p38-MAPK and CDK5,signaling pathways in neuroinflammation:a potential therapeutic intervention in Alzheimer's disease?

Alzheimer’s disease(AD),the most common type of dementia,affects millions of people worldwide,putting a significant strain on healthcare infrastructure and societal resources.AD is characte rized by the build-up of amyloid-beta(Aβ)plaques and neurofibrillary to ngles containing hyperphosphorylated tau protein.

Monomeric C-reactive protein:a link between chronic inflammation and neurodegeneration?

Pre-diabetic insulin resistance is associated with sub-clinical inflammation and concomitant increase in systemic C-reactive protein(CRP)levels.Type 2 diabetes mellitus(T2DM)patients register even higher chronic levels of inflammation,with excess circulating CRP originating from both typical hepatic synthesis,and also visceral white adipose tissue.

Extracellular vesicles-coupled miRNAs from oviduct and uterus modulate signaling pathways related to lipid metabolism and bovine early embryo development

Background Extracellular vesicles(EVs) present in oviductal(OF) and uterine fluid(UF) have been shown to enhance bovine embryo quality during in vitro culture by reducing lipid contents and modulating lipid metabolism-related genes(LMGs), while also influencing cell proliferation, suggesting their involvement on the regulation of different biological pathways. The regulation of signaling pathways related to cell differentiation, proliferation, and metabo-lism is crucial for early embryo development and can determine the success or failure of the pregnancy. Bioactive molecules within EVs in maternal reproductive fluids, such as micro RNAs(miRNAs), may contribute to this regulatory process as they modulate gene expression through post-transcriptional mechanisms.Results This study evaluated miRNA cargo in OF-EVs from the early luteal phase and UF-EVs from the mid-luteal phase, coinciding with embryo transit within oviduct and uterus in vivo, and its possible influence on LMGs and sign-aling pathways crucial for early embryo development. A total of 333 miRNAs were detected, with 11 exclusive to OF, 59 to UF, and 263 were common between both groups. From the 20 differentially expressed miRNAs, 19 up-regulated in UF-EVs(bta-miR-134, bta-miR-151-3p, bta-miR-155, bta-miR-188, bta-miR-181b, bta-miR-181d, bta-miR-224, bta-miR-23b-3p, bta-miR-24-3p, bta-miR-27a-3p, bta-miR-29a, bta-miR-324, bta-miR-326, bta-miR-345-3p, bta-miR-410, bta-miR-652, bta-miR-677, bta-miR-873 and bta-miR-708) and one(bta-miR-148b) in OF-EVs. These miRNAs were predicted to modulate several pathways such as Wnt, Hippo, MAPK, and lipid metabolism and degradation. Differ-ences in miRNAs found in OF-EVs from the early luteal phase and UF-EVs from mid-luteal phase may reflect differ-ent environments to meet the changing needs of the embryo. Additionally, miRNAs may be involved, particularly in the uterus, in the regulation of embryo lipid metabolism, immune system, and implantation.Conclusions Our study suggests that miRNAs within OF- and UF-EVs could modulate bovine embryo development and quality, providing insights into the intricate maternal-embryonic communication that might be involved in mod-ulating lipid metabolism, immune response, and implantation during early pregnancy.

Optimal dose of busulfan for depleting testicular germ cells of recipient mice before spermatogonial transplantation

Successful spermatogonial transplantation requires depletion of the host germ cells to allow efficient colonization of the donor spermatogonial stem cells. Although a sterilizing drug,busulfan （Myleran）,is commonly used for preparing a recipient mouse before transplantation,the optimal dose of this drug has not yet been defined.The present study investigated the effects of different doses of busulfan （10-50 mg per kg body weight） on survival rate,testicular mass and histomorphology,and on the haploid spermatids and spermatozoa of male BALB/c mice.The results suggest that a dosage of 30 mg kg^-1 is optimal for the ablative treatment withbusulfan used to prepare the recipient mice. This dose results in an adequate depletion of the host germ cells for colonization of donorderived spermatogonial stem cells and causes the lowest death rate of the animals.

Anatomy and embryology of umbilicus in newborns： a review and clinical correlations

Umbilicus is considered a mirror of the abdomen in newborns. Despite its importance, the umbilicus has been stated in literature and textbooks as discrete subjects with many body systems, such as the urinary, digestive, and cardiovascular ones. This article aimed to address the basic knowledge of the umbilicus in relation to clinical disorders under one integrated topic to aid physicians and surgeons in assessing newborns and infants. The umbilicus appears as early as the fourth week of fetal life when the folding of the embryonic plate occurs. The umbilicus appears initially as a primitive umbilical ring on the ventral aspect of the body. The primitive umbilicus contains the connecting stalk, umbilical vessels, vitelline duct and vessels, allantois, and loop of the intestine. Changes occur to form the definitive cord, which contains three umbilical vessels, namely, ＂one vein and two arteries,＂ embedded in Wharton＇s jelly. After birth, the umbilical vessels inside the body obliterate and gradually form ligaments. Congenital disorders at the umbilicus include herniation, bleeding, and discharge of mucous, urine, or feces. Some of these disorders necessitate emergent surgical interference, whereas others may be managed conservatively. The umbilicus has many embryological remnants. Thus, the umbilicus is prone to various clinical disorders. Detecting these disorders as early as possible is essential to prevent or minimize possible complications.

Extracellular vesicles from oviductal and uterine fluids supplementation in sequential in vitro culture improves bovine embryo quality

Background:In vitro production of bovine embryos is a well-established technology,but the in vitro culture(IVC)system still warrants improvements,especially regarding embryo quality.This study aimed to evaluate the effect of extracellular vesicles(EVs)isolated from oviductal(OF)and uterine fluid(UF)in sequential IVC on the development and quality of bovine embryos.Zygotes were cultured in SOF supplemented with either BSA or EVs-depleted fetal calf serum(dFCS)in the presence(BSA-EV and dFCS-EV)or absence of EVs from OF(D1 to D4)and UF(D5 to D8),mimicking in vivo conditions.EVs from oviducts(early luteal phase)and uterine horns(mid-luteal phase)from slaughtered heifers were isolated by size exclusion chromatography.Blastocyst rate was recorded on days 7-8 and their quality was assessed based on lipid contents,mitochondrial activity and total cell numbers,as well as survival rate after vitrification.Relative mRNA abundance for lipid metabolism-related transcripts and levels of phosphorylated hormonesensitive lipase(pHSL)proteins were also determined.Additionally,the expression levels of 383 miRNA in OF-and UF-EVs were assessed by qRT-PCR.Results:Blastocyst yield was lower(P<0.05)in BSA treatments compared with dFCS treatments.Survival rates after vitrification/warming were improved in dFCS-EVs(P<0.05).EVs increased(P<0.05)blastocysts total cell number in dFCS-EV and BSA-EV compared with respective controls(dFCS and BSA),while lipid content was decreased in dFCSEV(P<0.05)and mitochondrial activity did not change(P>0.05).Lipid metabolism transcripts were affected by EVs and showed interaction with type of protein source in medium(PPARGC1B,LDLR,CD36,FASN and PNPLA2,P<0.05).Levels of pHSL were lower in dFCS(P<0.05).Twenty miRNA were differentially expressed between OF-and UF-EVs and only bta-miR-148b was increased in OF-EVs(P<0.05).Conclusions:Mimicking physiological conditions using EVs from OF and UF in sequential IVC does not affect embryo development but improves blastocyst quality regarding survival rate after vitrification/warming,total cell number,lipid content,and relative changes in expression of lipid metabolism transcripts and lipase activation.Finally,EVs miRNA contents may contribute to the observed effects.

Study on the role of JAK/STAT signaling pathway during chicken spermatogonial stem cells generation based on RNA-Seq

Spermatogonia! stem cells（SSCs） form the foundation for spermatogenesis and sustain male fertility.To explore the regulatory mechanisms of chicken SSCs generation,we obtained highly purified chicken embryonic stem cells（ESCs）,primordial germ cells（PGCs） and SSCs by fluorescence-activated cell sorting（FACS）.High-throughput analysis methods（RNA-Seq） were used to sequence the transcriptome level of these cells.Gene ontology and Kyoto encyclopedia of genes and genomes（KEGG） pathway enrichment were used to analyze RNA-Seq results.BMP4 was used to induce chicken ESCs differentiation to SSCs-like cells in vitro.The quantitative real-time（qRT）-PCR was used to detect the expression changes of the key genes.The results showed that 22 relevant critical pathways were found by RNA-Seq,one of them was the Janus kinase/signal transducer and activator of transcription（JAK/STAT） signaling pathway.Total of 103 related genes were detected in this pathway.Protein-protein interactions analysis found that 87 proteins were significantly related to 19 key proteins in this pathway.These 87 proteins were enriched in 21 biological processes and 18 signaling pathways.Moreover,during the differentiation of chicken ESCs to SSCs-like cells induced by BMP4 in vitro,JAK2 and STAT3 were activated.The qRT-PCR results showed that the expression trends of JAK2 and STAT3 were basically the same as in vivo.We concluded that JAK/STAT signaling pathway plays an important role in the process of chicken SSCs generation both in vivo and in vitro;it may achieve its function through multiple biological processes and other related pathways.

Endoscopic monitoring the estrous phase of Arabian mares with assaying its biopsy

Objective:To evaluate the changes occur in the vagina, cervix and endometrium during the pre- ovulatory period in Arabian mares by using endoscope as a diagnostic tool as well as the availability of taking an endoscopic biopsy during this stage.Methods:Ten cyclic and healthy arabian mares were subjected to ultrasound scanning of their ovaries to estimate the diameter of the preovulatory follicles, collection of blood samples for estimating the hormonal levels (Estradiol-17β and progestrone) for confirming the estrous phase, endoscopic monitoring their vagina, cervix and endometrium, the availability of taking biopsical samples and histological examination of the obtained samples.Results:The obtained data revealed that, the mean diameter of the preovulatory follicles was (3.95±0.34) cm, the plasma estradiol and progestrone levels were (85.98±5.26) pg/mL and (0.73±0.23) ng/mL, respectively, endoscopic monitoring the vagina, cervix and endometrium revealed hyperemic vaginal mucous membrane, soft and opened cervical ostium with abundant estrous mucous and folding, hyperemic and edematous appearance of the endometrium, respectively and the histological features of the biopsical endometrial samples revealed that, The lamina propria-sub mucosa was packed with simple or branched tubular glands lined with simple columnar epithelium showing oval or rounded dark nuclei with different degrees of secretory activities of the glands.Conclusions: The endoscope proved to be a reliable tool for confirming the estrous phase in mares and monitoring the gross features of the vagina, the cervix and the endometrium, in addition to the availability of taking biopsical smears.

Impact of Therapeutic Electrical Stimulation of Sacral Surface Considering Individual Anatomical Sacral Variations on Early Recovery Urinary Continence after Radical Prostatectomy

Objectives: To investigate the effect of electrical stimulation of different anatomical variations of sacral surface on early recovery of urinary continence after radical prostatectomy. Methods: Twenty of 53 consecutive patients who underwent prostatectomy by a single surgeon were enrolled in this study. Ten patients were prospectively randomized to two groups;five patients in Sacral foramena stimulation group received postoperative surface electrical stimulation of sacral foramina area while five patients in control group did not received any electrical stimulation. Selection of remaining ten patients depended on sacral hiatus anatomical variations, assessed by plan X-rays. Of the ten patients, five patients with sacral hiatus subtotals were grouped under SHS1 while 5 patients with sacral hiatus totals were grouped as SHS2. Electrical stimulation for each group began 7 days after catheter removal, thrice a week for 8 weeks. Each of the 24 treatment sessions for each group composed of 20 minutes for sacral electrical stimulation. Continence was evaluated at baseline, 4 and 8 weeks using the 24-hour pad test and according to the incontinence section of the International Continence Society questionnaire. Results: After 2 weeks of treatment, the mean leakage weight was comparable between SFS group and SHS1 group while it was significantly lowered in SHS2 as compared to SFS and SHS1 groups. Comparing mean leakage weight at 8 weeks revealed further significant reduction in SHS2 group than in SFS and SHS1 groups. Moreover, percentage of continent patients was highest in SHS2 group after 8 weeks of treatment followed by SHS1, SFS and control respectively. Conclusions: Electrical stimulation of sacral hiatus surface area may provide better stimulation for sacral nerve than sacral foramena surface area and appears to be effective treatment for early recovery of urinary continence after radical prostatectomy.

Maternal Anthropometric Study of Low Birth Weight Newborns in Saudi Arabia: A Hospital-Based Case-Control Study

Background: The aim of the study is to investigate the role of socio-demographic, life-style and clinical risk factors of low birth weight (LBW) among pregnant women in Saudi Arabia. It is a hospital-based, case-control study of mothers of 135 LBW and 65 normal birth weight neonates at the Obstetrics and Gynecology Unit of the Maternity and Children Hospital, KSA. Methods: On comparison by Duncan’s test, the gestational age of three LBW groups was found to be significantly different (P = 0.0026). The mean duration of hospital stay of the infants also increased for the LBW, very LBW and extreme LBW groups, and their difference was statistically significant (P = 0.0012). Results: A statistically significant, progressive decline was observed in the weight, length and circumference of the head of infants in the LBW to VLBW to ELBW groups. Conclusion: The present study has assessed the state of this significant public health problem of LBW in KSA, and identified several maternal modifiable risk factors. There is an urgent need for the development of reference charts using current data for the Middle Eastern population.

Antiulcer Activities of Commiphora molmol (Myrrh) Extract in Male Rats

Medicinal plants used in folk medicine contain a wide range of substances that can prevent and treat many diseases. The Antiulcer Activities effects of myrrh or Commiphora molmol extract (CME) were assessed in rats. In this experiment, thirty rats were divided into 6 groups as follows: G1) normal control (vehicle);G2) received aspirin without any treatment;G3) pretreated with Omeprazole (antiulcer drug) and groups (4), (5) and (6) were pretreated with CME at 125, 250 and 500 mg/kg b.wt, respective-ly for 2 weeks. At the end of experiment the volume, pH and total acidity of gastric juices;mucus content and ulcer lengths were measured and protection percentages were calculated. Gross and histopathological examinations of stomachs were also performed. CME induced an antiulcer effect manifested by decreased volume and total acidity of gastric juice and increased mucus content and percentages of protec-tion from ulcer as well as partial amelioration of gross and histopathological lesions seen in stomach of ulcerated rats. In conclusion, the results denote that Commiphora molmol extract possess antiulcer effects in rats. These results affirm the traditional use of Myrrh extract for the treatment of gastric ulcer.

Ankfy1 is dispensable for neural stem/precursor cell development

There are few studies on the membrane protein Ankfyl. We have found Ankfyl is specifically expressed in neural stem/precursor cells during early development in mice （murine）. To further explore Ankfyl function in neural development, we developed a gene knockout mouse with a mixed Balb/C and C57/BL6 genetic background. Using immunofluorescence and in situ hybridization, neural defects were absent in mixed genetic Ankfyl null mice during development and in adults up to 2 months old. However, Ankfyl gene knockout mice with a pure genetic background were found to be lethal in the C57/BL6 inbred mice embryos, even after seven generations of backcrossing. Polymerase chain reaction confirmed homozygotes were unattainable as early as embryonic day 11.5. We conclude that Ankfyl protein is dispensable in neural stem/precursor ceils, but could be critical for early embryonic murine development, depending on the genetic background.

Relationship between the Level of Serum Golgi Protein 73 and the Risk of Short-term Death in Patients with ALD-ACLF

Background and Aims:As a hepatocellular carcinoma biomarker,serum Golgi protein 73(GP73)is reportedly related to inflammation.Acute-on-chronic liver failure(ACLF)is characterized by severe systemic inflammation.In this study,we aimed to explore the association between the GP73 level and short-term mortality in patients with alcohol-associated liver disease-related ACLF(ALD-ACLF).Methods:This retrospective cohort study involved 126 Chinese adults with ALD-ACLF.Baseline serum GP73 level was measured using enzymelinked immunosorbent assay.Patients were followed-up for 90 d and outcomes were assessed.Data were analyzed using multivariate Cox regression and piecewise linear regression analyses.The predictive value of GP73 and classic models for the short-term prognosis of participants were evaluated and compared using receiver operating characteristic curves.Results:The serum GP73 level was independently associated with an increased mortality risk in patients with ALD-ACLF.Compared with the lowest tertile,the highest serum GP73 level predisposed patients with ALD-ACLF to a higher mortality risk in the fully adjusted model[at 28 days:hazard ratio(HR):4.29(0.99–18.54),p=0.0511;at 90 days:HR:3.52(1.15–10.79),p=0.0276].Further analysis revealed a positive linear association.GP73 significantly improved the accuracy of the Child-Turcotte-Pugh score,model for end-stage liver disease score,and model for end-stage liver diseasesodium score in predicting short-time prognosis of patients with ALD-ACLF.Conclusions:The serum GP73 level is a significant predictor of the subsequent risk of death in patients with ALD-ACLF.GP73 improved the predictive value of classic prognostic scores.

Methylene blue attenuates white matter damage after focal cerebral ischemia-reperfusion in rats

Methylene blue(MB)was reported to have neuronal protective effect after brain ischermia.In this study,we aimed to investigate the effect of MB on white matter in rats after focal cerebral ischemia-reperfusion(MCAO/R)injury.MCAO/R model was set and 54 male SD rats were randomly divided into 3 groups:control(sham surgery group),middle cerebral artery occlusion and reperfusion(MCAO),MCAO treated with MB of 10 mg/kg(MB)by intraperitoneal injection 1.5 h after surgery.We observed the neurological deficits in different groups using foot fault test 24 h after MCAO.We measured the infarction volume using TTC staining and showed the morphological changes of neurons and myelin using Nissl and black gold staining.

Pifithrin-α reduces cerebral vasospasm by attenuating apoptosis of endothelial cells in a subarachnoid haemorrhage model of rat

Background The mechanism of cerebral vasospasm following subarachnoid haemorrhage （SAH） is not understood. Here, we hypothesized that apoptosis of endothelial cells induced by p53 and its target gene em dash p53 upregulated modulator of apoptosis （PUMA） played an important role in development of cerebral vasospasm. We also observed the effects of a p53 inhibitor, pifithrin-α （PFT-α）, on reducing the expression of p53 and PUMA, consequently decreasing the apoptosis of endothelial cells and alleviating cerebral vasospasm. Methods Male Sprague-Dawley rats weighing 300-350 g were randomly divided into five groups： a control group （sham surgery）, a SAH group, a SAH＋dimethyl sulfoxide （DMSO） group, a SAH＋PFT-α （0.2 mg/kg） group and a SAH＋PFT-α （2.0 mg/kg） group. PFT-α was injected intraperitoneally immediately after SAH. Rats were sacnficed 24 hours after SAH. Western blot and immunohistochemical staining were used to detect the levels of p53, PUMA and caspase-3 protein. In addition, mortality and neurological scores were assessed for each group. Statistical significance was assured by analysis of variance performed in one way ANOVA followed by the Tukey test. The neurological and mortality scores were analyzed by Dunn＇s method and Fisher exact test, respectively. Results After SAH, Western blot and immunohistochemical staining showed the levels of p53, PUMA and caspase-3 in the endothelial cells and the numbers of TdT mediated dUTP nick end labelling （TUNEL） positive endothelial cells were all significantly increased in the basilar arteries （P 〈0.05）, but significantly reduced by PFT-a （P 〈0.05）. These changes were accompanied by increasing diameters and declining wall thickness of basilar arteries （P〈O.05）, as well as reduced mortality and neurological deficits of the rats （P〈O.05）. Conclusions PFT-a could protect cerebral vessels from development of vasospasm and improve neurological outcome as well as reduce the mortality via suppressing apoptosis induced by p53 in the endothelial cells of cerebral vessels.

Application of serum Golgi protein-73 in the management of chronic liver disease

Chronic liver disease(CLD)causes approximately 2.14 million(2.06-2.30)deaths annually,and;therefore,represents a heavy global health burden.[1]Currently,chronic hepatitis B(CHB),hepatitis C,alcohol-related liver disease,and non-alcoholic liver disease(NAFLD)account for 29%,26%,25%,and 9%of cirrhosis-related deaths worldwide,respectively.[1]Although vaccination has resulted in reductions in the seroprevalence of hepatitis B surface antigen and the overall prevalence of liver-related mortality,CHB remains the principal cause of liver disease,especially in China.

Paclitaxel-loaded hollow-poly（4-vinylpyridine） nano- particles enhance drug chemotherapeutic efficacy in lung and breast cancer cell lines

Paclitaxel （PTX）, one of the most effective cytotoxins for the treatment of breast and lung cancer, is limited by its severe side effects and low tumor selectivity. In this work hollow-poly（4-vinylpyridine） （hollow-p4VP） nanoparticles （NPs） have been used for the first time to generate PTX@p4VP NPs, employing a novel technique in which a gold core in the center of the NP is further oxidized to produce the hollow structure into which PTX molecules can be incorporated. The hollow-p4VP NPs exhibit good physicochemical properties and displayed excellent biocompatibility when tested on blood （no hemolysis） and cell cultures （no cytotoxicity）. Interestingly, PTX@p4VP NPs significantly increased PTX cytotoxicity in human lung （A-549） and breast （MCF-7） cancer cells with a significant reduction of PTX ICs0 （from 5.9 to 3.6 nM in A-549 and from 13.75 to 4.71 nM in MCF-7）. In addition, PTX@p4VP caused a decrease in volume of A-549 and MCF-7 multicellular tumor spheroids （MTS）, an in vitro system that mimics in vivo tumors, in comparison to free PTX. This increased antitumoral activity is accompanied by efficient cell internalization and increased apoptosis, especially in lung cancer MTS. Our results offer the first evidence that hollow- p4VP NPs can improve the antitumoral activity of PTX. This system can be used as a new nanoplatform to overcome the limitations of current breast and lung cancer treatments.

Use of serum Golgi protein 73 for screening chronic hepatitis B virus infection patients needing antiviral therapy in the community

Chronic hepatitis B virus (HBV) infection is a major global public health problem. Approximately 887,000 people die of HBV infection-related diseases annually, with cirrhosis and hepatocellular carcinoma (HCC) being the principal causes of mortality.[1] Timely antiviral therapy greatly reduces the risks of cirrhosis and HCC. However, unfortunately, of those patients who are eligible for antiviral treatment, only 25% of patients in clinic settings and 12% of those in community settings obtain timely antiviral therapy.[2] Therefore, reliable means of identifying patients with chronic HBV infection that require antiviral therapy are necessary, particularly for use in the community.

Liver Stiffness Measurement Can Reflect the Active Liver Necroinflammation in Population with Chronic Liver Disease:A Real-world Evidence Study

Background and Aims: Non-invasive evaluation of liver nec-roinflammation in patients with chronic liver disease is an un-met need in clinical practice.The diagnostic accuracy of transient elastography-based liver stiffness measurement(LSM)for liver fibrosis could be affected by liver necroinflam-mation,the latter of which could intensify stiffness of the liver.Such results have prompted us to explore the diagnosis potential of LSM for liver inflammation.Methods: Three cross-sectional cohorts of liver biopsy-proven chronic liver dis-ease patients were enrolled,including 1417 chronic hepatitis B(CHB)patients from 10 different medical centers,106 non-al-coholic steatohepatitis patients,and 143 patients with auto-immune-related liver diseases.Another longitudinal cohort of 14 entecavir treatment patients was also included.The re-ceiver operating characteristic(ROC)curve was employed to explore the diagnostic value of LSM.Results: In CHB patients,LSM value ascended with the increased severity of liver nec-roinflammation in patients with the same fibrosis stage.Such positive correlation between LSM and liver necroinflammation was also found in non-alcoholic steatohepatitis and autoim-mune-related liver diseases populations.Furthermore,the ROC curve exhibited that LSM could identify moderate and se-vere inflammation in CHB patients(area under the ROC curve as 0.779 and 0.838)and in non-alcoholic steatohepatitis pa-tients(area under the ROC curve as 0.826 and 0.871),respec-tively.Such moderate diagnostic value was also found in autoimmune-related liver diseases patients.In addition,in the longitudinal entecavir treated CHB cohort,a decline of LSM values was observed in parallel with the control of inflam-matory activity in liver.Conclusions: Our study implicates a diagnostic potential of LSM to evaluate the severity of liver necroinflammation in chronic liver disease patients.