The evolution of lineage-specific regulatory activities in the human embryonic limb.

The evolution of human anatomical features likely involved changes in gene regulation during development. However, the nature and extent of human-specific developmental regulatory functions remain unknown. We obtained a genome-wide view of cis-regulatory evolution in human embryonic tissues by comparing the histone modification H3K27ac, which provides a quantitative readout of promoter and enhancer activity, during human, rhesus, and mouse limb development. Based on increased H3K27ac, we find that 13% of promoters and 11% of enhancers have gained activity on the human lineage since the human-rhesus divergence. These gains largely arose by modification of ancestral regulatory activities in the limb or potential co-option from other tissues and are likely to have heterogeneous genetic causes. Most enhancers that exhibit gain of activity in humans originated in mammals. Gains at promoters and enhancers in the human limb are associated with increased gene expression, suggesting they include molecular drivers of human morphological evolution.

HERVK-mediated regulation of neighboring genes: implications for breast cancer prognosis.

Human endogenous retroviruses (HERVs) are the remnants of ancient retroviral infections integrated into the human genome. Although most HERVs are silenced or rendered inactive by various regulatory mechanisms, they retain the potential to influence the nearby genes. We analyzed the regulatory map of 91 HERV-Ks on neighboring genes in human breast cancer and investigated the impact of HERV-Ks on the tumor microenvironment (TME) and prognosis of breast cancer. Nine RNA-seq datasets were obtained from GEO and NCBI SRA. Differentially expressed genes and HERV-Ks were analyzed using DESeq2. Validation of high-risk prognostic candidate genes using TCGA data. These included Overall survival (multivariate Cox regression model), immune infiltration analysis (TIMER), tumor mutation burden (maftools), and drug sensitivity analysis (GSCA). A total of 88 candidate genes related to breast cancer prognosis were screened, of which CD48, SLAMF7, SLAMF1, IGLL1, IGHA1, and LRRC8A were key genes. Functionally, these six key genes were significantly enriched in some immune function-related pathways, which may be associated with poor prognosis for breast cancer (p = 0.00016), and the expression levels of these genes were significantly correlated with the sensitivity of breast cancer treatment-related drugs. Mechanistically, they may influence breast cancer development by modulating the infiltration of various immune cells into the TME. We further experimentally validated these genes to confirm the results obtained from bioinformatics analysis. This study represents the first report on the regulatory potential of HERV-K in the neighboring breast cancer genome. We identified three key HERV-Ks and five neighboring genes that hold promise as novel targets for future interventions and treatments for breast cancer.

Integrated analysis of miRNA-mRNA expression of newly emerging swine H3N2 influenza virus cross-species infection with tree shrews.

BACKGROUND: Cross-species transmission of zoonotic IAVs to humans is potentially widespread and lethal, posing a great threat to human health, and their cross-species transmission mechanism has attracted much attention. miRNAs have been shown to be involved in the regulation of IAVs infection and immunity, however, few studies have focused on the molecular mechanisms underlying miRNAs and mRNAs expression after IAVs cross-species infection. METHODS: We used tree shrews, a close relative of primates, as a model and used RNA-Seq and bioinformatics tools to analyze the expression profiles of DEMs and DEGs in the nasal turbinate tissue at different time points after the newly emerged swine influenza A virus SW2783 cross-species infection with tree shrews, and miRNA-mRNA interaction maps were constructed and verified by RT-qPCR, miRNA transfection and luciferase reporter assay. RESULTS: 14 DEMs were screened based on functional analysis and interaction map, miR-760-3p, miR-449b-2, miR-30e-3p, and miR-429 were involved in the signal transduction process of replication and proliferation after infection, miR-324-3p, miR-1301-1, miR-103-1, miR-134-5p, miR-29a, miR-31, miR-16b, miR-34a, and miR-125b participate in negative feedback regulation of genes related to the immune function of the body to activate the antiviral immune response, and miR-106b-3p may be related to the cross-species infection potential of SW2783, and the expression level of these miRNAs varies in different days after infection. CONCLUSIONS: The miRNA regulatory networks were constructed and 14 DEMs were identified, some of them can affect the replication and proliferation of viruses by regulating signal transduction, while others can play an antiviral role by regulating the immune response. It indicates that abnormal expression of miRNAs plays a crucial role in the regulation of cross-species IAVs infection, which lays a solid foundation for further exploration of the molecular regulatory mechanism of miRNAs in IAVs cross-species infection and anti-influenza virus targets.

Association of lifestyle behaviors and oral health care needs: Mediating effects of inflammatory markers.

OBJECTIVE: Mounting evidence indicates that modifiable risk factors such as lifestyle behaviors may be involved in the occurrence of oral diseases. However, existing research doesn't come to a unanimous consent. This study aims to evaluate the association between lifestyle behaviors and oral health care needs. METHODS: This study used the nationally representative dataset from the National Health and Nutrition Examination Survey (NHANES) from March 2017 to 2020 pre-pandemic. Binary logistic regression analysis was used to evaluate lifestyle behavioral factors that influence oral health care needs. Mediation analysis was performed to explore the roles of inflammatory markers in the relationship between physical activities and oral problems. RESULTS: After adjusting for covariates, multivariate analysis indicated that flossing (OR = 0.590, 95% CI, 0.510-0.682, P < 0.001), moderate alcohol consumption (per week: OR = 0.717, 95% CI, 0.588-0.873, P < 0.001; per month/year: OR = 0.794, 95% CI, 0.669-0.942, P = 0.008) and participation in recreational activities (vigorous recreational activities: OR = 0.548, 95% CI, 0.462-0.648, P < 0.001; moderate recreational activities: OR = 0.629, 95% CI, 0.549-0.721, P < 0.001) significantly reduced oral health care needs. In addition, sleep duration of 7-9 h was associated with lower oral health care needs compared to less or more sleep duration (<7 h or > 9 h) (OR = 0.851, 95% CI, 0.741-0.976, P = 0.021). Mediation analysis suggested that white blood cell (WBC) counts and high-sensitivity C-reactive protein (hs-CRP) concentrations acted significant mediating roles in the association between recreational activities and oral problems. CONCLUSIONS: The possible beneficial effects of healthy lifestyle behaviors on oral health will guide individuals to develop good habits, thereby reducing the burden of oral diseases.

A spatiotemporal atlas of organogenesis in the development of orchid flowers.

Development of floral organs exhibits complex molecular mechanisms involving the co-regulation of many genes specialized and precisely functioning in various tissues and developing stages. Advance in spatial transcriptome technologies allows for quantitative measurement of spatially localized gene abundance making it possible to bridge complex scenario of flower organogenesis with genome-wide molecular phenotypes. Here, we apply the 10× Visium technology in the study of the formation of floral organs through development in an orchid plant, Phalaenopsis Big Chili. Cell-types of early floral development including inflorescence meristems, primordia of floral organs and identity determined tissues, are recognized based on spatial expression distribution of thousands of genes in high resolution. In addition, meristematic cells on the basal position of floral organs are found to continuously function in multiple developmental stages after organ initiation. Particularly, the development of anther, which primordium starts from a single spot to multiple differentiated cell-types in later stages including pollinium and other vegetative tissues, is revealed by well-known MADS-box genes and many other downstream regulators. The spatial transcriptome analyses provide comprehensive information of gene activity for understanding the molecular architecture of flower organogenesis and for future genomic and genetic studies of specific cell-types.

E-prostanoid 3 receptor deficiency on myeloid cells protects against ischemic acute kidney injury via breaking the auto-amplification loop of necroinflammation.

Necroinflammation plays an important role in disease settings such as acute kidney injury (AKI). We and others have elucidated that prostaglandins, which are critically involved in inflammation, may activate E-prostanoid 3 receptor (EP3) at low concentrations. However, how EP3 blockade interacts with regulated cell death and affects AKI remains unknown. In this study, AKI was induced by ischemia-reperfusion (30 minutes/24 hours) in Ep3 knockout (Ep3-/-), bone marrow chimeric, myeloid conditional EP3 knockout and corresponding control mice. The production of prostaglandins E2 and I2 was markedly increased after ischemia-reperfusion, and either abrogation or antagonism of EP3 ameliorated the injury. EP3 deficiency curbed inflammatory cytokine release, neutrophil infiltration and serum high-mobility group box 1 levels, but additional TLR4 inhibition with TAK-242 did not offer further protection against the injury and inflammation. The protection of Ep3-/- was predominantly mediated by suppressing Mixed Lineage Kinase domain-Like-dependent necroptosis, resulting from the inhibition of cytokine generation and the switching of cell death modality from necroptosis to apoptosis through caspase-8 up-regulation, in part due to the restraint of IL-6/JAK2/STAT3 signaling. EP3 deficiency failed to further alleviate the injury when necroptosis was inhibited. Ep3-/- in bone marrow-derived cells, particularly that in myeloid cells, protected kidneys to the same extent as that of global EP3 deletion. Thus, our results demonstrate that EP3 deficiency especially that on myeloid cells, ameliorates ischemic AKI via curbing inflammation and breaking the auto-amplification loop of necroinflammation. Hence, EP3 may be a promising target for the prevention and/or treatment of AKI.

A recurrent SHANK1 mutation implicated in autism spectrum disorder causes autistic-like core behaviors in mice via downregulation of mGluR1-IP3R1-calcium signaling.

The genetic etiology and underlying mechanism of autism spectrum disorder (ASD) remain elusive. SHANK family genes (SHANK1/2/3) are well known ASD-related genes. However, little is known about how SHANK missense mutations contribute to ASD. Here, we aimed to clarify the molecular mechanism of and the multilevel neuropathological features induced by Shank1 mutations in knock-in (KI) mice. In this study, by sequencing the SHANK1 gene in a cohort of 615 ASD patients and 503 controls, we identified an ASD-specific recurrent missense mutation, c.2621 G > A (p.R874H). This mutation demonstrated strong pathogenic potential in in vitro experiments, and we generated the corresponding Shank1 R882H-KI mice. Shank1 R882H-KI mice displayed core symptoms of ASD, namely, social disability and repetitive behaviors, without confounding comorbidities of abnormal motor function and heightened anxiety. Brain structural changes in the frontal cortex, hippocampus and cerebellar cortex were observed in Shank1 R882H-KI mice via structural magnetic resonance imaging. These key brain regions also showed severe and consistent downregulation of mGluR1-IP3R1-calcium signaling, which subsequently affected the release of intracellular calcium. Corresponding cellular structural and functional changes were present in Shank1 R882H-KI mice, including decreased spine size, reduced spine density, abnormal morphology of postsynaptic densities, and impaired hippocampal long-term potentiation and basal excitatory transmission. These findings demonstrate the causative role of SHANK1 in ASD and elucidate the underlying biological mechanism of core symptoms of ASD. We also provide a reliable model of ASD with core symptoms for future studies, such as biomarker identification and therapeutic intervention studies.

Adjustable continence therapy (proACT) for the treatment of male stress urinary incontinence post-prostatectomy: a systematic review and meta-analysis (2023 update).

PURPOSE: Stress urinary incontinence (SUI) is a key factor for post-prostatectomy (RP) quality of life. Current international guidelines struggle to find the adequate place for each kind of surgeries. The aim of this systematic review and meta-analysis considering updated evidence is to assess the efficacy and safety of proACT in treating male patients with post-RP SUI. METHODS: A review of the literature was performed by searching the PubMed database. We narrowed included studies with adult male patients with SUI; outcomes included pads or pad weight per day and quality of life (QOL) questionnaires, as well as safety outcomes. RESULTS: 18 studies involving 1570 patients mean age of 68.8 (EC 2.1) were included. The mean follow-up reported was 34.7 months (EC 17.7; median 38.5; range 1-128 months). An average of 60.7% (EC 27) and 40.4% of patients suffered from mild-to-moderate and severe incontinence, respectively. The overall dryness rate was 55.1% (EC 19.3) while respecting the definition of 0-1 pads per day, and the mean dryness rate was 53% (EC 0.2). The mean overall complication rate was 31.2% (EC 18.3%), including an explantation rate of 26.5% (EC 15.3) and a reoperation rate of 22.7% (EC 8.7). The methodological quality of the 18 studies was very heterogeneous. CONCLUSION: Implantation of proACT adjustable balloons is a minimally invasive technique that provides medium outcomes (53%) with a strict definition of dryness (0-1 PPD) and important complication rate (31.2%). Past of irradiation is a negative predictive factor for incontinence.

Epidemiology of extrapulmonary tuberculosis in central Guangxi from 2016 to 2021.

The burden of extrapulmonary tuberculosis (EPTB) has gradually increased in recent years, but not enough epidemiological data is available from central Guangxi. To better understand the epidemiology of EPTB in central Guangxi and identify risk factors associated with them, we retrospectively investigated the epidemiology of tuberculosis (TB), especially EPTB, among patients admitted to the Chest Hospital of Guangxi Zhuang Autonomous Region between 2016 and 2021. We excluded those infected with both pulmonary tuberculosis (PTB) and EPTB, reported the proportion and incidence of PTB or EPTB, and compared the demographic characteristics and risk factors of EPTB and PTB cases using univariate and multivariate logistic regression models. Among 30,893 TB patients, 67.25% (20,774) had PTB and 32.75% (10,119) had EPTB. Among EPTB, pleural, skeletal, lymphatic, pericardial, meningeal, genitourinary, intestinal, and peritoneal TB accounted for 49.44%, 27.20%, 8.55%, 4.39%, 3.36%, 1.48%, 0.87%, and 0.79%, respectively. Patients who were younger (age < 25), from rural areas, Zhuang and other ethnic groups, and diagnosed with anemia and HIV infection were more likely to develop EPTB. However, patients with diabetes and COPD were less likely to have EPTB. From 2016 to 2021, the proportion of PTB cases decreased from 69.73 to 64.07%. The percentage of EPTB cases increased from 30.27 to 35.93%, with the largest increase in skeletal TB from 21.48 to 34.13%. The epidemiology and risk factors of EPTB in central Guangxi are different from those of PTB. The incidence of EPTB is increasing and further studies are needed to determine the reasons for it.

Dihydrotanshinone Triggers Porimin-Dependent Oncosis by ROS-Mediated Mitochondrial Dysfunction in Non-Small-Cell Lung Cancer.

Lung cancer is one of the leading causes of cancer death. Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer diagnoses. Dihydrotanshinone (DHT) is a compound extract from Salvia miltiorrhiza, which has favorable anti-inflammatory and anti-cancer activities. However, the role of DHT in NSCLC has not been fully studied. The anti-cancer drugs used for treating lung cancer often lead to apoptosis; however, the drug resistance of apoptosis restricts the effect of these drugs. Oncosis is a passive form of cell death that is different from apoptosis. It is characterized by cell swelling, and Porimin is a specific marker for oncosis. In this study, the role of DHT in mediating oncosis in A549 cells was investigated. In vitro, the MTS assay was used to detect cell activity after DHT treatment. Microscopy and electron microscopy were used to observe cell morphology changes. Western blotting was used to detect protein expression. Flow cytometry was used to detect intracellular reactive oxygen species (ROS) level, calcium ion (Ca2+) level, and cell mortality. The intracellular Lactic dehydrogenase (LDH) level was detected by an LDH detection kit after DHT treatment. The ATP level was detected using an ATP detection kit. In vivo, Lewis lung cancer (LLC) xenograft mice were used to evaluate the anti-tumor effect of DHT. Hematoxylin and eosin (HE) staining was used to detect the pathology of lung cancer tumors. The detection of Porimin in the tumor tissues of the mice after DHT administration was assessed by immunohistochemistry (IHC). The results of this study showed that DHT treatment changed the cell morphology; destroyed the mitochondrial structure; increased the expression of Porimin; increased the levels of LDH, ROS, and Ca2+; decreased the mitochondrial membrane potential and ATP level; and played an anti-tumor role in vitro by mediating oncosis in A549 cells. The in vivo studies showed that DHT could effectively inhibit tumor growth. The results of protein detection and IHC detection in the tumor tissues showed that the expression of Porimin was increased and that oncosis occurred in the tumor tissues of mice. DHT triggered Porimin-dependent oncosis by ROS-mediated mitochondrial dysfunction in NSCLC. The in vivo studies showed that DHT could inhibit tumor growth in LLC xenograft mice by triggering oncosis. This study indicates the potential for DHT to treat NSCLC.

Integrative identification of human serpin PAI-1 inhibitors from Dracaena dragon blood and molecular implications for inhibitor-induced PAI-1 allosterism.

Human plasminogen activator inhibitor-1 (PAI-1) is an important component of the coagulation system and has been recognized as a potential therapeutic target of diverse cardiovascular disorders. Previously, it was found that the extracts from the Chinese medicine Dracaena dragon blood have potent inhibitory activity against PAI-1, but it is unclear which constituents directly participate in the inhibition and how do they regulate PAI-1 at molecular level. Here, we describe an integrated strategy to identify the dragon blood's chemical constituents that can directly target PAI-1. With the strategy, five compounds 1-5 are hit as promising PAI-1 inhibitor candidates, from which three are measured to have high or moderate activity against PAI-1. In particular, the compound 3 is determined to exhibit the highest potency; this value is roughly comparable with the widely used PAI-1 inhibitor Tiplaxtinin. We further examine the molecular effect of compound 3 on PAI-1 conformation at structural level. It is supposed that small-molecule inhibitor regulates the reactive center loop (RCL) of PAI-1 through an allosterism, that is, binding of compound 3 to PAI-1 can allosterically stabilize RCL in latent form, thus promoting PAI-1 conformational conversion from metastable active form to the inactive latent form. Long-term atomistic simulations also demonstrate that removal of compound 3 can destabilize the structured ß-stranded conformation of RCL in latent form, although the current simulations are still not sufficient to characterize the full conversion dynamics trajectory.

Generation of high cross-presentation ability human dendritic cells by combination of interleukin 4, interferon ß and GM-CSF.

Dendritic cell (DC)-based immunotherapies have been utilized for the treatment of numerous diseases. However, the conventional generation strategies of DCs in vitro require 7 days and these DCs showed an unsatisfactory function, which prompted us to explore new approaches. We found that in vitro culture of human CD14+ cells, in the medium containing granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4, as well as interferon ß (IFN-ß) for 48 h, followed by the maturation stimuli of IL-1ß and poly I:C for another 24 h can be differentiated into high cross-presentation ability DCs (G4B-DCs). These DCs express high levels of CD11c, CD86, and HLA-DR, producing a high level of tumor necrosis factor α (TNF-α). Of note, compared with the conventional DCs, G4B-DCs showed a higher ability to promote allogeneic naïve CD4+ T cell and CD8+ T cell proliferation and interferon (IFN)-γ production. These DCs also have the remarkable ability to induce Flu-M1-specific CD8+ T cells. In addition, we found that these G4B-DCs express partially the cDC1 phenotype. These data indicate that G4B-DC is unique and may provide a relatively rapid alternative method for potential clinical use.

Auger-Assisted Electron Transfer between Adjacent Quantum Wells in Two-Dimensional Layered Perovskites.

Two-dimensional (2D) layered perovskites are naturally formed multiple quantum-well (QW) materials, holding great promise for applications in many optoelectronic devices. However, the further use of 2D layered perovskites in some devices is limited by the lack of QW-to-QW carrier transport/transfer due to the energy barrier formed by the insulating ligands between QWs. Herein, we report an Auger-assisted electron transfer between adjacent QWs in (CmH2m+1NH3)2PbI4 2D perovskites particularly with m = 12 and 18, where the electron energy barrier (Eb) is similar to the QW band gap energy (Eg). This Auger-assisted QW-to-QW electron transfer mechanism is established by the observation of a long-lived and derivative-like transient absorption feature, which is a signature of the quantum confined Stark effect induced by the electron-hole separation (thus an internal electric field) between different QW layers. Our finding provides a new guideline to design 2D perovskites with an optically tunable QW-to-QW charge transport property, advancing their applications in optoelectronics and optical modulations.

Ultrafast and High-Yield Polaronic Exciton Dissociation in Two-Dimensional Perovskites.

Layered two-dimensional (2D) lead halide perovskites are a class of quantum well (QW) materials, holding dramatic potentials for optical and optoelectronic applications. However, the thermally activated exciton dissociation into free carriers in 2D perovskites, a key property that determines their optoelectronic performance, was predicted to be weak due to large exciton binding energy (Eb, about 100-400 meV). Herein, in contrast to the theoretical prediction, we discover an ultrafast (<1.4 ps) and highly efficient (>80%) internal exciton dissociation in (PEA)2(MA)n-1PbnI3n+1 (PEA = C6H5C2H4NH3+, MA = CH3NH3+, n = 2-4) 2D perovskites despite the large Eb. We demonstrate that the exciton dissociation activity in 2D perovskites is significantly promoted because of the formation of exciton-polarons with considerably reduced exciton binding energy (down to a few tens of millielectronvolts) by the polaronic screening effect. This ultrafast and high-yield exciton dissociation limits the photoluminescence of 2D perovskites but on the other hand well explains their exceptional performance in photovoltaic devices. The finding should represent a common exciton property in the 2D hybrid perovskite family and provide a guideline for their rational applications in light emitting and photovoltaics.

A Pan-Cancer Analysis of the BIRC Gene Family and Its Association with Prognosis, Tumor Microenvironment, and Therapeutic Targets.

The inhibitors of apoptosis protein (IAP)/baculoviral IAP repeat containing (BIRC) gene families are necessary for cell protection, and most of these genes act as endogenous inhibitors of apoptosis. In some cancers, the over-expression of the BIRC gene is associated with cancer progression, multidrug resistance, poor prognosis and short-term survival. In this study, we aimed to assess the effect of the BIRC family in pan-cancer. We downloaded transcriptome and clinical data from 33 types of TCGA tumor samples and adjacent tissues. Then, the expression characteristics of IAP family members BIRC2, BIRC3, BIRC5, BIRC6 and BIRC7 in pan-cancer were analyzed. R packet and Cox regression were used to analyze the clinical correlation. In addition, the transcription level of BIRC and immune subtypes, stem cells, immune tumor microenvironment (TME) and drug sensitivity were analyzed by multidimensional correlation. Our studies have shown that the expression of IAP family members BIRC2, BIRC3, BIRC5, BIRC6, and BIRC7 is different in different tumor types, and the heterogeneity is obvious in cancers. Overall, our analysis showed that BIRC2, BIRC3, BIRC6, and BIRC7 were mainly down-regulated in tumors, whereas BIRC5 was mainly up-regulated in tumors. The expression of IAP family members is related to the overall survival of patients. However, the direction of the association varies depending on specific IAP subtypes and specific types of cancer. More specifically, BIRC5 is mainly related to poor prognosis. The rest of the IAP family showed either a survival advantage or a survival disadvantage, depending on the type of cancer. In addition, BIRC2, BIRC3, BIRC5, BIRC6 and BIRC7 were significantly correlated with immune infiltration subtypes and had different degrees of correlation with the degree of interstitial cell infiltration and tumor cell dryness. Finally, our study revealed that BIRC2, BIRC5, and BIRC7 genes may be related to drug resistance of tumor cells. Our systematic analysis of (IAP) gene expression and its relationship with immune infiltration, TME, cancer stem cells, drug sensitivity and prognosis of cancer patients highlights the need to study IAP family members as separate entities in each specific cancer type. In addition, our study confirmed that IAP family genes are promising therapeutic targets for cancer and potential prognostic indicators for clinical application, although further laboratory verification is needed.

Progressive emergence of an S153F plus R263K combination of integrase mutations in the proviral DNA of one individual successfully treated with dolutegravir.

OBJECTIVES: The development of HIV drug resistance against the integrase strand transfer inhibitor dolutegravir is rare. We report here the transient detection, by near full-genome ultradeep sequencing, of minority HIV-1 subtype B variants bearing the S153F and R263K integrase substitutions in the proviral DNA from blood cells of one patient who successfully initiated dolutegravir-based ART, over 24 weeks. Our objective was to study the effects of these substitutions. METHODS: Strand transfer and DNA-binding activities of recombinant integrase proteins were measured in cell-free assays. Cell-based resistance, infectivity and replicative capacities were measured using molecular clones. Structural modelling was performed to understand experimental results. RESULTS: R263K emerged first, followed by the addition of S153F at Week 12. By Week 24, both mutations remained present, but at lower prevalence. We confirmed the coexistence of S153F and R263K on single viral genomes. Combining S153F or S153Y with R263K decreased integration and viral replicative capacity and conferred high levels of drug resistance against all integrase inhibitors. Alone, S153Y and S153F did little to infectivity or dolutegravir resistance. We identified altered DNA binding as a mechanism of resistance. The patient remained with undetectable viral loads at all timepoints. CONCLUSIONS: Drug-resistant minority variants have often been reported under suppressive ART. Our study adds to these observations by unravelling a progression towards higher levels of resistance through a novel pathway despite continuous undetectable viral loads. Poorly replicative HIV drug-resistant minority proviral variants did not compromise viral suppression in one individual treated with dolutegravir.

Differential properties of E prostanoid receptor-3 and thromboxane prostanoid receptor in activation by prostacyclin to evoke vasoconstrictor response in the mouse renal vasculature.

Vasomotor reactions of prostacyclin (prostaglandin I2 ; PGI2 ) can be collectively modulated by thromboxane prostanoid receptor (TP), E-prostanoid receptor-3 (EP3), and the vasodilator I prostanoid receptor (IP). This study aimed to determine the direct effect of PGI2 on renal arteries and/or the whole renal vasculature and how each of these receptors is involved. Experiments were performed on vessels or perfused kidneys of wild-type mice and/or mice with deficiency in TP (TP-/- ) and/or EP3. Here we show that PGI2 did not evoke relaxation, but instead resulted in contraction of main renal arteries (from ~0.001-0.01 µM) or reduction of flow in perfused kidneys (from ~1 µM); either of them was reversed into a dilator response in TP-/- /EP3-/- counterparts. Also, we found that in renal arteries although it has a lesser effect than TP-/- on the maximal contraction to PGI2 (10 µM), EP3-/- but not TP-/- resulted in relaxation to the prostanoid at 0.01-1 µM. Meanwhile, TP-/- only significantly reduced the contractile activity evoked by PGI2 at ≥0.1 µM. These results demonstrate that PGI2 may evoke an overall vasoconstrictor response in the mouse renal vasculature, reflecting activities of TP and EP3 outweighing that of the vasodilator IP. Also, our results suggest that EP3, on which PGI2 can have a potency similar to that on IP, plays a major role in the vasoconstrictor effect of the prostanoid of low concentrations (≤1 µM), while TP, on which PGI2 has a lower potency but higher efficacy, accounts for a larger part of its maximal contractile activity.

Prostaglandin E2 sequentially activates E-prostanoid receptor-3 and thromboxane prostanoid receptor to evoke contraction and increase in resistance of the mouse renal vasculature.

Although recognized to have an in vivo vasodepressor effect blunted by the vasoconstrictor effect of E-prostanoid receptor-3 (EP3), prostaglandin E2 (PGE2 ) evokes contractions of many vascular beds that are sensitive to antagonizing the thromboxane prostanoid receptor (TP). This study aimed to determine the direct effect of PGE2 on renal arteries and/or the whole renal vasculature and how each of these two receptors is involved in the responses. Experiments were performed on isolated vessels and perfused kidneys of wild-type mice and/or mice with deficiency in TP (TP-/- ), EP3 (EP3-/- ), or both TP and EP3 (TP-/- /EP3-/- ). Here we show that PGE2 (0.001-30 µM) evoked not only contraction of main renal arteries, but also a decrease of flow in perfused kidneys. EP3-/- diminished the response to 0.001-0.3 µM PGE2 , while TP-/- reduced that to the prostanoid of higher concentrations. In TP-/- /EP3-/- vessels and perfused kidneys, PGE2 did not evoke contraction but instead resulted in vasodilator responses. These results demonstrate that PGE2 functions as an overall direct vasoconstrictor of the mouse renal vasculature with an effect reflecting the vasoconstrictor activities outweighing that of dilation. Also, our results suggest that EP3 dominates the vasoconstrictor effect of PGE2 of low concentrations (≤0.001-0.3 µM), but its effect is further added by that of TP, which has a higher efficacy, although activated by higher concentrations (from 0.01 µM) of the same prostanoid PGE2 .

Platycodin D suppresses cisplatin-induced cytotoxicity by suppressing ROS-mediated oxidative damage, apoptosis, and inflammation in HEK-293 cells.

Cisplatin, a proven effective chemotherapeutic agent, has been used clinically to treat malignant solid tumors, whereas its clinical use is limited by serious side effect including nephrotoxicity. Platycodin D (PD), the major and marked saponin isolated from Platycodon grandiflorum, possesses many pharmacological effects. In this study, we evaluated its protective effect against cisplatin-induced human embryonic kidney 293 (HEK-293) cells injury and elucidated the related mechanisms. Our results showed that PD (0.25, 0.5, and 1 µM) can dose-dependently alleviate oxidative stress by decreasing malondialdehyde and reactive oxygen species, while increasing the levels of glutathione, superoxide dismutase, and catalase. Moreover, the elevation of apoptosis including Bax, Bad, cleaved caspase-3,-9, and decreased protein levels of Bcl-2, Bcl-XL induced by cisplatin were reversed after PD treatment. Importantly, PD pretreatment can also regulate PI3K/Akt and ERK/JNK/p38 signaling pathways. Furthermore, PD was found to reduce NF-κB-mediated inflammatory relative proteins. Our finding indicated that PD exerted significant effects on cisplatin induced oxidative stress, apoptosis and inflammatory, which will provide evidence for the development of PD to attenuate cisplatin-induced nephrotoxicity.

Saponins derived from the stems and leaves of Panax ginseng attenuate scrotal heat-induced spermatogenic damage via inhibiting the MAPK mediated oxidative stress and apoptosis in mice.

Heat stress (HS) reaction is a stress response caused by adverse conditions. Currently, the incidence of reproductive malignancies particularly in males has been constantly increasing. This work investigated the effects of saponins derived from the stems and leaves of Panax ginseng (GSLS) on testicular injury induced by scrotal hyperthermia in mice. GSLS (150, 300 mg/kg) were administered intragastrically to mice for 14 days, then exposed to a single scrotal heat treatment at 43°C for 18 min on seventh day. HS induced a significant loss of multinucleate giant cells, desquamation of germ cells in destructive seminiferous tubules. Moreover, HS reduced the serum testosterone, testicular tissue superoxide dismutase activity and glutathione (GSH) content, while significantly enhanced the production of malondialdehyde (p < .05). GSLS exhibited the protective potential against HS-induced injury not only by modulating Bcl-2 family and caspase protease family, but also by suppressing the protein levels of heme oxygenase-1 (HO-1), heat shock protein 70 (HSP70), hypoxia inducible factor-1α (HIF-1α) and activation of Mitogen-activated protein kinase (MAPK) signaling pathways (p < .05). In conclusion, we clearly demonstrated that GSLS exhibited a significant protective effect against HS-induced testicular dysfunction, mainly the inhibition of oxidative stress associated apoptosis partly via regulation of the MAPK signaling pathway.