Water Extract of Portulaca Oleracea Inhibits PEDV Infection-Induced Pyrolysis by Caspase-1/GSDMD.

Porcine epidemic diarrhea virus (PEDV) belongs to the coronavirus family and the coronavirus genus, causing contact enteric infection in pigs. It is one of the most serious diseases that threatens the pig industry. However, there is currently no specific drug to prevent and treat the disease, indicating that we need to be vigilant about the spread of the disease and the development of anti-PEDV drugs. The dried aerial parts of the plant Portulaca oleracea in the family Portulacaceous, whose decoction can be used to treat acute enteritis, dysentery, diarrhea, and other diseases. This study explored the potential mechanism of water extract of Portulaca oleracea (WEPO) in PEDV-induced pyroptosis in Vero cells. PEDV decreased the viability of Vero cells in a dose- and time-dependent manner, causing cell damage, upregulating the level of intracellular Nlrp3, and inhibiting the level of Gasdermin D (GSDMD) and the activation of Caspase-1. WEPO can inhibit PEDV-induced pyroptosis, reduce the elevation of inflammatory factors caused by infection, and exhibit a dose-dependent effect. Knockdown of Caspase-1 and GSDMD separately can induce the production of the inflammatory factor IL-1ß to significantly decrease and increase, respectively. These results suggest that WEPO can inhibit cell pyroptosis caused by PEDV and that the Caspase-1 and GSDMD pathways play an important role in this process.

Antibiotic resistance and drug modification: Synthesis, characterization and bioactivity of newly modified potent pleuromutilin derivatives with a substituted piperazine moiety.

Antibiotic-resistant bacteria pose a major global public health concern, owing to the lack of effective antibacterial drugs. Consequently, the discovery and development of innovative antibacterial drug classes with unique mechanisms of action are urgently needed. In this study, we designed, synthesised, and tested a series of novel pleuromutilin derivatives with piperazine linker substituted by amino acids moieties to determine their antibacterial properties. Most synthesized compounds exhibited potent activities against Staphylococcus aureus (S. aureus), methicillin-resistant S. aureus (MRSA), and methicillin-resistant Staphylococcus epidermidis. Compound 6l, the most potent antibacterial agent created in this study, displayed a rapid bactericidal activity against MRSA, Klebsiella pneumoniae and S. aureus cfr N12. Moreover, pharmacokinetics study of compound 6l exhibited good PK performance with a low in vivo clearance (CL = 1965 mL/h/kg) and a suitable half-life (T1/2 = 11.614 ± 5.123 h). Molecular docking experiments revealed the binding model of compound 6l to the unmethylated A2503 of peptidyl transferase centre of 23S rRNA. Interaction pattern of 6l with cfr-mediated ribosomes revealed by molecular dynamics. Moreover in vivo mouse systemic infection experiments with compound 6l revealed its effectiveness against MRSA and S. aureus cfr N12 with the ED50 of 11.08 mg/kg and 14.63 mg/kg body weight, respectively.

Novel gold-platinum nanoparticles serve as broad-spectrum antioxidants for attenuating ischemia reperfusion injury of the kidney.

Kidney ischemia reperfusion injury (IRI) is a common and inevitable pathological condition in routine urological practices, especially during transplantation. Severe kidney IRI may even induce systemic damage to peripheral organs, and lead to multisystem organ failure. However, no standard clinical treatment option is currently available. It has been reported that kidney IRI is predominantly associated with abnormally increased endogenous reactive oxygen species (ROS). Scavenging excessive ROS may reduce the damage caused by oxidative stress and subsequently alleviate kidney IRI. Here, we reported a simple and efficient one-step synthesis of gold-platinum nanoparticles (AuPt NPs) with a gold core having a loose and branched outer platinum shell with superior ROS scavenging capacity to possibly treat kidney IRI. These AuPt NPs exhibited multiple enzyme-like anti-oxidative properties simultaneously possessing catalase- and peroxidase-like activity. These particles showed excellent cell protective capability, and alleviated kidney IRI both in vitro and in vivo without obvious toxicity, by suppressing cell apoptosis, inflammatory cytokine release, and inflammasome formation. Meanwhile, AuPt NPs also had an effect on inhibiting the transition to chronic kidney disease by reducing kidney fibrosis in the long term. Thus, AuPt NPs might be a good therapeutic agent for kidney IRI management and may be helpful for the development of clinical treatments for kidney IRI.

Tacrolimus variability score outperforms coefficient of variation in predicting clinical outcomes of living kidney transplantation.

AIMS: Intrapatient variability (IPV) was previously defined as coefficient of variation (CV) or standard deviation of tacrolimus (Tac) exposure while none of them was easily being interpreted and translated into clinical practice after kidney transplantation. METHODS: We developed a novel Tac variability score (TVS) to evaluate IPV by calculating the frequency of clinically significant changes of Tac trough levels after kidney transplantation. Multivariate Cox proportional analyses were conducted to compare the impact of TVS and CV on transplant outcomes. RESULTS: A total of 1343 patients were divided into high TVS (>0.30) and low TVS (<0.30) groups, and low CV (<0.30) and high CV (>0.30) groups. Univariate analyses showed that high TVS (hazard ratio [HR]: 2.323, 95% confidence interval [CI]: 1.455-3.709) and high CV (HR: 1.606, 95%CI: 1.044-2.471) were associated with inferior graft survival. However, only TVS was an independent predictor for graft failure in multivariate analyses (HR: 1.972, 95%CI: 1.2-3.24), and the correlation maintained in high CV (P = .020) and low CV (P = .037) subgroups, while CV failed to predict graft loss in neither low (P = .387) nor high TVS (P = .600) subgroups. In addition, TVS had a higher correlation with graft survival in patients with Tac exposure within the therapeutic range and the correlation was less influenced by mean Tac trough levels. CONCLUSION: TVS is a novel measure of Tac IPV with higher correlation with graft survival and more convenience in clinical use than CV after kidney transplantation.

Kidney Transplantation From Hepatitis B Surface Antigen (HBsAg)-Positive Living Donors to HBsAg-Negative Recipients: Clinical Outcomes at a High-Volume Center in China.

BACKGROUND: Data on kidney transplantation (KTx) from hepatitis B surface antigen (HBsAg)-positive (HBsAg+) donors to HBsAg-negative (HBsAg-) recipients [D(HBsAg+)/R(HBsAg-)] are limited. We aimed to report the outcomes of D(HBsAg+)/R(HBsAg-) KTx in recipients with or without hepatitis B surface antibody (HBsAb). METHODS: Eighty-three D(HBsAg+)/R(HBsAg-) living KTx cases were retrospectively identified. The 384 cases of KTx from hepatitis B core antibody-positive (HBcAb+) living donors to HBcAb-negative (HBcAb-) recipients [D(HBcAb+)/R(HBcAb-)] were used as the control group. The primary endpoint was posttransplant HBsAg status change from negative to postive (-- →+). RESULTS: Before KTx, 24 donors (28.9%) in the D(HBsAg+)/R(HBsAg-) group were hepatitis B virus (HBV) DNA positive, and 20 recipients were HBsAb-. All 83 D(HBsAg+)/R(HBsAg-) recipients received HBV prophylaxis, while no D(HBcAb+)/R(HBcAb-) recipients received prophylaxis. After a median follow-up of 36 months (range, 6-106) and 36 months (range, 4-107) for the D(HBsAg+)/R(HBsAg-) and D(HBcAb+)/R(HBcAb-) groups, respectively, 2 of 83 (2.41%) D(HBsAg+)/R(HBsAg-) recipients and 1 of 384 (0.26%) D(HBcAb+)/R(HBcAb-) became HBsAg+, accompanied by HBV DNA-positive (P = .083). The 3 recipients with HBsAg-→+ were exclusively HBsAb-/HBcAb- before KTx. Recipient deaths were more frequent in the D(HBsAg+)/R(HBsAg-) group (6.02% vs 1.04%, P = .011), while liver and graft function, rejection, infection, and graft loss were not significantly different. In univariate analyses, pretransplant HBsAb-/HBcAb- combination in the D(HBsAg+)/R(HBsAg-) recipients carried a significantly higher risk of HBsAg-→+, HBV DNA-→+, and death. CONCLUSIONS: Living D(HBsAg+)/R(HBsAg-) KTx in HBsAb+ recipients provides excellent graft and patient survivals without HBV transmission. HBV transmission risks should be more balanced with respect to benefits of D(HBsAg+)/R(HBsAg-) KTx in HBsAb-/HBcAb- candidates.

Highly individual- and tissue-specific expression of glycoprotein group A and B blood antigens in the human kidney and liver.

BACKGROUND: Currently, research on the quantitative distribution of ABO antigens in different organs and tissues remains limited. We aimed to examine the individual characteristics of blood group glycoprotein A and B antigen expression in human kidneys and livers. METHODS: We obtained human samples, including the renal artery, renal vein, renal tissue, hepatic artery, hepatic vein, portal vein, and hepatic tissue, from 24 deceased organ transplant donors. The expression of the blood group antigens glycoprotein A and B was analysed and compared by Western blotting. RESULTS: There was no significant difference in the expression between blood group glycoprotein A and B antigens at any of the seven sites (p > 0.05). The expression of both A and B antigens was highest in renal tissue and the portal vein and was lowest in the renal artery. A large difference in glycoprotein antigen expression was observed among various donors or different regions of the same individual. Univariate analysis revealed that glycoprotein A/B antigens were affected by the age and sex of donors and were significantly higher in males and in young people. CONCLUSIONS: Our study found that blood group glycoprotein antigen expression showed certain trends and distinct distribution in the kidney, liver, and vessels among individuals and in different regions of the same individual, which may explain the different clinical outcomes of patients who received ABO-incompatible transplantation.

Early Monitoring and Subsequent Gain of Tacrolimus Time-In-Therapeutic Range May Improve Clinical Outcomes After Living Kidney Transplantation.

BACKGROUND: The early identification of recipients at high risk of graft loss is clinically relevant after kidney transplantation. The authors explored whether the earlier monitoring of tacrolimus (Tac) time-in-therapeutic range (TTR) is predictive of and a subsequent gain in TTR improves transplant outcomes. METHODS: The TTR within 3, 6, 9, and 12 months was evaluated. Multivariate Cox analyses were performed to explore when TTR was predictive of transplant outcomes. Patients were divided into 3 groups based on incremental TTR change [TTR gain (increase >10%), TTR stable (maintained within 10%), and TTR loss (decrease >10%)] and 4 groups based on predefined cutoff values [low-low (LL), low-high (LH), high-low (HL), and high-high (HH)] using 6- and 12-month TTRs. Death-censored graft loss and patient death were primary outcomes. RESULTS: Nonlinear associations were observed between 6-, 9-, and 12-month TTR and death-censored graft and patient survival rates. In multivariate analysis, every 10% increase in 6-, 9-, and 12-month TTRs was associated with reduced patient death [hazard ratio (HR): 0.83; HR: 0.68; HR: 0.61, respectively] and graft loss (HR: 0.88; HR: 0.73; HR: 0.66, respectively). A nonlinear relationship was observed between transplant outcomes and incremental changes in TTR. TTR gain and stable TTR contributed to higher graft survival (HR: 0.20; HR: 0.21) and patient survival (HR: 0.14; HR: 0.15) rates than TTR loss, whereas the former 2 had comparable outcomes. Furthermore, compared with those in the HH group, the LL and HL groups had inferior graft survival (HR: 3.33; HR: 5.17) and patient survival (HR: 5.15; HR: 8.94) rates, whereas the LH group had similar outcomes (P = 0.63, P = 0.97). Nonadherence was the main controllable risk factor for low TTR. CONCLUSIONS: The 6-month TTR identified patients at higher risk of worse outcomes. The subsequent gain of TTR may contribute to better transplant outcomes.

Pre-transplant donor HBV DNA+ and male recipient are independent risk factors for treatment failure in HBsAg+ donors to HBsAg- kidney transplant recipients.

BACKGROUND: In order to reduce the burden on organ shortage around the world, using potential infectious donor might be an option. However, scarce evidences have been published on kidney transplantation (KTx) from hepatitis B surface antigen (HBsAg) + donors to HBsAg- recipients [D (HBsAg+)/R(HBsAg-)] without hepatitis B virus (HBV) immunity. Here, we reported the results of D(HBsAg+/HBV DNA- or +)/R(HBsAg-) living KTx recipients with or without HBV immunity. METHODS: We retrospectively identified 83 D(HBsAg+)/R(HBsAg-) living KTx recipients, and 83 hepatitis B core antibody (HBcAb) + living donors to HBcAb- recipients [D(HBcAb+)/R(HBcAb-)] were used as control group by reviewing medical archives and propensity score matching. Treatment failure (defined as any HBV serology conversion, liver injury, graft loss, or recipient death) is the primary endpoint. RESULTS: Twenty-four donors (28.9%) were HBV DNA+, and 20 recipients had no HBV immunity in the D(HBsAg+)/R(HBsAg-) group pre-transplantation. HBV prophylaxis was applied in all D(HBsAg+)/R(HBsAg-) recipients, while none was applied in the D(HBcAb+)/R(HBcAb-) group. We observed a significant higher treatment failure in D(HBsAg+)/R(HBsAg-) than D(HBcAb+)/R(HBcAb-) group (21.7% vs. 10.8%, P < 0.001). Interestingly, no significant difference was found between groups on HBV seroconversion, liver and graft function, rejection, infection, graft loss, or death. However, 2/20 recipients without HBV immunity in the D(HBsAg+)/R(HBsAg-) group developed HBV DNA+ or HBsAg+, while none observed in the D(HBcAb+)/R(HBcAb-) group. HBV DNA+ donor and male recipient were significant risk factors for treatment failure. CONCLUSION: D(HBsAg+)/R(HBsAg-) should be considered for living kidney transplantation, but with extra caution on donors with HBV DNA+ and male candidates.

A recombinant vaccine of Riemerella anatipestifer OmpA fused with duck IgY Fc and Schisandra chinensis polysaccharide adjuvant enhance protective immune response.

Riemerella anatipestifer (R. anatipestifer) causes septicemia and infectious serositis in domestic ducks, leading to high mortality and great economic losses worldwide. Vaccination is currently considered the best strategy to prevent R. anatipestifer infection in ducklings. In this study, we fused the duck IgY Fc gene to the outer membrane protein A (ompA) of R. anatipestifer. The eukaryotic expression plasmid carrying the fusion gene was transformed into Pichia pastoris (P. pastoris) to express the recombinant ompA and ompA-Fc proteins. Then, the effects of fused Fc on the vitality and antigen processing efficiency of duck peritoneal macrophages (PMø) were evaluated in vitro, whereas their immunogenicity was evaluated in vivo. Furthermore, Schisandra chinensis polysaccharide (SCP) was used to evaluate its immune-conditioning effects on the activation of PMø. SCP was also used as adjuvant to investigate immunomodulation on immunoresponses induced by the fused ompA-Fc in ducklings. The conventional Freund's incomplete adjuvant served as the control of SCP. Notably, ompA-Fc promoted phagocytosis of PMø and significantly increased serum antibody titers, CD4+ and CD8+ T-lymphocyte counts, lymphocyte transformation rate, and serum levels of IL-2 and IL-4. In addition, ducklings injected with the ompA-Fc vaccine exhibited considerably greater resistance to the R. anatipestifer challenge than those that received vaccines based on standalone ompA. Of note, SCP was demonstrated to boost the secretion of nitric oxide (NO), IL-1ß, IL-6, TNF-α, and IFN-ß by duck macrophages. In addition, the supplementation of SCP adjuvant to the ompA-Fc vaccines led to the further enhancement of immune response and vaccine protection. The dose of 200 µg/mL showed the most pronounced effects. This study provided valuable insights into protective strategies against R. anatipestifer infection.

Single kidney transplantation from donors with acute kidney injury: A single-center experience.

INTRODUCTION: Despite a severe shortage of organ supply, patients are reluctant to accept organs from deceased donors with AKI, let alone from pediatric AKI donors. METHODS: We assessed 70 patients who received kidneys from donors with AKI (10 with pediatric and 60 with adult donors) and 176 contemporaneous patients who received kidneys from non-AKI donors (41 with pediatric and 135 with adult donors) between March 2012 and February 2017 for retrospectively evaluating the clinical outcomes. RESULTS: AKI was defined and staging by the RIFLE criteria and pediatric-modified RIFLE criteria. Median age was 11.00 years IQR (4.50-14.00 years), and median weight was 25.00 kg (IQR, 17.00-45.00 kg) for all pediatric donors. Median follow-up was 8 months (range, 1-49 months). Adult AKI group had the highest incidence of DGF (35.0% vs 10%, 9.8%, and 19.3%, P = 0.011). There was a significant increase in DGF in higher AKI stages (Risk: 20.7%, Injury: 46.7%, Failure: 50.0%; P = 0.014) among patients with adult donors. No significant differences were noted in 1-year (100.0%, 95.1%, 98.3%, and 97.8%; P = 0.751) and 3-year (100.0%, 95.1%, 98.3%, and 97.8%; P = 0.751) patient survival, and 1-year (90.0%, 97.6%, 98.3%, and 95.6%; P = 0.535) and 3-year (90.0%, 97.6%, 98.3%, and 95.6%; P = 0.535) graft survival. CONCLUSION: Transplants procured from donors with AKI, particularly pediatric ones, could achieve excellent intermediate-term clinical outcomes and thus potentially expand the donor pool.

Taishan Pinus massoniana Pollen Polysaccharides Enhance Immune Responses in Chickens Infected by Avian Leukosis Virus Subgroup B.

Immunosuppressive virus, which can cause suppressed immunity and vaccination failure, frequently occurs in chicken flocks and seriously destroys the poultry industry. Our previous studies have reported that Taishan Pinus massoniana pollen polysaccharide (TPPPS) possess immunomodulatory effects and improve the immune effects of vaccines. In this study, avian leukosis virus subgroup B (ALV-B) was chosen as immunosuppressive virus to artificially establish immunosuppressive models in chickens, and the immune modulatory ability of TPPPS on the immune response of chickens was evaluated. Four randomly assigned groups (Group I-IV) of these immunosuppressed chickens were administered with TPPPS at doses of 0, 100, 200, and 400 mg/kg (every kilogram chick), respectively. Group V was administered with saline as control. At seven day old, 10 chickens randomly selected from Group I-V were inoculated with the attenuated Newcastle disease (ND) vaccine. The results showed that during the monitoring period, TPPPS significantly enhanced weight of immune organs, peripheral lymphocyte proliferation, the percentage of CD4+ and the ratio of CD4+/CD8+, IL-2 and IFN-γ production, and ALV-B antibody positive rate of chickens in a dose-dependent manner, with 400 mg/kg TPPPS being the most effective. In addition, the antibody titer against Newcastle disease virus (NDV) in Group IV with 400 mg/kg was significantly higher than those in other groups. We observed the stronger immunity in the TPPPS group, which indicates that TPPPS could be used as an immunoenhancer to relieve immunosuppression caused by ALV-B in the poultry industry.

Outcomes of single kidney transplantation from pediatric donors: A single-center experience.

Kidneys from pDDs are increasingly used to narrow the huge gap between incremental demand and static supply. However, there is still controversy on the clinical outcome of SKT from pDDs. We conducted a retrospective cohort study of 452 adult recipients in our center between March 2012 and February 2017. Outcomes of 3 groups, transplants with organs from pDDs (n=50), aDDs (n=207), and LDs (n=195), were compared. The mean age and weight of pDDs were 8.98 years (range 8 months-17 years) and 30.05 kg (range 8.2-55 kg), respectively. There was no difference in 1-year (96.0%, 98.1%, and 99.0%, respectively, P=.277) and 3-year patient survival (96.0%, 98.1%, and 99.0%, respectively, P=.277) or in 1-year (96.0%, 96.6%, and 98.5%, P=.307) and 3-year (96.0%, 96.6% and 97.9%, P=.437) graft survival. SCr, eGFR, and allograft size were similar among the 3 groups at 6th month post-transplant and thereafter. Incidence of DGF was higher in patients of the aDD group than those in the pDD group (22.7% vs 10.0%, P<.001), but there was no difference in AR and infection. SKT from pDDs to adult recipients is effective and safe with acceptable outcomes, and it will be a promising expansion to the donor pool.

Pharmacokinetics and tissue distribution of pefloxacin mesylate in chickens.

A specific, sensitive and stable high-performance liquid chromatography (HPLC)-based analytical method was established to determine the level of pefloxacin mesylate (PM) in the plasma and various tissues of chickens. Chickens were randomly assigned to 12 equal experiment groups, including 11 treatment groups and one control group. The chickens in the treatment groups received oral administration of PM and were sacrificed at different pre-determined time points, with their blood and various organs harvested, extracted and analyzed by HPLC to quantify the level of the residual antibiotic. Method validation studies indicated that the HPLC measurement showed excellent precision, reproducibility, stability and robustness. The obtained pharmacokinetic parameters suggested that PM reached peak levels in various tissues within 1-2 h after its oral administration, and was mainly concentrated in liver and kidney. The antibiotic was also found to be cleared from chicken crureus, brain, testes, ovaries and pancreas at higher rates compared with other organs. Overall, the rapid accumulation of PM could at least be partially attributed to its relatively slow organ clearance. These results could serve as a useful guidance for the rational use of PM and other quinolone-derived antimicrobials in the treatment of infectious diseases in chickens and other animals.

The Taishan Robinia pseudoacacia polysaccharides enhance immune effects of rabbit haemorrhagic disease virus inactivated vaccines.

Robinia pseudoacacia flower, a common component in traditional Chinese medicine, has long been well-known for its high pharmaceutical value. This study aimed to assess the immunopotentiating effects of Taishan Robinia Pseudoacacia polysaccharides (TRPPS) in rabbits inoculated with a rabbit haemorrhagic disease virus (RHDV) inactivated vaccine. The rabbits were administered with the RHDV vaccine in conjunction with varying concentrations of TRPPS, and their blood samples were collected at different time points to analyze the ratio and number of blood lymphocytes. In addition, sera were prepared and analyzed to determine the overall antibody titer and the level of IL-2, a cytokine commonly used as an indicator of immune activity. The various TRPPS-supplemented vaccines were shown to be more effective in enhancing the immune functions of the inoculated rabbits compared to their polysaccharide-free counterpart, with 200 mg/mL of TRPPS exhibiting the most pronounced benefits that were comparable to those of propolis. In addition, the TRPPS-supplemented RHDV inactivated vaccines could significantly improve the survival rates of the immunized rabbits against RHDV infection. Our studies offered convincing experimental evidence for the development of TRPPS as a new type of plant-derived immunopotentiator.

[Learning Curve of Retroperitoneal Laparoscopic Donor Nephrectomy and Risk Analysis of Intraoperative Complications].

OBJECTIVES: To investigate the learning curve of retroperitoneal laparoscopic donor nephrectomy (LDN) and evaluate the risk factors of intraoperative complications with data from a single center. METHODS: We evaluated perioperative data of 527 consecutive kidney donors who received retroperitoneal LDN between April 2009 and April 2014. The patients were divided into two groups according to the learning curve which was determined by the operation time:group 1 (on the learning curve) and group 2 (learning curve completed). RESULTS: The mean operation time was (88.4±38.07) min. The asymptote of the surgeon's learning curve for retroperitoneal LDN was achieved at the 100th case. The operation time and the incidence of intraoperative complications in group 1 were significantly higher than those of group 2. When cases completed, body mass index (BMI) and intraoperative complications were correlated to operative time. The incidence of intraoperative complications was 1.90% and BMI was correlated to the incidence of intraoperative complications. When the learning curve was completed, renal artery numbers and right kidney were found being correlated to operative time. CONCLUSIONS: Retroperitoneal LDN is a safe and effective operation method with a low incidence of complications. Technical proficiency in retroperitoneal LDN could be achieved after 100 surgeries.

The pre-transplant anemic condition is independent of long-term outcome in living-related kidney transplantation.

The relationship between pre-transplant Hemoglobin (Hb) concentration and long-term outcome of living-related kidney transplantation is far from well addressed. A retrospective cohort study was conducted by reviewing the medical profile of the patients who received living-related kidney transplantations at our center from January 2006 to January 2013. Patients were divided into two groups: high Hb group (≥10 g/dL) and low Hb group (<10 g/dL). Cox regression model was utilized to analyze the effect of pre-transplant hemoglobin concentration on the patient and graft survival. About 422 patients were of Hb level <10 g/dL (78.30 ± 14.18 g/dL), 280 were >10 g/dL (116.2 ± 14.43 g/dL) (p < 0.001). In a follow-up of 35.34 ± 18.12 months, we did not find any difference in serum creatinine between the two groups. Low Hb concentration is not associated with increased risk of developing DGF (HR = 1.186, 95% CI: 0.53-2.654), acute rejection (HR = 1.338, 95% CI: 0.919-1.947), overall infection (HR = 1.263, 95% CI: 0.847-1.885) nor perioperational infection (HR = 1.019, 95% CI: 0.513-2.026). Though we detected a trend that low Hb level group were of higher incidence of patient death and graft failure, the two groups did not differ significantly (2.38% vs. 0.71%, p = 0.096; and 4.04% vs. 2.14%, p = 0.165, respectively). Cox regression model revealed that pre-transplant Hb level <10 g/dL was independent of increased overall mortality (HR = 3.379; 95% CI: 0.706-17.172) and increased death censored allograft failure risk (HR = 1.556; 95% CI: 0.595-4.069). Pre-transplant Hb concentration <10 g/dL is independent of poor long-term outcome of living-related kidney transplantation.

The Etiology and Pathogenesis of Benign Prostatic Hyperplasia: The Roles of Sex Hormones and Anatomy.

Benign prostatic hyperplasia (BPH) mainly causes lower urinary tract symptoms in ageing men, but its exact etiology and pathogenesis have not been established. The objective of this review was to design an update on the advances of human BPH research. We undertook a literature search for identifying studies of the roles of sex hormones (androgens and estrogens) in the onset and development of human BPH using the Pubmed database. In literature, many studies have indicated that ageing and obesity are the factors for preceding the onset of BPH. No evidence for the role of testosterone (T) or dihydrotestosterone (DHT) is found in BPH initiation. Since BPH exclusively occurs in the transitional zone (TZ) surrounding the urethra, it is postulated that years of exposure to uncharacterized urinary toxins could disrupt the homeostasis of the stroma and/or epithelium of this prostatic zone that are typically occurring in ageing men. After cellular damage and subsequent inflammation generated, the intraprostatic DHT produced mainly from T by 5α-reductase promotes BPH development. Further, estrogens could take part in the nodular proliferation of stromal cells in some BPH patients. The confounding of BPH may attenuate the development of prostate tumor in the TZ. In conclusion, evidence in literature suggests that androgens are not etiological factors for BPH, and intraprostatic DHT along with chronic inflammation are mainly responsible for nodular proliferation of stromal and/or epithelial cells in prostatic TZ. The urinary factors for the etiology of BPH and BPH as a prediction of PCa progression still need further investigation.

A genetic study to identify pathogenic mechanisms and drug targets for benign prostatic hyperplasia: a multi-omics Mendelian randomization study.

Benign prostatic hyperplasia (BPH) as a common geriatric disease in urology, the incidence and prevalence are rapidly increasing with the aging society, prompting an urgent need for effective prevention and treatment of BPH. However, limited therapeutic efficacy and higher risk of complications result in the treatment of BPH remaining challenging. The unclear pathogenic mechanism also hampers further exploration of therapeutic approaches for BPH. In this study, we used multi-omics methods to integrate genomics, transcriptomics, immunomics, and metabolomics data and identify biomolecules associated with BPH. We performed transcriptomic imputation, summary data-based Mendelian randomization (SMR), joint/conditional analysis, colocalization analysis, and FOCUS to explore high-confidence genes associated with BPH in blood and prostate tissue. Subsequently, three-step SMR was used to identify the DNA methylation sites regulating high-confidence genes to improve the pathogenic pathways of BPH. We also used cis-instruments of druggable genes to conduct SMR analysis to find potential drug targets for BPH. Finally, we used MR analysis to explore the immune pathways and metabolomics related to BPH. Multiple analytical methods identified BTN3A2 (Blood: TWAS Z score = 5.02912, TWAS P = 4.93 × 10-7; Prostate: TWAS Z score = 4.89, TWAS P = 1.01 × 10-6) and C4A (Blood: TWAS Z score = 4.90754, TWAS P = 9.22 × 10-7; Prostate: TWAS Z score = 5.084, TWAS P = 3.70 × 10-7) as high-confidence genes for BPH and identified the cg14345882-BTN3A2-BPH pathogenic pathway. We also used druggable gene data to identify 30 promising therapeutic target genes, including BTN3A2 and C4A. For MR analysis of immune pathways, we identified immune cell surface molecules as well as the inflammatory factor IL-17 (OR = 1.25, 95% CI = 1.09-1.43, PFDR = 0.12, Maximum likelihood) as risk factors for BPH. In addition, we found that disulfide levels of cysteinylglycine (OR = 1.11, 95% CI = 1.05-1.18, P = 5.18 × 10-4, Weighted median), oxidation levels of cysteinylglycine (OR = 1.09, 95% CI = 1.04-1.14, P = 3.87 × 10-4, Weighted median), and sebacate levels (OR = 1.05, 95% CI = 1.02-1.08, P = 3.0 × 10-4, Maximum likelihood) increase the risk of BPH. This multi-omics study explored biomolecules associated with BPH, improved the pathogenic pathways of BPH, and identified promising therapeutic targets. Our results provide evidence for future studies aimed at developing appropriate therapeutic interventions.

Comparison of gut microbiota immunity and pathology in specific-pathogen-free chickens with glandular and muscular gastritis using different methods.

The objective of this study is to review different methods to screen for the optimal model for preventing and treating chicken glandular and muscular gastritis syndrome. Twenty-four 40-day-old specific pathogen-free (SPF) chickens were randomly allocated into four groups (N = 6): polyethylene glycol + ammonium chloride group (M1 group), acetic acid + rhubarb group (M2 group), polyethylene glycol + rhubarb group (M3 group), and control group. The control group had free access to water, while the remaining groups received different doses of molding reagents added to their drinking water. The animal models were assessed based on clinical manifestations, histopathology findings, serological analysis, and composition of intestinal microbiota to establish an optimal approach for constructing an avian model of glandular and muscular gastritis. The SPF chickens in each model group exhibited typical symptoms of glandular and muscular gastritis, poor spirit, yellow loose stools with undigested feed, and enlargement and ulceration of the glandular and muscular stomach. Among these groups, the M3 group had the highest incidence rate of 100%. Compared to the control group, the body weight and body temperature of the chicken in the three model groups were reduced, and the glandular and muscular stomachs and duodenum showed different degrees of bleeding, mucosal abscission, and other pathological injuries. Additionally, the levels of serum IL-2 and α-amylase activity decreased while the content of IL-4 increased. After conducting 16s rDNA sequencing, it was observed that the abundance of Bacteroides, Faecalibacterium, and Ruminococcaceae UCG-014 was significantly increased in the model group compared to the control group. Conversely, there was a notable decrease in the levels of Megamonas and Lactobacillus, which are speculated to be associated with arachidonic acid metabolism, the NF-κB signaling pathway, and TNF signaling pathways. The combination of polyethylene glycol and rhubarb emerged as the most effective method for establishing the glandular and muscular gastritis model in SPF chickens. This constructed chicken model displayed distinct signs of damage to the glandular and muscular stomach, inflammatory response, and disturbance in the intestinal flora, thereby providing a foundation for future research on the prevention and treatment of this syndrome.

Novel pyridinium cationic pleuromutilin analogues overcoming bacterial multidrug resistance.

A series of pyridinium cation-substituted pleuromutilin analogues were designed, synthesized and evaluated for their antibacterial activities in vitro and in vivo. Most derivatives showed potent antibacterial activities, especially e4 that displayed the highest antibacterial activity against multi-drug resistant bacteria and was subjected to time-kill kinetics, resistance studies, cytotoxicity and molecular docking assays. Molecular docking results, scanning electron microscopy and o-nitrophenyl-ß-galactopyranoside tests showed that e4 not only inhibited bacterial protein synthesis but also disrupted bacterial cell walls. Compound e4 showed an ED50 of 5.68 mg/kg against multi-drug resistant Staphylococcus aureus in infected mice model. In in vivo and in vitro toxicity tests, e4 showed low toxic effects with an LD50 of 879 mg/kg to mice. These results suggest that compound e4 may be considered as a new therapeutic candidate for bacterial infections.