mu50-infected mice and was associated with reductions of bacterial titers in several tissue types. The inhibitory effects on ftsZ mRNA and FtsZ protein expression and inhibition of the bacterial cell division process are considered to be the major mechanisms of PLNA. PLNA787 demonstrated activity against MRSA infections in vitro and in vivo. Our findings suggest that ftsZ mRNA is a promising new target for developing novel antisense antibiotics.

Ferroptosis and EMT resistance in cancer: a comprehensive review of the interplay.

Ferroptosis differs from traditional cell death mechanisms like apoptosis, necrosis, and autophagy, primarily due to its reliance on iron metabolism and the loss of glutathione peroxidase activity, leading to lipid peroxidation and cell death. The dysregulation of iron metabolism is a hallmark of various cancers, contributing to tumor progression, metastasis, and notably, drug resistance. The acquisition of mesenchymal characteristics by epithelial cells is known as Epithelial-Mesenchymal Transition (EMT), a biological process intricately linked to cancer development, promoting traits such as invasiveness, metastasis, and resistance to therapeutic interventions. EMT plays a pivotal role in cancer progression and contributes significantly to the complex dynamics of carcinogenesis. Research findings indicate that mesenchymal cancer cells exhibit greater susceptibility to ferroptosis compared to their epithelial counterparts. The induction of ferroptosis becomes more effective in eliminating drug-resistant cancer cells during the process of EMT. The interplay between ferroptosis and EMT, a process where epithelial cells transform into mobile mesenchymal cells, is crucial in understanding cancer progression. EMT is associated with increased cancer metastasis and drug resistance. The review delves into how ferroptosis and EMT influence each other, highlighting the role of key proteins like GPX4, which protects against lipid peroxidation, and its inhibition can induce ferroptosis. Conversely, increased GPX4 expression is linked to heightened resistance to ferroptosis in cancer cells. Moreover, the review discusses the implications of EMT-induced transcription factors such as Snail, Zeb1, and Twist in modulating the sensitivity of tumor cells to ferroptosis, thereby affecting drug resistance and cancer treatment outcomes. Targeting the ferroptosis pathway offers a promising therapeutic strategy, particularly for tumors resistant to conventional treatments. The induction of ferroptosis in these cells could potentially overcome drug resistance. However, translating these findings into clinical practice presents challenges, including understanding the precise mechanisms of ferroptosis induction, identifying predictive biomarkers, and optimizing combination therapies. The review underscores the need for further research to unravel the complex interactions between ferroptosis, EMT, and drug resistance in cancer. This could lead to the development of more effective, targeted cancer treatments, particularly for drug-resistant tumors, offering new hope in cancer therapeutics.

Upregulation of TRPC1 in microglia promotes neutrophil infiltration after ischemic stroke.

Neutrophil infiltration has been linked to worse clinical outcomes after ischemic stroke. Microglia, a key type of immune-competent cell, engage in cross-talk with the infiltrating immune cells in the inflamed brain area, yet the molecular mechanisms involved remain largely unexplored. In this study, we investigated the mechanisms of how canonical transient receptor potential 1 (TRPC1) modulated neutrophil infiltration in male mouse cerebral ischemia and reperfusion injury (CIRI) models. Our findings revealed a notable upregulation of TRPC1 in microglia within both middle cerebral artery occlusion reperfusion (MCAO/R) and in vitro oxygen-glucose deprivation/regeneration (OGD/R) model. Conditional Trpc1 knockdown in microglia markedly reduced infarct volumes and alleviated neurological deficits. Microglia conditional Trpc1 knockdown mice displayed less neutrophil infiltration in peri-infarct area. Trpc1 knockdown microglia exhibited a reduced primed proinflammatory phenotype with less secretion of CC-Chemokines ligand (CCL) 5 and CCL2 after MCAO/R. Blocking CCL5/2 significantly mitigated neutrophil infiltration in microglia/neutrophil transwell co-culture system upon OGD/R condition. Trpc1 knockdown markedly reduced store-operated calcium entry and nuclear factor of activated T-cells c1 (NFATc1) level in OGD/R treated microglia. Overexpression of Nfatc1 reversed the CCL5/2 reducing effect of Trpc1 knockdown, which is mediated by small interfering RNA in BV2 cells upon OGD/R. Our data indicate that upregulation of TRPC1 in microglia stimulates the production of CCL5/2 through the Ca2+/NFATc1 pathway. Upregulated CCL5/2 leads to an increase in neutrophil infiltration into the brain, thereby aggravating reperfusion injury. Our results demonstrate the importance of TRPC1 in microglia-mediated neuroinflammation and suggest a potential means for reducing CIRI induced neurological injury.

Astrocyte KDM4A mediates chemokines and drives neutrophil infiltration to aggravate cerebral ischemia and reperfusion injury.

Neutrophils plays a crucial role in acute ischemic brain injury and have emerged as potential treatment targets to mitigate such injuries. Lysine-specific demethylase 4 A (KDM4A), a member of the histone lysine demethylase family of enzymes involved in transcriptional regulation of gene expression, is upregulated during hypoxic events. However, the exact role of KDM4A in the pathological process of ischemic stroke remains largely unexplored. Our findings reveal that there was an upregulation of KDM4A levels in reactive astrocytes within both stroke mouse models and in vitro oxygen-glucose deprivation/regeneration (OGD/R) models. Using a conditional knockout mouse, we observed that astrocytic Kdm4a knockout regulates neutrophil infiltration and alleviates brain injury following middle cerebral artery occlusion reperfusion. Furthermore, Kdm4a deficiency astrocytes displayed lower chemokine C-X-C motif ligand 1 (CXCL1) level upon OGD/R and decreased neutrophil infiltration in a transwell system. Mechanistically, KDM4A, in cooperation with nuclear factor-kappa B (NF-κB), activates Cxcl1 gene expression by demethylating histone H3 lysine 9 trimethylation at Cxcl1 gene promoters in astrocytes upon OGD/R injury. Our findings suggest that astrocyte KDM4A-mediated Cxcl1 activation contributes to neutrophil infiltration via cooperation with NF-κB, and KDM4A in astrocytes may serve as a potential therapeutic target to modulate neutrophil infiltration after stroke.

Association of obesity profiles and metabolic health status with liver injury among US adult population in NHANES 1999-2016.

The combined effect of obesity and metabolic abnormalities on liver injury is unclear. Aiming to address this knowledge gap, this cross-sectional study was conducted among 16,201 US adults. Multiple linear regression and logistic regression analyses were conducted to assess the associations of obesity profiles, metabolic health status, and weight change with the levels of liver enzymes. The analysis revealed that general obesity and abdominal obesity were positively associated with the levels of liver enzymes and the prevalence of abnormal liver enzymes (P and Ptrend < 0.05). The associations remained significant in both metabolically healthy and metabolically unhealthy subgroups. Additionally, the liver injury index levels of the metabolically unhealthy participants were higher than those of the metabolically healthy individuals within the non-obese, overweight/pre-abdominal obesity, and general/abdominal obesity subgroups (P and Ptrend < 0.05). Furthermore, the subgroup characterized by general/abdominal obesity and metabolic dysfunction exhibited the most robust association with the liver injury index compared to all other subgroups examined. In addition, positive associations were observed between the 1-year and 10-year weight changes and the levels of liver injury indicators (P and Ptrend < 0.05). In conclusion, this study demonstrates that both obesity and metabolic impairment are independently associated with liver injury, and their combined presence have an additional adverse effect on liver health. These findings underscore the importance of addressing both obesity and metabolic dysfunction in order to mitigate the risk of liver injury.

A Pressure and Temperature Dual-Parameter Sensor Based on a Composite Material for Electronic Wearable Devices.

Wearable sensors integrating multiple functionalities are highly desirable in artificial wearable devices, which are of great significance in the field of biomedical research and for human-computer interactions. However, it is still a great challenge to simultaneously perceive multiple external stimuli such as pressure and temperature with one single sensor. Combining the piezoresistive effect with the negative temperature coefficient of resistance, in this paper, we report on a pressure-temperature dual-parameter sensor composed of a polydimethylsiloxane film, carbon nanotube sponge, and poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate). The proposed multifunctional sensor can stably monitor pressure signals with a high sensitivity of 16 kPa-1, has a range of up to 2.5 kPa, and also has a fast response time. Meanwhile, the sensor can also respond to temperature changes with an ultrahigh sensitivity rate of 0.84% °C-1 in the range of 20 °C to 80 °C. To validate the applicability of our sensor in practical environments, we conducted real-scene tests, which revealed its capability for monitoring = human motion signals while simultaneously sensing external temperature stimuli, reflecting its great application prospects for electronic wearable devices.

Asymmetric Synthesis of Triphenylmethanes via Organocatalytic Regio- and Enantioselective Friedel-Crafts Alkylation of Aniline Derivatives.

Herein, we described a highly regio- and enantioselective Friedel-Crafts alkylation of aniline derivatives with in situ generated ortho-quinone methides enabled by chiral phosphoric acid, furnishing a wide range of enantioenriched triarylmethanes bearing three similar benzene rings in high yields (up to 98%) with excellent stereoselectivities (up to 98% ee). Furthermore, the large-scale reactions and diversified transformations of product demonstrate the practicality of the protocol. Density functional theory calculations elucidate the origin of the enantioselectivity.

PJA1 mediates the effects of astrocytic GPR30 on learning and memory in female mice.

Hormone replacement therapy (HRT) is not recommended for treating learning and memory decline in menopausal women because it exerts adverse effects by activating classic estrogen receptors ERα and ERß. The membrane estrogen receptor G protein-coupled receptor 30 (GPR30) has been reported to be involved in memory modulation; however, the underlying mechanisms are poorly understood. Here, we found that GPR30 deletion in astrocytes, but not in neurons, impaired learning and memory in female mice. Astrocytic GPR30 depletion induced A1 phenotype transition, impairing neuronal function. Further exploration revealed that Praja1 (PJA1), a RING ubiquitin ligase, mediated the effects of astrocytic GPR30 on learning and memory by binding to Serpina3n, which is a molecular marker of neuroinflammation in astrocytes. GPR30 positively modulated PJA1 expression through the CREB signaling pathway in cultured murine and human astrocytes. Additionally, the mRNA levels of GPR30 and PJA1 were reduced in exosomes isolated from postmenopausal women while Serpina3n levels were increased in the plasma. Together, our findings suggest a key role for astrocytic GPR30 in the learning and memory abilities of female mice and identify GPR30/PJA1/Serpina3n as potential therapeutic targets for learning and memory loss in peri- and postmenopausal women.

Canonical transient receptor potential channel 1 aggravates myocardial ischemia-and-reperfusion injury by upregulating reactive oxygen species.

The canonical transient receptor potential channel (TRPC) proteins form Ca2+-permeable cation channels that are involved in various heart diseases. However, the roles of specific TRPC proteins in myocardial ischemia/reperfusion (I/R) injury remain poorly understood. We observed that TRPC1 and TRPC6 were highly expressed in the area at risk (AAR) in a coronary artery ligation induced I/R model. Trpc1-/- mice exhibited improved cardiac function, lower serum Troponin T and serum creatine kinase level, smaller infarct volume, less fibrotic scars, and fewer apoptotic cells after myocardial-I/R than wild-type or Trpc6-/- mice. Cardiomyocyte-specific knockdown of Trpc1 using adeno-associated virus 9 mitigated myocardial I/R injury. Furthermore, Trpc1 deficiency protected adult mouse ventricular myocytes (AMVMs) and HL-1 cells from death during hypoxia/reoxygenation (H/R) injury. RNA-sequencing-based transcriptome analysis revealed differential expression of genes related to reactive oxygen species (ROS) generation in Trpc1-/- cardiomyocytes. Among these genes, oxoglutarate dehydrogenase-like (Ogdhl) was markedly downregulated. Moreover, Trpc1 deficiency impaired the calcineurin (CaN)/nuclear factor-kappa B (NF-κB) signaling pathway in AMVMs. Suppression of this pathway inhibited Ogdhl upregulation and ROS generation in HL-1 cells under H/R conditions. Chromatin immunoprecipitation assays confirmed NF-κB binding to the Ogdhl promoter. The cardioprotective effect of Trpc1 deficiency was canceled out by overexpression of NF-κB and Ogdhl in cardiomyocytes. In conclusion, our findings reveal that TRPC1 is upregulated in the AAR following myocardial I/R, leading to increased Ca2+ influx into associated cardiomyocytes. Subsequently, this upregulates Ogdhl expression through the CaN/NF-κB signaling pathway, ultimately exacerbating ROS production and aggravating myocardial I/R injury.

Hydrophilic magnetic covalent triazine frameworks for differential N-glycopeptides enrichment in breast cancer plasma membranes.

Alterations in plasma membrane glycoproteins (PMGs) have been identified as a hallmark of cancer. The comparison and identification of differential PMGs is significant for finding new markers and understanding pathological processes. However, the research on PMGs is often constrained by the low abundance and the disturbance of abundant endogenous biomolecules during direct analysis. Here, we report a bottom-up strategy to enrich the PMGs of breast cancer cells using hydrophilic magnetic covalent triazine frameworks (CTFs). A total of 972 N-glycopeptides and 1006 N-glycosites belonging to 526 N-glycoproteins were enriched in MCF-10A plasma membrane tryptic digest by magnetic CTFs. And 680 N-glycopeptides and 806 N-glycosites belonging to 443 N-glycoproteins were enriched in SK-BR-3 plasma membrane tryptic digest. Furthermore, comparative analysis was performed based on gene ontology to verify breast cancer biomarkers (SUSD2 and ALCAM) and differential PMGs' function. This strategy which systematically integrates efficient enrichment of differential PMGs and in-depth comparative analysis has great potential for helping illuminate the atlas of breast cancer PMGs and the causes of tumor metastasis.

Interaction of Nucleic Acids with Metal-Organic Framework Nanosheets by Fluorescence Spectroscopy and Molecular Dynamics Simulations.

The integration of nanomaterials and nucleic acids has attracted great attention in various research fields, especially biomedical applications. Designing two-dimensional nanomaterials and studying the mechanism of their interaction with nucleic acids are still attractive tasks. Herein, we designed and prepared a class of ultrathin two-dimensional metal-organic framework (MOF) nanosheets, named Zr-BTB MOF nanosheets, composed of Zr-O clusters and 1,3,5-benzenetribenzoate by a bottom-up synthesis strategy. The Zr-BTB MOF nanosheets possessed inherent excellent performance such as a high specific surface area, porosity, and biocompatibility. In addition, we clarified the interaction difference between the Zr-BTB MOF nanosheets and fluorophore-labeled double-stranded DNA and single-stranded DNA via molecular dynamics simulations and fluorescence measurement. Through molecular dynamics simulations, specific interactions between DNA and nanosheets such as forces, binding energies, and binding modes were deeply analyzed and clearly presented. Based on the affinity difference, the system showed the biosensing potential for target DNA detection with considerable specificity, sensitivity, and linearity. Our research results presented the Zr-BTB MOF nanosheet as a platform for nucleic acid detection, showing the potential for hybridization-based biosensing and related biological applications.