Swimming Exercise Protocol and Care Methods for Pregnant Rats.

The developmental origins of health and disease concept highlights the impact of early environments on chronic non-communicable diseases like diabetes, cardiovascular disease, and cancer. Studies using animal models have investigated how maternal factors such as undernutrition, overnutrition, obesity, and exposure to chemicals or hypoxia affect fetal development and offspring health, leading to issues like low birth weight, high blood pressure, dyslipidemia, and insulin resistance. Given the increasing prevalence of overweight and obesity among reproductive-age women, effective interventions are critical. Maternal exercise during pregnancy has emerged as a key intervention, benefiting both mother and offspring and reducing the risk of disease. This study compares the differences of three exercise models on pregnant rats: voluntary wheel running, motorized treadmills, and swimming. Swimming is the most beneficial option due to its safe and controlled intensity levels. This protocol details the rat breeding methods, swimming training during pregnancy, and post-breeding nursing protocols. This model, suitable for various rat and mouse species, is useful for studying the benefits of maternal exercise on offspring health and intergenerational wellness.

Arterial Smooth Muscle Cell AKAP150 Mediates Exercise-Induced Repression of CaV1.2 Channel Function in Cerebral Arteries of Hypertensive Rats.

BACKGROUND: Hypertension is a major, prevalent risk factor for the development and progression of cerebrovascular disease. Regular exercise has been recommended as an excellent choice for the large population of individuals with mild-to-moderate elevations in blood pressure, but the mechanisms that underlie its vascular-protective and antihypertensive effects remain unknown. Here, we describe a mechanism by which myocyte AKAP150 (A-kinase anchoring protein 150) inhibition induced by exercise training alleviates voltage-dependent L-type Ca2+ channel (CaV1.2) activity and restores cerebral arterial function in hypertension. METHODS: Spontaneously hypertensive rats and newly generated smooth muscle-specific AKAP150 knockin mice were used to assess the role of myocyte AKAP150/CaV1.2 channel in regulating cerebral artery function after exercise intervention. RESULTS: Activation of the AKAP150/PKCα (protein kinase Cα) signaling increased CaV1.2 activity and Ca2+ influx of cerebral arterial myocyte, thus enhancing vascular tone in spontaneously hypertensive rats. Smooth muscle-specific AKAP150 knockin mice were hypertensive with higher CaV1.2 channel activity and increased vascular tone. Furthermore, treatment of Ang II (angiotensin II) resulted in a more pronounced increase in blood pressure in smooth muscle-specific AKAP150 knockin mice. Exercise training significantly reduced arterial myocyte AKAP150 expression and alleviated CaV1.2 channel activity, thus restoring cerebral arterial function in spontaneously hypertensive rats and smooth muscle-specific AKAP150 knockin mice. AT1R (AT1 receptor) and AKAP150 were interacted closely in arterial myocytes. Exercise decreased the circulating Ang II and Ang II-involved AT1R-AKAP150 association in myocytes of hypertension. CONCLUSIONS: The current study demonstrates that aerobic exercise ameliorates CaV1.2 channel function via inhibiting myocyte AKAP150, which contributes to reduced cerebral arterial tone in hypertension.

Dissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level.

Homotypic membrane fusion of the endoplasmic reticulum (ER) is mediated by dynamin-like GTPase atlastin (ATL). This fundamental process relies on GTP-dependent domain rearrangements in the N-terminal region of ATL (ATLcyto), including the GTPase domain and three-helix bundle (3HB). However, its conformational dynamics during the GTPase cycle remain elusive. Here, we combine single-molecule FRET imaging and molecular dynamics simulations to address this conundrum. Different from the prevailing model, ATLcyto can form a loose crossover dimer upon GTP binding, which is tightened by GTP hydrolysis for membrane fusion. Furthermore, the α-helical motif between the 3HB and transmembrane domain, which is embedded in the surface of the lipid bilayer and self-associates in the crossover dimer, is required for ATL function. To recycle the proteins, Pi release, which disassembles the dimer, activates frequent relative movements between the GTPase domain and 3HB, and subsequent GDP dissociation alters the conformational preference of the ATLcyto monomer for entering the next reaction cycle. Finally, we found that two disease-causing mutations affect human ATL1 activity by destabilizing GTP binding-induced loose crossover dimer formation and the membrane-embedded helix, respectively. These results provide insights into ATL-mediated homotypic membrane fusion and the pathological mechanisms of related disease.

Design, synthesis and biological evaluation of quinazoline and pyrrolo[3,2-d]pyrimidine derivatives as TLR7 agonists for antiviral agents.

Pattern recognition receptors (PRRs) play a critical role in the innate immune response, and toll-like receptor 7 (TLR7) is an important member of PRRs. Although several TLR7 agonists are available, most of them are being tested clinically, with only one available on the market. Thus, it is imperative to develop new TLR7 agonists. In this study, we designed and synthesized three kinds of quinazoline derivatives and five kinds of pyrrolo[3,2-d]pyrimidine derivatives targeting TLR7. The antiviral efficacy of these compounds was evaluated in vitro and in vivo. Our findings indicated that four kinds of compounds showed exceptional antiviral activity. Furthermore, molecular docking studies confirmed that compound 11 successfully positioned itself in the pocket of the TLR7 guanosine loading site with a binding energy of -4.45 kcal mol-1. These results suggested that these compounds might be potential antiviral agents.

Advances in exercise-induced vascular adaptation: mechanisms, models, and methods.

Insufficient physical activity poses a significant risk factor for cardiovascular diseases. Exercise plays a crucial role in influencing the vascular system and is essential for maintaining vascular health. Hemodynamic stimuli generated by exercise, such as shear stress and circumferential stress, directly impact vascular structure and function, resulting in adaptive changes. In clinical settings, incorporating appropriate exercise interventions has become a powerful supplementary approach for treating and rehabilitating various cardiovascular conditions. However, existing models for studying exercise-induced vascular adaptation primarily rely on in vivo animal and in vitro cellular models, each with its inherent limitations. In contrast, human research faces challenges in conducting mechanistic analyses due to ethics issues. Therefore, it is imperative to develop highly biomimetic in vitro/ex vivo vascular models that can replicate exercise stimuli in human systems. Utilizing various vascular assessment techniques is also crucial to comprehensively evaluate the effects of exercise on the vasculature and uncover the molecular mechanisms that promote vascular health. This article reviews the hemodynamic mechanisms that underlie exercise-induced vascular adaptation. It explores the advancements in current vascular models and measurement techniques, while addressing their future development and challenges. The overarching goal is to unravel the molecular mechanisms that drive the positive effects of exercise on the cardiovascular system. By providing a scientific rationale and offering novel perspectives, the aim is to contribute to the formulation of precise cardiovascular rehabilitation exercise prescriptions.

Development and Immunological Evaluation of a Multiantigen Thermostable Nanovaccine Adjuvanted with T-Cell-Activating Scaffold for African Swine Fever.

African swine fever is an acute and highly contagious infectious disease with a mortality rate of up to 100%. The lack of commercial vaccines and drugs is a serious economic threat to the global pig industry. Cell-mediated immunity plays an essential role in protection against viral infection. We previously reported the rational design of a T-cell-activating thermostable scaffold (RPT) for antigen delivery and improved cellular immunity. We conjugated antigens P30, P54, P72, CD2 V, and CP312R to RPT, using a SpyCatcher/SpyTag covalent attachment strategy to construct nanovaccines (multiantigens-RPT). Multiantigens-RPT exhibited significantly higher thermal, storage, and freeze-thaw stability. The specific antibodies IgG and IgG2a of the multiantigen-RPT-immunized were higher than the antigens cocktail-immunized by approximately 10-100 times. ELISpot demonstrated that more IFN-γ-secreting cells were produced by the multiantigen-RPT-immunized than by the antigens cocktail-immunized. Delivery of the multiantigen nanovaccine by a T-cell-activating scaffold induced strong humoral and cellular immune responses in mice and pigs and is a potentially useful candidate vaccine for the African swine fever virus.

Pancreatic diffuse large B-cell lymphoma: a case report and literature review.

Primary pancreatic lymphoma is an extremely rare malignant tumor that accounts for 1% and 0.5% of all extranodal malignant lymphomas and pancreatic tumors, respectively. The clinical and radiographic characteristics of primary pancreatic lymphoma are non-specific, and it is often misdiagnosed as pancreatic cancer or pancreatic tuberculosis, delaying treatment. The most common histological subtype of primary pancreatic lymphoma is diffuse large B-cell lymphoma. Herein, we report a case of a 48-year-old female patient who was hospitalized for complaints of lower back pain, jaundice, dark brown urine, nausea, and ascites. Radiological evaluation revealed a pancreatic head mass that was diagnosed as diffuse large B-cell lymphoma following ultrasound-guided percutaneous fine-needle biopsy. During hospitalization, the patient's jaundice worsened, and percutaneous transhepatic drainage was performed. However, hemorrhagic ascites and disorders of consciousness occurred after surgery, and the patient died due to multiple organ failure. Considering the outcome of this case, we reviewed the existing relevant literature on primary pancreatic lymphoma to better understand the disease to facilitate timely diagnosis and initiation of treatment.

Direct access to carbamates via acylation of arylamines with dialkyl azodicarboxylates under metal-free conditions.

A novel C-N coupling of various arylamines with dialkyl azodicarboxylates under metal-free conditions for the rapid assembly of carbamates has been achieved. This established protocol features mild reaction conditions, simple operation, broad substrate scope, moderate to excellent yields and good tolerance of functional groups. Moreover, the potential synthetic utility of products was exemplified by a series of intriguing chemical operations.

Diagnostic accuracy of dual-energy CT for bone marrow edema in patients with acute knee injury: a systematic review and meta-analysis.

BACKGROUND: Knee injuries are prevalent, and early diagnosis is crucial for guiding clinical therapy. MRI is the diagnostic gold standard for bone marrow edema (BME) in patients with acute knee injuries, yet there are still limitations. Dual-energy CT, a possible viable replacement, is being explored (DECT). METHODS: We systematically retrieved studies from EMBASE, Scopus, PUBMED, and the Cochrane Library and collected gray literatures. In accordance with the PRISMA-DTA standards, a systematic review was conducted between the study's initiation and July 31, 2021, utilizing an MRI reference standard and at least 10 adult patients with acute knee injuries to evaluate the diagnostic effectiveness of DECT for diagnosing BME. Two reviewers collected the study's details independently. For the meta-analysis, a bivariate mixed-effects regression model was utilized, and subgroup analysis was employed to determine the sources of variability. RESULTS: The research included nine studies that examined 290 individuals between the ages of 23 and 53 with acute knee injuries who had DECT and MRI. Overall, the sensitivity, specificity, and AUC of the BME were 85% (95% confidence interval [CI]: 77-90%), 96% (95% CI: 93-97%), and 0.97 (95% CI: 0.95-0.98), respectively. To account for the assumed diversity of research, there were no statistically significant differences between the comparison groups in terms of specificity and sensitivity. CONCLUSION: DECT is a viable alternative to MRI for individuals with acute knee injuries when MRI is inappropriate or unavailable.

Characteristics of Transcriptome and Metabolome Concerning Intramuscular Fat Content in Beijing Black Pigs.

To study the characteristics of genes and metabolites related to intramuscular fat (IMF) content with less influence by breed background and individual differences, the skeletal muscle samples from 40 Beijing black pigs with either high or low IMF content were used to perform transcriptome and metabolome analyses. About 99 genes (twofold-change) were differentially expressed. Up-regulated genes in the high IMF pigs were mainly related to fat metabolism. The key genes in charge of IMF deposition are ADIPOQ, CIDEC, CYP4B1, DGAT2, LEP, OPRL1, PLIN1, SCD, and THRSP. KLHL40, TRAFD1, and HSPA6 were novel candidate genes for the IMF trait due to their high abundances. In the low IMF pigs, the differentially expressed genes involved in virus resistance were up-regulated. About 16 and 18 differential metabolites (1.5 fold-change) were obtained in the positive and negative modes, respectively. Pigs with low IMF had weaker fatty acid oxidation due to the down-regulation of various carnitines. Differentially expressed genes were more important in determining IMF deposition than differential metabolites because relatively few differential metabolites were obtained, and they were merely the products under the physiological status of diverged IMF content. This study provided valuable information for further studies on IMF deposition.

Maternal exercise represses Nox4 via SIRT1 to prevent vascular oxidative stress and endothelial dysfunction in SHR offspring.

Maternal exercise during pregnancy has emerged as a potentially promising approach to protect offspring from cardiovascular disease, including hypertension. Although endothelial dysfunction is involved in the pathophysiology of hypertension, limited studies have characterized how maternal exercise influences endothelial function of hypertensive offspring. In this study, pregnant spontaneously hypertensive rats and Wistar-Kyoto rats were assigned either to a sedentary lifestyle or to swimming training daily, and fetal histone deacetylase-mediated epigenetic modification and offspring vascular function of mesenteric arteries were analyzed. Maternal exercise ameliorated the impairment of acetylcholine-induced vasodilation without affecting sodium nitroprusside-induced vasodilation in mesenteric arteries from the hypertensive offspring. In accordance, maternal exercise reduced NADPH oxidase-4 (Nox4) protein to prevent the loss of nitric oxide generation and increased reactive oxygen species production in mesenteric arteries of hypertensive offspring. We further found that maternal exercise during pregnancy upregulated vascular SIRT1 (sirtuin 1) expression, leading to a low level of H3K9ac (histone H3 lysine 9 acetylation), resulting in the transcriptional downregulation of Nox4 in mesenteric arteries of hypertensive fetuses. These findings show that maternal exercise alleviates oxidative stress and the impairment of endothelium-dependent vasodilatation via SIRT1-regulated deacetylation of Nox4, which might contribute to improved vascular function in hypertensive offspring.

PTEN Inhibitor Treatment Lowers Muscle Plasma Membrane Damage and Enhances Muscle ECM Homeostasis after High-Intensity Eccentric Exercise in Mice.

Exercise-induced muscle damage (EIMD) is a common occurrence in athletes and can lead to delayed onset muscle soreness, reduced athletic performance, and an increased risk of secondary injury. EIMD is a complex process involving oxidative stress, inflammation, and various cellular signaling pathways. Timely and effective repair of the extracellular matrix (ECM) and plasma membrane (PM) damage is critical for recovery from EIMD. Recent studies have shown that the targeted inhibition of phosphatase and tension homolog (PTEN) in skeletal muscles can enhance the ECM environment and reduce membrane damage in Duchenne muscular dystrophy (DMD) mice. However, the effects of PTEN inhibition on EIMD are unknown. Therefore, the present study aimed to investigate the potential therapeutic effects of VO-OHpic (VO), a PTEN inhibitor, on EIMD symptoms and underlying mechanisms. Our findings indicate that VO treatment effectively enhances skeletal muscle function and reduces strength loss during EIMD by upregulating membrane repair signals related to MG53 and ECM repair signals related to the tissue inhibitor of metalloproteinases (TIMPs) and matrix metalloproteinase (MMPs). These results highlight the potential of pharmacological PTEN inhibition as a promising therapeutic approach for EIMD.

Efficacy of diet restriction with or without probiotic for treatment of patients with IBS-D: Phase I-II clinical trial.

BACKGROUND AND AIM: Diet is a major contributor to irritable bowel syndrome (IBS) and is also a powerful tool for treatment of IBS. This study compared two diets and explored the effectiveness of the diets when combined with a probiotic for treatment of IBS-D patients. METHODS: Phase I, patients were randomized into groups; control, cold/spicy/fried restricted diet (CSF res diet), IgG positive restricted diet (IgG res diet), and a combination both diets (CSF + IgG res diet). Phase II, patients were randomized into IgG res diet + placebo and IgG res diet + probiotic. Both interventions were 12 weeks in duration. Symptom Severity Scale (IBS-D-SSS) and IgG titer were assessed at the beginning and the end of the study. RESULTS: Totals of 214 and 167 patients completed the two parts of the study, respectively. After intervention, IBS-D-SSS and TIgG grade were significantly improved compared to baseline, with results similar to the control group. In general, there were decreases in IBS-D-SSS and TIgG grade that were significantly different among the groups. There were exceptions; no differences were observed for IBS-D-SSS between the IgG res diet and CSF + IgG res diet, or TIgG grade between the CSF res diet, IgG res diet, and CSF + IgG res diet. However, the CSF res diet and IgG res diet had a synergistic effect that decreased IBS-D-SSS and TIgG titer, with a greater contribution by the IgG res diet. Therefore, we evaluated the IgG res diet with either placebo or probiotic and found that IBS-D-SSS and TIgG grade decreased from baseline. There was a significant decrease in IBS-D-SSS with the probiotic but TIgG grade was not significantly different between the IgG diet + placebo and IgG diet + probiotic diet. CONCLUSIONS: Both the CSF res diet and IgG res diet improved IBS symptoms and demonstrated synergy, although the IgG res diet had a greater contribution. Further, when intolerant foods cannot be eliminated from a diet, avoiding uncooked, cold, spicy, fried, and alcoholic foods is a superior choice. The IgG res diet combined with Bifidobacteria was the best dietary choice and may function though a non-IgG pathway.

Phase-contrast imaging with synchrotron hard X-ray reveals the effect of icariin on bone tissue morphology and microstructure in rabbits with early glucocorticoid-induced osteonecrosis of the femoral head.

Background: Phase-contrast imaging (PCI) with synchrotron hard X-ray was used to observe the changes in bone tissue morphology and microstructure in rabbit models of early glucocorticoid-induced osteonecrosis of the femoral head (ONFH), and to evaluate the intervention effect of Icariin. Methods: Fifty mature New Zealand rabbits (weighing 2.5-3.0 kg) were randomly divided into a control group (n = 10), a glucocorticoid group (n = 20), and an Icariin group (n = 20). The glucocorticoid group and the Icariin group were sequentially injected with lipopolysaccharide (LPS) and methylprednisolone (MPS) to establish a glucocorticoid-induced ONFH animal model. The Icariin group was given Icariin solution when methylprednisolone was injected for the first time, and the control group and glucocorticoid group were given the same amount of normal saline. Animals were sacrificed after 6 weeks, and bilateral femoral head specimens were taken for research. The right femoral head was observed by PCI with synchrotron hard X-ray technology, and the left femoral head was verified by Micro-CT scanning and HE staining. Results: Forty-three animals (nine in the control group, sixteen in the glucocorticoid group, and eighteen in the Icariin group) were included in the study. PCI with synchrotron hard X-ray revealed that the trabecular bone in the glucocorticoid group was thinned, broken, and structurally damaged, whereas the trabecular bone in the Icariin group had normal volume, thickness, and a relatively intact structure. Micro-CT scan reconstruction and HE staining were used to verify the reliability of this technique in identifying osteonecrosis. Conclusion: The effects of Icariin were observed in an early glucocorticoid-induced ONFH rabbit model using PCI with synchrotron hard X-ray. Icariin weakens the destructive effect of glucocorticoids on bone tissue structure, improves bone tissue morphology, and stabilizes bone microstructure. This technique may provide a definitive, non-invasive alternative to histological examination for the diagnosis of early ONFH.

Effectiveness and safety of Qingfei Dayuan granules for treating influenza and upper respiratory tract infections manifested by the pulmonary heat-toxin syndrome: A multicenter, randomized, double-blind, placebo-controlled trial.

Background: Patients diagnosed with influenza and upper respiratory tract infections (URTIs) have similar clinical manifestations and biochemical indices and a low detection rate of viral pathogens, mixed infection with diverse respiratory viruses, and targeted antiviral treatment difficulty in the early stage. According to the treatment strategy of "homotherapy for heteropathy" in traditional Chinese medicine (TCM), different diseases with the same clinical symptoms can be treated with the same medicines. Qingfei Dayuan granules (QFDY), a type of Chinese herbal preparation included in the TCM Diagnosis and Treatment Protocol for COVID-19 of Hubei Province issued by the Health Commission of Hubei Province in 2021, are recommended for patients suffering from COVID-19 with symptoms of fever, cough, and fatigue, among others. Additionally, recent studies have shown that QFDY effectively alleviates fever, cough, and other clinical symptoms in patients with influenza and URTIs. Materials and methods: The study was designed as a multicenter, randomized, double-blind, placebo-controlled clinical trial for treatment for influenza and URTIs manifested by pulmonary heat-toxin syndrome (PHTS) with QFDY. A total of 220 eligible patients were enrolled from eight first-class hospitals in five cities of Hubei Province in China and randomly assigned to receive either 15 g of QFDY or a placebo three times a day for 5 days. The primary outcome was the complete fever relief time. Secondary outcomes included efficacy evaluation of TCM syndromes, scores of TCM syndromes, cure rate of each single symptom, incidence of comorbidities and progression to severe conditions, combined medications, and laboratory tests. Safety evaluations mainly involved adverse events (AEs) and changes in vital signs during the study. Results: Compared with the placebo group, the complete fever relief time was shorter in the QFDY group, 24 h (12.0, 48.0) in the full analysis set (FAS) and 24 h (12.0, 49.5) in the per-protocol set (PPS) (p ≤ 0.001). After a 3-day treatment, the clinical recovery rate (22.3% in the FAS and 21.6% in the PPS) and cure rate of cough (38.6% in the FAS and 37.9% in the PPS), a stuffy and running nose, and sneezing (60.0% in the FAS and 59.5% in the PPS) in the QFDY group were higher than those in the placebo group (p < 0.05). The number of patients taking antibiotics for more than 24 h in the placebo group (nine cases) was significantly higher than that in the QFDY group (one case) (p < 0.05). There were no significant differences between the two groups in terms of scores of TCM syndromes, incidence of comorbidities or progression to severe conditions, combined use of acetaminophen tablets or phlegm-resolving medicines, and laboratory tests (p > 0.05). Meanwhile, no significant difference was found in the incidence of AEs and vital signs between the two groups (p > 0.05). Conclusion: The trial showed that QFDY was an effective and safe treatment modality for influenza and URTIs manifested by PHTS because it shortened the complete fever relief time, accelerated clinical recovery, and alleviated symptoms such as cough, a stuffy and running nose, and sneezing during the course of treatment. Clinical trial registration: https://www.chictr.org.cn/showproj.aspx?proj=131702, identifier ChiCTR2100049695.

Toward Antifragility: Social Defeat Stress Enhances Learning and Memory in Young Mice Via Hippocampal Synaptosome Associated Protein 25.

Social adversity not only causes severe psychological diseases but also may improve people's ability to learn and grow. However, the beneficial effects of social adversity are often ignored. In this study, we investigated whether and how social adversity affects learning and memory in a mouse social defeat stress (SDS) model. A total of 652 mice were placed in experimental groups of six to 23 mice each. SDS enhanced spatial, novelty, and fear memory with increased synaptosome associated protein 25 (SNAP-25) level and dendritic spine density in hippocampal neurons among young but not middle-aged mice. Chemogenetic inhibition of hippocampal CaMK2A+ neurons blocked SDS-induced enhancement of learning or memory. Knockdown of SNAP-25 or blockade of N-methyl-D-aspartate (NMDA) receptor subunit GluN2B in the hippocampus prevented SDS-induced learning memory enhancement in an emotion-independent manner. These findings suggest that social adversity promotes learning and memory ability in youths and provide a neurobiological foundation for biopsychological antifragility.

Downregulation of ITIH3 contributes to cisplatin-based chemotherapy resistance in ovarian carcinoma via the Bcl-2 mediated anti-apoptosis signaling pathway.

Platinum resistance of ovarian cancer is one of the primary factors of poor prognosis and inter-α-trypsin inhibitor heavy chain 3 (ITIH3) is a potential DDP resistance-associated gene. The present study assessed protein expression levels of ITIH3 in human ovarian cancer and evaluated the relationship between its expression and platinum-resistance in patients. Furthermore, the effect of ITIH3 on cisplatin (DDP)-resistant ovarian cancer cells and the underlying molecular mechanism were evaluated. Tissue microarrays of ovarian cancer samples were used to assess the association between ITIH3 protein expression levels and drug resistance and the prognosis of ovarian cancer. ITIH3 RNA interference (RNAi) ovarian cancer cell lines were constructed and expression levels of anti- and pro-apoptotic proteins of the Bcl-2 associated pathway, including Bcl-2, Bcl-xL, Mcl-1, Bak, Bim, Bax, caspase 3 and poly ADP-ribose polymerase (PARP), were assessed following DDP treatment. The Bcl-2 inhibitor ABT-737 was used to rescue DDP-resistance induced by loss of ITIH3 in vitro. Finally, a subcutaneous xenograft tumor model was used to evaluate the effect of multiple DDP injections on expression levels of apoptosis-related proteins like Bcl-2, Bcl-xL, Bak, caspase 3 and PARP. The results of tissue microarray immunohistochemistry revealed that decreased ITIH3 protein expression levels were associated with a shorter overall survival for patients with ovarian cancer. The results of Cell Counting Kit-8 assay showed that the half-maximal inhibitory concentration and resistance index of DDP in SKOV3-ITIH3 and OVCAR3-ITIH3 RNAi cells were significantly higher than in control groups. Following DDP treatment, the results of western blotting revealed that expression levels of anti-apoptotic proteins of the Bcl-2 family significantly increased in SKOV3-ITIH3 and OVCAR3-ITIH3 RNAi cells. Pro-apoptotic protein expression was not significantly changed following DDP treatment, whereas cleaved caspase 3, caspase 3 and cleaved (C-PARP) were markedly downregulated. The Bcl-2 inhibitor ABT-737 was demonstrated to reverse increased DDP resistance induced by ITIH3 expression in flow cytometric and western blotting analysis. In the subcutaneous murine xenograft model, an increased number of DDP injections yielded a decrease in phosphorylated Bcl-2, cleaved caspase 3, caspase 3 and C-PARP protein expression levels in the SKOV3-ITIH3 RNAi group tested by western blotting. To the best of our knowledge, this is the first study to demonstrate that ITIH3 could be a vital molecule involved in chemosensitivity via regulation of the Bcl-2 family-mediated apoptotic pathway. Lower protein expression levels of ITIH3 were significantly associated with platinum resistance and poor prognosis in ovarian cancer. ITIH3 may predict cisplatin-resistance in ovarian cancer.

Integrated analysis of transcriptome and metabolome revealed biological basis of sows from estrus to lactation.

Characterization of molecular mechanisms underlying pregnancy development of sows is important for the genetic improvement of pig breeding traits, and also provides resources for biomedical research on human pregnancy diseases. However, the transcriptome and metabolome across multiple developmental stages of sow pregnancy were still lacking. In this study, we obtained 84 distinct RNA sequencing and 42 metabolome datasets of pig blood across six development stages from estrus to lactation. We confirmed the initial sequence and exonic structural features, stage-specific molecules, expression or accumulation pattern of molecules, the regulatory mechanism of transcriptome and metabolome, and important pregnancy-related metabolites both in pigs and humans. In conclusion, we proposed the key differences among the stages of sows from estrus to lactation in RNAs and metabolites and put forward key markers. These data results were expected to provide essential resources for pig breeding and biomedical research on human pregnancy disease.

Maternal exercise upregulates the DNA methylation of Agtr1a to enhance vascular function in offspring of hypertensive rats.

The angiotensin II signaling system regulates vascular dysfunction and is involved in the programming of hypertension. Maternal exercise has been linked to both short-term and long-term benefits for the mother and fetus. However, the impacts of maternal exercise on the intravascular renin-angiotensin system (RAS) in hypertensive offspring remain unexamined. This study examined whether maternal exercise has an epigenetic effect in repressing angiotensin II type 1 receptor (AT1R) expression, which leads to favorable alterations in the mesenteric artery (MA) function of spontaneously hypertensive offspring. Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) pregnant rats were randomly divided into an exercise group and a control group. Blood pressure, vascular tone, AT1R protein and mRNA expression, and AT1R gene (Agtr1a) promoter methylation status were examined in the MAs of 3-month-old male offspring. Maternal exercise significantly reduced the resting blood pressure and cardiovascular reactivity of offspring from SHRs. Furthermore, Ang II-AT1R activity in regulating vascular tone and AT1R expression was decreased in the MAs of the SHR offspring from the exercise groups. Importantly, exercise during gestation suppressed AT1R expression via hypermethylation of the Agtr1a promoter region and upregulated DNA methyltransferase (DNMT) expression in MAs of SHR offspring. These results suggest that maternal exercise upregulates DNMT expression, resulting in hypermethylation and repression of the Agtr1a gene, which may prevent MA dysfunction in the offspring of SHRs. A mechanistic model on the epigenetics of exercise during pregnancy. Maternal exercise during pregnancy triggers hypermethylation and transcriptional suppression of the Agtr1a gene via increased DNMT1 and DNMT3B expression in MAs of SHR offspring. Downregulation of AT1R expression reduces the contribution of Ang II to vascular tone, ultimately improving vascular structure and function. VSMC vascular smooth muscle cell; Ang II angiotensin II; AT1aR angiotensin type 1 receptor (AT1R) alpha subtypes; Agtr1a AT1R alpha isoform gene; MAs mesenteric arteries; BP blood pressure.