CIRP attenuates acute kidney injury after hypothermic cardiovascular surgery by inhibiting PHD3/HIF-1α-mediated ROS-TGF-ß1/p38 MAPK activation and mitochondrial apoptotic pathways.

BACKGROUND: The ischemia-reperfusion (IR) environment during deep hypothermic circulatory arrest (DHCA) cardiovascular surgery is a major cause of acute kidney injury (AKI), which lacks preventive measure and treatment. It was reported that cold inducible RNA-binding protein (CIRP) can be induced under hypoxic and hypothermic stress and may have a protective effect on multiple organs. The purpose of this study was to investigate whether CIRP could exert renoprotective effect during hypothermic IR and the potential mechanisms. METHODS: Utilizing RNA-sequencing, we compared the differences in gene expression between Cirp knockout rats and wild-type rats after DHCA and screened the possible mechanisms. Then, we established the hypothermic oxygen-glucose deprivation (OGD) model using HK-2 cells transfected with siRNA to verify the downstream pathways and explore potential pharmacological approach. The effects of CIRP and enarodustat (JTZ-951) on renal IR injury (IRI) were investigated in vivo and in vitro using multiple levels of pathological and molecular biological experiments. RESULTS: We discovered that Cirp knockout significantly upregulated rat Phd3 expression, which is the key regulator of HIF-1α, thereby inhibiting HIF-1α after DHCA. In addition, deletion of Cirp in rat model promoted apoptosis and aggravated renal injury by reactive oxygen species (ROS) accumulation and significant activation of the TGF-ß1/p38 MAPK inflammatory pathway. Then, based on the HK-2 cell model of hypothermic OGD, we found that CIRP silencing significantly stimulated the expression of the TGF-ß1/p38 MAPK inflammatory pathway by activating the PHD3/HIF-1α axis, and induced more severe apoptosis through the mitochondrial cytochrome c-Apaf-1-caspase 9 and FADD-caspase 8 death receptor pathways compared with untransfected cells. However, silencing PHD3 remarkably activated the expression of HIF-1α and alleviated the apoptosis of HK-2 cells in hypothermic OGD. On this basis, by pretreating HK-2 and rats with enarodustat, a novel HIF-1α stabilizer, we found that enarodustat significantly mitigated renal cellular apoptosis under hypothermic IR and reversed the aggravated IRI induced by CIRP defect, both in vitro and in vivo. CONCLUSION: Our findings indicated that CIRP may confer renoprotection against hypothermic IRI by suppressing PHD3/HIF-1α-mediated apoptosis. PHD3 inhibitors and HIF-1α stabilizers may have clinical value in renal IRI.

A Monocyte-Orchestrated IFN-I-to-IL-4 Cytokine Axis Instigates Protumoral Macrophages and Thwarts Poly(I:C) Therapy.

Type I IFNs (IFN-I) are important for tumor immune surveillance and contribute to the therapeutic responses for numerous treatment regimens. Nevertheless, certain protumoral activities by IFN-I have been increasingly recognized. Indeed, our recent work showed that systemic poly(I:C)/IFN treatment can undesirably trigger high arginase (ARG1) expression within the tumor-associated monocyte/macrophage compartment. Using a line of CRISPR-generated Arg1-YFP reporter knock-in mice, we have determined that a subset of tumor-associated macrophages represent the major Arg1-expressing cell type following poly(I:C)/IFN stimulation. More detailed analyses from in vitro and in vivo models demonstrate a surprising IFN-to-IL-4 cytokine axis in transitional monocytes, which can subsequently stimulate IL-4 target genes, including Arg1, in macrophages. Intriguingly, IFN stimulation of transitional monocytes yielded concurrent M2 (YFP+)- and M1 (YFP-)-skewed macrophage subsets, correlated with an inhibitory crosstalk between IFN-I and IL-4. Genetic abrogation of IL-4 signaling in mice diminished poly(I:C)/IFN-induced ARG1 in tumors, leading to enhanced activation of CD8+ T cells and an improved therapeutic effect. The present work uncovered a monocyte-orchestrated macrophage phenotype conversion mechanism that may have broad implications.

Signal transducer and transcriptional activation 1 protects against pressure overload-induced cardiac hypertrophy.

Signal transducers and transcriptional activation 1 (Stat1) is a member of the STATs family, and its role in various biological responses, including cell proliferation, differentiation, migration, apoptosis, and immune regulation has been extensively studied. We aimed to investigate its role in pathological cardiac hypertrophy, which is currently poorly understood. Experiments using H9C2 cardiomyocytes, Stat1, and IfngR cardiomyocyte-specific knockout mice revealed that Stat1 had a protective effect on cardiac hypertrophy. Using transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice, we analyzed the degree of hypertrophy using echocardiography, pathology, and at the molecular level. Mice lacking Stat1 had more pronounced cardiac hypertrophy and fibrosis than wild-type TAC mice. Analysis of the molecular mechanisms suggested that Stat1 downregulated the mRNA levels of hypertrophy and fibrosis markers to inhibit cardiac hypertrophy, and promotes mitochondrial fission through the Ucp2/P-Drp1 pathway, enhancing mitochondrial function, and increasing compensatory myocardial ATP production in the compensatory phase for cardiac hypertrophy inhibition. Overall, this comprehensive analysis revealed that Stat1 inhibits cardiac hypertrophy by downregulating hypertrophic and fibrotic marker genes and enhancing the mitochondrial function to enhance cardiomyocyte function through the Ucp2/P-Drp1 signaling pathway.

The lower threshold of hypothermic oxygen delivery to prevent neonatal acute kidney injury.

BACKGROUND: Oxygen delivery during cardiopulmonary bypass (CPB) is closely related to postoperative acute kidney injury (AKI). The value of critical indexed oxygen delivery (DO2i) is a key indicator to reflect oxygen supply in cardiovascular surgery. However, the target DO2i value for neonates undergoing hypothermic CPB remains unclear. METHODS: One hundred and twenty-six consecutive newborns (≤28 days) undergoing arterial switch operations were retrospectively divided into two groups according to AKI occurrence. Baseline characteristics, intraoperative variables, and clinical outcomes were collected. Multivariate logistic regression analysis and receiver-operating characteristic curve were performed to investigate the association between DO2i and AKI. RESULTS: Neonates in the no-AKI group (n = 67) had significantly higher nadir bypass flow and DO2i during the hypothermic phase compared with the AKI group (n = 59). AKI group had remarkably higher incidences of hepatic dysfunction and peritoneal dialysis requirement compared with newborns without AKI. Mixed venous oxygen saturation (SvO2) was comparable between the two groups. Base excess (BE)(P = 0.011) value during the hypothermic phase of the AKI group was higher than the no-AKI group. Multivariate analysis showed that hypothermic DO2i was negatively associated with AKI. The cut-off value of hypothermic DO2i was 269 mL min-1 m-2. CONCLUSIONS: The importance of hypothermic DO2i should be highlighted, even when SvO2 was satisfactory. A lower threshold of DO2i > 269 mL min-1 m-2 may help protect neonates from the risk of postoperative AKI. IMPACT: The key message of our article is that the lower threshold of DO2i > 269 mL min-1 m-2 may help protect neonates from the risk of AKI after on-pump hypothermic cardiovascular surgery. The critical DO2i value for neonates undergoing hypothermic CPB remains unclear, and our study may add new evidence for this matter based on the 6-year experience of our center. In this study, the lowest critical value of DO2i in neonatal hypothermic CPB is determined for the first time, which provides a reference for intra-CPB management strategy to improve the postoperative outcomes of newborns.

Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats.

BACKGROUND: Sevoflurane (SEVO) increases neuronal excitation in neonatal rodent brains through alteration of gamma aminobutyric acid (GABA)(A) receptor signaling and increases corticosterone release. These actions may contribute to mechanisms that initiate the anesthetic's long-term neuroendocrine and neurobehavioral effects. Dexmedetomidine (DEX), a non-GABAergic α2-adrenergic receptor agonist, is likely to counteract SEVO-induced neuronal excitation. We investigated how DEX pretreatment may alter the neurodevelopmental effects induced by SEVO in neonatal rats. METHODS: Postnatal day (P) 5 Sprague-Dawley male rats received DEX (25 µg/kg, intraperitoneal) or vehicle before exposure to 2.1% SEVO for 6 hours (the DEX + SEVO and SEVO groups, respectively). Rats in the DEX-only group received DEX without exposure to SEVO. A subcohort of P5 rats was used for electroencephalographic and serum corticosterone measurements. The remaining rats were sequentially evaluated in the elevated plus maze on P80, prepulse inhibition of the acoustic startle response on P90, Morris water maze (MWM) starting on P100, and for corticosterone responses to physical restraint for 30 minutes on P120, followed by assessment of epigenomic DNA methylation patterns in the hippocampus. RESULTS: Acutely, DEX depressed SEVO-induced electroencephalogram-detectable seizure-like activity (mean ± SEM, SEVO versus DEX + SEVO, 33.1 ± 5.3 vs 3.9 ± 5.3 seconds, P < .001), but it exacerbated corticosterone release (SEVO versus DEX + SEVO, 169.935 ± 20.995 versus 280.853 ± 40.963 ng/mL, P = .043). DEX diminished, but did not fully abolish, SEVO-induced corticosterone responses to restraint (control: 11625.230 ± 877.513, SEVO: 19363.555 ± 751.325, DEX + SEVO: 15012.216 ± 901.706, DEX-only: 12497.051 ± 999.816; F[3,31] = 16.878, P < .001) and behavioral deficiencies (time spent in the target quadrant of the MWM: control: 31.283% ± 1.722%, SEVO: 21.888% ± 2.187%, DEX + SEVO: 28.617% ± 1.501%, DEX-only: 31.339% ± 3.087%; F[3,67] = 3.944, P = .012) in adulthood. Of the 391 differentially methylated genes in the SEVO group, 303 genes in the DEX + SEVO group had DNA methylation patterns that were not different from those in the control group (ie, they were normal). DEX alone did not cause acute or long-term functional abnormalities. CONCLUSIONS: This study suggests that the ability of DEX to depress SEVO-induced neuronal excitation, despite increasing corticosterone release, is sufficient to weaken mechanisms leading to long-term neuroendocrine/neurobehavioral abnormalities. DEX may prevent changes in DNA methylation in the majority of genes affected by SEVO, epigenetic modifications that could predict abnormalities in a wide range of functions.

Investigation of myocardial protection during pediatric CPB: Practical experience in 100 Chinese hospitals.

Many measures have been proposed for myocardial protection in pediatric congenital heart surgeries, but little data is available for China. This study investigates myocardial protection strategies in pediatric cardiopulmonary bypass (CPB) throughout China. Online questionnaires were delivered to 100 hospitals in 27 provinces. The number of yearly on-pump pediatric cardiovascular surgeries in these hospitals varied greatly. About 91.0% of respondents believe that each surgery should have at least two perfusionists, while only 64.0% of hospitals actually met this requirement. For pediatric patients, crystalloid cardioplegia was more prevalent than blood-based cardioplegia. Histidine-tryptophan-ketoglutarate solution and St. Thomas crystalloid solution were dominant among crystalloid cardioplegia. Del Nido cardioplegia and St. Thomas blood-based cardioplegia ranked the top two in the popularity of blood-based cardioplegia. Dosages varied among different kinds of cardioplegia. In the choice of different cardioplegia, perfusionists mainly focused on myocardial protective effect and cost. Hypothermia of cardioplegia solution was maintained by ice buckets in 3/4 of the hospitals in this survey. In conclusion, the essence of myocardial protection management during pediatric CPB was cardiac arrest induced by cardioplegia under systemic hypothermia. However, there is no uniform standard for the type of cardioplegia, or dosages. Therefore, well-designed multicenter randomized controlled trials are warranted to provide tangible evidence for myocardial protection of cardioplegia in pediatric CPB.

Contrast media exposure in the perioperative period confers no additional risk of acute kidney injury in infants and young children undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Recently, there has been an interest in the temporal relationship between contrast exposure (CM) and cardiac surgery suggesting that a "double hit" on the kidney function in close succession increases the risk of acute kidney injury (AKI) after cardiac surgery. However, data from young children is limited. The purpose of this study was to retrospectively evaluate the effects of preoperative CM exposure on postoperative AKI in infant and young children patients and to further analyze the influence of exposure time interval. METHODS: Patients (age ≤ 3 years) who underwent diagnostic imaging within 14 days before on-pump cardiac surgery between 1 May 2017 and 31 May 2018 in Fuwai Hospital, Beijing, were analyzed. Kidney outcome was assessed according to Kidney Disease: Improving Global Outcomes creatinine-based criteria. RESULTS: One thousand four hundred pediatric patients (192 CM and 1,248 non-CM) were identified. Postoperative AKI occurred in 57 (29.7%) of the 192 patients who were exposed to CM. Following propensity score adjustment, no difference in risk for AKI was observed between the CM and non-CM groups (RR 1.142, 95% CI 0.916-1.424; P = 0.264). Multivariable logistic regression of the CM group indicated that independent predictors of postoperative AKI were lower weight, lower preoperative creatinine level, and longer CPB duration. Time interval between CM exposure and on-pump cardiac surgery was not significantly associated with increased risk of AKI (OR 0.853, 95% CI 0.265~2.747; P = 0.790). CONCLUSIONS: For pediatric patients who are soon to undergo on-pump cardiac procedures, there appears to be no need to hesitate in performing the diagnostic imaging investigations requiring CM, or delay CPB after CM exposure. These patients may benefit from increased diagnostic utility without increasing their risk of postoperative AKI.

Outcomes and factors associated with early mortality in pediatric postcardiotomy veno-arterial extracorporeal membrane oxygenation.

Mortality and morbidity of children received veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support after cardiac surgery remain high despite remarkable advances in medical management and devices. The purpose of this study was to describe outcomes and risk factors of applying VA-ECMO in the surgical pediatric population. We retrospectively analyzed 85 consecutive pediatric patients (aged <18 years) who received postcardiotomy VA-ECMO from January 2010 to December 2018. Median (IQR) age at ECMO implantation in this cohort was 12.7 (6.4, 43.2) months, median weight was 8.5 (6.0, 12.8) kg, mean ECMO duration was 143.2 ± 81.6 hours and mean hospital length of stay was 48.4 ± 32.4 days. Seventy-five patients (88.2%) were indicated for postcardiotomy cardiogenic shock. The successful ECMO weaning rate was 70.6% and in-hospital mortality was 52.9%. The most common diagnosis was transposition of great arteries (n = 18, 21.2%), while acute kidney injury occurred most often (n = 64, 75.3%). Multivariate logistic regression analysis showed that thrombocytopenia, hemolysis, and nosocomial infection were positively correlated with in-hospital mortality. Multivariate Cox proportional hazard regression analysis presented that thrombocytopenia significantly increased the 180-day mortality in patients with successful weaning. Therefore, multiple factors had adverse effects on prognosis. Patient selection and procedures from ECMO implantation to weaning need to be closely monitored and performed in a timely manner to improve outcome.

Perioperative blood product transfusion of two different perfusion strategies on pediatric patients undergoing aortic arch surgery.

Simple regional cerebral perfusion (SRCP) or cerebro-myocardial perfusion (CMP) is selectively used in one-stage complex aortic arch malformation repair. This analysis was performed to investigate the effect of CMP and SRCP on perioperative blood product consumption, and to evaluate whether these two strategies have different effects on the clinical outcomes. A retrospective analysis of 284 children with complicated aortic malformation from January 2010 to June 2018 was performed. The overall cohort was divided into SRCP group (n = 202) and CMP group (n = 82). A comprehensive comparison of perioperative blood product consumption-related indexes was performed. Cardiopulmonary bypass time, cardiac arrest time, cooling, and rewarming time in the CMP group were significantly shorter than those in the SRCP group (P < .05). Chest tube time was 3.82 ± 1.33 days in the SRCP group compared to 3.42 ± 0.97 days in the CMP group (P = .005). Moreover, intraoperative platelet (PLT) transfusion volume (mL/kg) and rate (%) were significantly lower in the CMP group (P < .001). Multivariate regression analysis found that intraoperative PLT transfusion was significantly negatively correlated with CMP management [OR = 0.237 (0.110-0.507), P < .001] and CPB time was independently associated with delayed chest tube removal (>3 days) [OR = 1.010 (1.001-1.020), P = .031]. In-hospital mortality and early postoperative adverse events were not significantly different between the two groups. In children with on-pump complex aortic arch surgeries, CMP is more preferable than SRCP in blood protection. However, overall prognosis was not remarkably different between these two perfusion groups. They are both safe and feasible.

Effect of two different colloid priming strategies in infants weighing less than 5 kg undergoing on-pump cardiac surgeries.

Our aim was to explore the effect of two different priming strategies (artificial colloid only vs. artificial colloid combined with human serum albumin) on the prognosis of children weighing less than 5 kg undergoing on-pump congenital heart disease (CHD) surgery. A total of 65 children weighing less than 5 kg who underwent on-pump CHD surgery in our hospital from September 2016 to December 2017 were enrolled in this study. The children were randomly divided into two groups: artificial colloid priming group (AC group, n = 33) and artificial colloid combined albumin priming group (ACA group, n = 32). The primary clinical endpoint was the peri-CPB colloid osmotic pressure (COP). Secondary clinical endpoints included perioperative blood product and hemostatic drug consumption, postoperative renal function, coagulation function, postoperative renal function, and postoperative recovery parameters. COP values were not significant in the priming system as well as peri-CPB time points between the two groups (P > .05). Platelet consumption in the AC group was significantly lower than that in the ACA group (P < .05). There were no significant differences in the use of other blood products and hemostatic drugs as well as perioperative coagulation parameters between the two groups (P > .05). Postoperative length of stay in the AC group was significantly lower than that in the ACA group (P < .05). There were no significant differences in mortality, postoperative mechanical ventilation time, ICU time, and perioperative adverse events (including postoperative AKI) occurrences between the two groups (P > .05). In the on-pump cardiac surgeries of patients weighing less than 5 kg, total colloidal priming would not affect peri-CPB COP values, postoperative coagulation function, and blood products consumption. Total artificial colloidal priming strategy is feasible in low-weight patients.

[Analysis of hot spots and trend of molecular pharmacognosy research based on project supported by National Natural Science Foundation of 1995-2014].

This study collected 1995-2014 molecular pharmacognosy study, a total of 595 items, funded by Natural Science Foundation of China (NSFC). TDA and Excel software were used to analyze the data of the projects about general situation, hot spots of research with rank analytic and correlation analytic methods. Supported by NSFC molecular pharmacognosy projects and funding a gradual increase in the number of, the proportion of funds for pharmaceutical research funding tends to be stable; mainly supported by molecular biology methods of genuine medicinal materials, secondary metabolism and Germplasm Resources Research; hot drugs including Radix Salviae Miltiorrhizae, Radix Rehmanniae, Cordyceps sinensis, hot contents including tanshinone biosynthesis, Rehmannia glutinosa continuous cropping obstacle.

[Application of molecular biotechnology in Pharmacognosy].

Using the methods of informetrics analysis, articles retrieved from the database of CNKI were statistically analyzed on development course and knowledge system, so as to reflect the overall situation of pharmacognostical studies by molecular biotechnology. The result shows that the research on pharmacognosy by molecular biotechnology is an inter-disciplinary research area, the major research fields can be divided into 7 categories, including molecular identification of Chinese medicinal materials, molecular systematics and genetic diversity analysis of Chinese medicinal materials, biosynthesis and bioregulation of secondary metabolites in medicinal plants, molecular mechanism and genetic basis of Dao-di Herbs, and tissue culture and molecular breeding in medicinal plants. The research on pharmacognosy by molecular have achieved remarkable progress in recent 20 years, and have broad development prospects.

[Development of molecular pharmacognosy in China based on bibliometric analysis].

The method of bibliometrics was used to analyze the literature about the application of molecular biotechnique to pharmacognosy which were searched and obtained from the CNKI database and Shanghai intellectual property information platform from the year 1995 to 2015.It was found that 22 462 articles were published and the 63% were funded, 50 core institutions and 888 authors, 18 core journals were engaged in this subject.496 items of patents were authorized and 90 kinds of Chinese Materia Medica were involved.In the view of the quantity and quality of published literature, the scale and influence of journals, institutions, and the extent of subject categories have made remarkable achievement. Molecular pharmacognosy has completed the germination stage of a new subject, and has been in a relatively mature and stable development status.

Effect of acupuncture combined with rehabilitation training on sensory impairment of patients with stroke: a network meta-analysis.

BACKGROUND: The refractory and disabling nature of sensory disorders after stroke seriously affects patients' daily lives and reduces hospital turnover. Acupuncture, as an alternative therapy, is commonly used in combination with rehabilitation training to improve sensory disorders. To compare the effects of different acupuncture-related treatments combined with rehabilitation training on sensory impairment and the daily living ability of patients with stroke, we conducted a network meta-analysis to provide evidence-based findings for clinical practice. METHODS: Randomized controlled trials on the treatment of sensory disorders in patients with stroke were systematically retrieved from several databases, including China National Knowledge Infrastructure (CNKI), China Science and Technology Journal(VIP), Wanfang Database, Chinese Biological Medical (CBM), PubMed, Embase, Web of Science, Cochrane Library, and Clinical trials. The retrieval period ranged from January 2012 to December 2023. Two independent reviewers screened the included literature, extracted the data, and assessed the risk quality using Cochrane Handbook 5.1.0 and ReviewManager 5.4.1. Stata16.0 software was employed for data analysis. The study protocol was registered in PROSPERO: CRD42023389180. RESULTS: After screening, 20 studies were included, involving a total of 1999 subjects. The network meta-analysis results indicate that, compared to standard rehabilitation, acupuncture plus massage plus rehabilitation showed the most significant reduction in Numbness Syndrome Scores (MD = -0.71(-1.11,-0.31)). Acupuncture combined with rehabilitation demonstrated the most substantial improvement in Sensory Impairment Scores (MD = -0.59,(-0.68,-0.51)) and daily living ability of patients (MD = 17.16,(12.20,22.12)). CONCLUSIONS: In comparison to standard rehabilitation, the combination of acupuncture-related treatments and modern rehabilitation training not only improves the symptoms of sensory impairment and numbness after stroke but also enhances the daily living ability of patients, especially when acupuncture is combined with rehabilitation. However, further demonstration is required to strengthen these conclusions.

Threshold effect of physical exercise on its association to diabetes mellitus in short sleep population: evidence from a nationwide study.

Background: The prevalence of diabetes mellitus (DM) is a significant public health concern, especially among individuals with short sleep duration. Understanding the relationship between physical exercise and DM in this population is crucial for developing effective prevention strategies. However, the presence of a potential threshold effect of exercise on DM risk remains unclear. Methods: Using data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2007 to 2018, this population-based study investigated the association between physical exercise and DM in individuals with short sleep duration (no more than 7 hours per night). Weighted logistic regression analyses were conducted, adjusting for demographic and lifestyle factors. Additionally, a two-piecewise linear regression model was employed to identify any threshold effect of exercise on DM risk. Results: This study included 15,092 participants identified with short sleep duration. Demographic characteristics stratified by DM status indicate higher prevalence among certain groups, such as middle-aged and older adults, males, and non-Hispanic Whites. The analysis revealed an inverse association between exercise levels and DM prevalence among the short sleep population. In the fully adjusted model, individuals engaging in sufficient exercise (> 600 MET-minutes/week) exhibited significantly reduced odds of developing DM [OR (95% CI): 0.624(0.527,0.738), p < 0.001]. Furthermore, the segmented regression model identified an inflection point at 2000 MET-minutes/week, below which a significant correlation between exercise and DM was observed. Conclusions: This study provides evidence of a threshold effect of physical exercise on its association with DM in individuals with short sleep duration. Tailored exercise interventions targeting this population may help mitigate DM risk and improve overall health outcomes. Further research is warranted to validate these findings and explore optimal exercise thresholds for DM prevention strategies.

Rapamycin-sensitive mTORC1 signaling is involved in physiological primordial follicle activation in mouse ovary.

In mammals, resting female oocytes reside in primordial ovarian follicles. An individual primordial follicle may stay quiescent for a protracted period of time before initiating follicular growth, which is also termed "activation." Female reproductive capacity is sustained by the gradual, streamlined activation of the entire population of primordial follicles, but this process also results in reproductive senescence in older animals. Based on the recent findings that genetically triggered, excessive mammalian target of rapamycin complex 1 (mTORC1) activation in mouse oocytes leads to accelerated primordial follicle activation, we examined the necessity of mTORC1 signaling in physiological primordial follicle activation. We found that induction of oocyte mTORC1 activity is associated with early follicular growth in neonatal mouse ovaries. Pharmacological inhibition of mTORC1 activity in vivo by rapamycin treatment leads to a marked, but partial, suppression of primordial follicle activation. The suppressive effect of rapamycin on primordial follicle activation was reproduced in cultured ovaries. While rapamycin did not apparently affect several plausible cellular targets in neonatal mouse ovaries, such as mTORC2, AKT, or cyclin-dependent kinase (CDK) inhibitor p27-KIP1, its inhibitory effect on Cyclin A2 gene expression implies that mTORC1 signaling in oocytes may engage a Cyclin A/CDK regulatory network that promotes primordial follicle activation. The current work strengthens the concept that mTORC1-dependent events in the oocytes of primordial follicles may represent potential targets for intervention in humans to slow the depletion of the ovarian reserve.

Review of controlled clinical trials on acupuncture versus sham acupuncture in Germany.

OBJECTIVE: To examine German controlled clinical trials on the therapeutic effects of acupuncture vs sham acupuncture, and to find whether there are problems with the conclusion that sham acupuncture has no significant deviation from acupuncture. METHODS: We focused on literature from the last ten years (2002-2011) included in PubMed about controlled clinical trials on acupuncture vs sham acupuncture carried out in Germany. The methods applied in sham acupuncture are summarized, and the difference between the acupuncture and sham groups were analyzed. We measured effects based on the following criteria: acupuncture is effective and superior to sham, acupuncture is effective but similar to sham, both of them have uncertainty regarding treatment effect, or no significant effect. Finally, we reviewed the hypotheses of different scholars on sham acupuncture and analyzed their results. RESULTS: Four types of controlled clinical trials including sham acupuncture on non-Traditional Chinese Medicine acupoints, minimal acupuncture on non-acupoints, placebo needle and sham laser acupuncture had varying results in the 57 articles analyzed. Some showed that acupuncture had a better effect than sham, while some suggest acupuncture and sham had similar effects. In all studies using sham acupuncture on non-therapeutic points, sham electrodes, and sham electro-acupuncture, the therapeutic effect was better than sham. Of the trials, 37 demonstrated that acupuncture had a better effect than sham acupuncture. Only nine trials found no significant difference between acupuncture and sham. Two controlled trials for the same condition (neck pain) conducted by two different German research institutes used the same control method, but reached contradictory conclusions. CONCLUSION: We found problems in conclusions based on results of controlled clinical trials of sham acupuncture in Germany. Therefore, there is still not enough evidence to support the statements that "acupuncture and sham acupuncture have no difference in treatment effect" and "acupuncture is just a placebo effect." The control methods of sham acupuncture used in Germany may not be standardized and may not be suitable for acupuncture clinical trial research. We suggest that research on the methodology of sham acupuncture should be given priority in the design of acupuncture trials in the future.

Content analysis of systematic reviews on effectiveness of traditional Chinese medicine.

OBJECTIVE: To evaluate evidence for the efficacy of Traditional Chinese Medicine (TCM) in systematic reviews. METHODS: Chinese (TCM Periodical Literature Database, Chinese Biological Medicine database, Chinese Medical Current Contents, China Hospital Knowledge Database journal fulltext database, Virtual Machining and Inspection System, and Wanfang) and English (Cochrane Database of Systematic Reviews, PubMed and Embase) databases were searched. RESULTS: Three thousand, nine hundred and fifty-five articles were initially identified, 606 of which met the inclusion criteria, including 251 in English (83 from the Cochrane Database) and 355 in Chinese. The number of articles published each year increased between 1989 and 2009, Cardiocerebrovascular disease was the most studied target disease. Intervention measures included TCM preparations (177 articles), acupuncture (133 articles) and combinations of TCM and Western Medicine (38 articles). Control measures included positive medical (177 articles), basic treatment (100 articles), placebo (219 articles), and blank and mutual (107 articles). All articles included at least one reference; the greatest number was 268. Six of 10 articles with high quality references demonstrated curative effectsagainst target diseases including upper respiratory tract infection, dementia and depression. Interventions that were not recommended were tripterygium for rheumatoid arthritis and TCM syndrome differentiation for pediatric nocturia. In 10.4% of the studies, the authors concluded that the intervention had a curative effect. The assessors agreed with the authors' conclusions in 88.32% of cases, but rejected 8.94% (54 articles). CONCLUSION: 1) Training in systematic review methods, including topic selection, study design, methods and technology, should be improved. 2) Upper respiratory tract infection, dementia and depression may become the predominant diseases treated by TCM, and the corresponding interventions could be developed into practical applications. 3) Use of non-recommended interventions should be controlled, and there should be more research on side effects.

Distribution of bacteria and risk factors in patients with multidrug-resistant pneumonia in a single center rehabilitation ward.

Stroke patients may have dysphagia and frequent aspiration increasing exposure to antibiotics and the chance of multidrug-resistant (MDR) bacteria infection. This study investigated clinical risk factors and related antibiotic use of MDR bacteria infection in stroke patients in the rehabilitation ward, hoping that it can help prevent and reduce the condition of MDR bacteria. A retrospective cohort study was conducted using the database of stroke patients with pneumonia admitted to the rehabilitation ward from January 1, 2020, to June 30, 2022. The selected stroke patients were divided into the MDR and non-MDR groups. Analyze the infection bacteria of the 2 groups. Forward logistic regression was applied to identify possible independent MDR bacteria infection risk factors. A total of 323 patients were included. The top 3 common MDR pathogens were Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Almost all Pseudomonas aeruginosa and Acinetobacter baumannii are resistant to ertapenem. National Institute of Health stroke scale at admission was associated with MDR bacteria infection pneumonia (OR [odds ratio] = 1.078, 95%CI [1.017, 1.142]). Long-term tracheotomy (OR = 2.695, 95%CI [1.232, 5.897]), hypoalbuminemia (OR = 473, 95%CI [1.318, 4.642]), and bilateral cerebral hemisphere stroke (OR = 4.021, 95%CI [2.009, 8.048]) were significant clinical risk factors of MDR pneumonia after stroke. The detection rate of MDR bacteria has increased. Understanding the distribution and drug resistance of MDR bacteria in stroke patients with pneumonia in the neurological rehabilitation ward and the related susceptibility of MDR bacteria infection is necessary. This way, the treatment plan can be adjusted more timely, avoiding the abuse of antibiotics.

ARE-PROTACs Enable Co-degradation of an Nrf2-MafG Heterodimer.

Proteolysis-targeting chimera (PROTAC) technology has emerged as a potential strategy to degrade "undruggable" proteins in recent years. Nrf2, an aberrantly activated transcription factor in cancer, is generally considered undruggable as lacking active sites or allosteric pockets. Here, we constructed the chimeric molecule C2, which consists of an Nrf2-binding element and a CRBN ligand, as a first-in-class Nrf2 degrader. Surprisingly, C2 was found to selectively degrade an Nrf2-MafG heterodimer simultaneously via the ubiquitin-proteasome system. C2 impeded Nrf2-ARE transcriptional activity significantly and improved the sensitivity of NSCLC cells to ferroptosis and therapeutic drugs. The degradation character of ARE-PROTACs suggests that the PROTAC hijacking the transcription element of TFs could achieve co-degradation of the transcription complex.