Mouse nerve growth factor suppresses neuronal apoptosis in valproic acid-induced autism spectrum disorder rats by regulating the phosphoinositide-3-kinase/serine/threonine kinase signaling pathway.

BACKGROUND: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by deficits in social communication and restrictive behaviors. Mouse nerve growth factor (mNGF), a neurotrophic factor, is critical for neuronal growth and survival, and the mNGF treatment is considered a promising therapy for neurodegeneration. In light of this, we aimed to evaluate the effect of mNGF on neurological function in ASD. METHODS: An ASD rat model was established by intraperitoneal injection of valproic acid (VPA). Social behavior, learning, and memory of the rats were measured. TdT-mediated dUTP Nick-end labeling and Nissl assays were performed to detect neuronal apoptosis and survival in the hippocampus and prefrontal cortex. Apoptosis-related proteins and oxidative stress markers were detected. RESULTS: mNGF improved locomotor activity, exploratory behavior, social interaction, and spatial learning and memory in VPA-induced ASD rats. In the hippocampus and prefrontal cortex, mNGF suppressed neuronal apoptosis, increased the number of neurons, superoxide dismutase, and glutathione levels, and decreased reactive oxygen species, nitric oxide, TNF-α, and IL-1ß levels compared with the VPA group. In addition, mNGF increased the levels of Bcl-2, p-phosphoinositide-3-kinase (PI3K), and p-serine/threonine kinase (Akt), and decreased the levels of Bax and cleaved caspase-3, while the PI3K inhibitor LY294002 reversed these effects. CONCLUSION: These data suggest that mNGF suppressed neuronal apoptosis and ameliorated the abnormal behaviors in VPA-induced ASD rats, in part, by activating the PI3K/Akt signaling pathway.

Comparison of the clinical efficacy of laparoscopic extralevator abdominoperineal excision (ELAPE) and non-ELAPE for low rectal cancer.

This study was performed to retrospectively analyze and compare the related clinical indicators between extralevator abdominoperineal excision (ELAPE) and non-ELAPE under laparoscopic for low rectal cancer. From June 2018 to September 2021, a total of 80 patients with low rectal cancer who underwent either of the above two types of surgeries at our Hospital were enrolled. Patients were divided into the ELAPE group and non-ELAPE group based on the different surgical methods. Preoperative general indicators, intraoperative indicators, postoperative complications, positive circumferential resection margin rate, local recurrence rate, hospital stay length, hospital expenses, and other related indicators were compared between the two groups. There were no significant differences in the comparison of preoperative indexes between the ELAPE group and non-ELAPE group, including age, preoperative BMI, and gender. Similarly, there were no significant differences in abdominal operation time, total operation time, and the number of intraoperative lymph nodes dissected between the two groups. However, the perineal operation time, intraoperative blood loss, intraoperative perforation rate, and positive circumferential resection margin rate were significantly different between the two groups. In the comparison of postoperative indexes, perineal complications, postoperative hospital stay length, and IPSS score were significantly different between the two groups. The use of ELAPE in treating T3-4NxM0 phase low rectal cancer was superior to non-ELAPE in reducing intraoperative perforation rate, positive circumferential resection margin rate, local recurrence rate, etc.

A Meta-Analysis on the Impact of Prenatal and Early Childhood Antimicrobial Use on Autism Spectrum Disorders.

OBJECTIVE: To investigate the impact of prenatal and early childhood antimicrobial use on autism spectrum disorders (ASD). DATA SOURCES: We searched PubMed and Embase databases for relevant studies from inception to August 2022. STUDY SELECTION AND DATA EXTRACTION: Peer-reviewed, observational studies were all acceptable. Raw data were extracted into a predefined worksheet and quality analysis was performed using the Newcastle-Ottawa Scale. DATA SYNTHESIS: Nineteen studies were identified in the meta-analysis. Prenatal antimicrobial exposure was not associated with ASD (P = 0.06 > 0.05), whereas early childhood antimicrobial exposure was associated with an increased odds ratio of ASD (OR = 1.17, 95% CI = [1.08-1.27], P value < 0.001). The sibling-matched analysis, with a very limited sample size, suggested that neither prenatal (P = 0.47 > 0.05) nor early childhood (P = 0.13 > 0.05) antimicrobial exposure was associated with ASD. Medical professionals may need to take the possible association into consideration when prescribing an antimicrobial in children. CONCLUSIONS: Early childhood antimicrobial exposure could increase the incidence of ASD. In future studies, it would be necessary to control for confounding factors, such as genetic factors, parenteral age at birth, or low birthweight, to further validate the association.

TCHis mitigate oxidative stress and improve abnormal behavior in a prenatal valproic acid-exposed rat model of autism.

Troxerutin is known for its anti-inflammatory and antioxidative effects in nerve impairment. The purpose of this study is to investigate the effect of troxerutin and cerebroprotein hydrolysate injections (TCHis) on prenatal valproic acid (VPA)-exposed rats. The VPA was administered to pregnant rats on gestational day 12.5 to induce a model of autism. The offspring were given the treatment of TCHis on postnatal day (PND) 21-50. On PND 43-50, the behavioral analysis of offspring was performed after the treatment of TCHis for 1 h. On PND 50, the offspring were harvested and the brains were collected. The hippocampus and prefrontal cortex were isolated for relevant biochemical detections. The administration of TCHis increased pain sensitivity and improved abnormal social behaviors in prenatal VPA-exposed rats. Prenatal exposure of VPA induced neuronal loss and apoptosis, enhanced reactive oxygen species (ROS) production, and promoted oxidative stress in hippocampus and prefrontal cortex, whereas these effects were reversed by the postnatal treatment of TCHis. In addition, postnatal administration of TCHis ameliorated mitochondrial function in hippocampus and prefrontal cortex of prenatal VPA-exposed rats. This study concluded that postnatal treatment of TCHis reduced oxidative stress and ameliorated abnormal behavior in a prenatal VPA-induced rat model of autism.

Cationic Conjugated Polyelectrolytes with Aggregation-Induced Ratiometric Fluorescence.

The molecular diversity of aggregation-induced emission remains a challenge due to the limitation of conventional synthesis methods. Here, a series of novel neutral and cationic conjugated polymers composed of various ratios of tetraarylethylene (TAE) containing a bridged oxygen (O) and fluorene (F) units is designed and synthesized via the geminal cross-coupling (GCC) of 1,1-dibromoolefins. The incorporation of TAE segments into the conjugated backbone of polyfluorene produces pronounced aggregation-induced ratiometric fluorescence, i.e., aggregation-induced emission (AIE) at 520-600 nm and grows synergistically with aggregations-caused quenching (ACQ) at 400-450 nm. The content of fluorene unit in the polymer backbones determines the intensity of the initial fluorescence in the blue light region. The huge distinction (about 150 nm) in dual emission wavelengths caused by the environment change makes these conjugated polyelectrolytes particularly suitable for ratiometric fluorescence sensing. Based on electrostatic interaction mechanism, the gradual addition of heparin into the cationic conjugated polymers aqueous solutions can induce dual-color fluorescence changes with a detection limit of 9 × 10-9 m. This work exhibits the great facility of using GCC reaction to synthesis the conjugated TAE polymers with superior AIE properties and special functions.

AIE-Based Dynamic in Situ Nanoscale Visualization of Amyloid Fibrillation from Hen Egg White Lysozyme.

Protein misfolding and denaturation, represented by amyloid fibrillation, are associated with many diseases. However, as a general chemical biological process, the dynamic structure information on amyloid fibrillation has not been demonstrated categorically. Herein, hen egg white lysozyme (HEWL) was used as the model protein of interest to realize in situ nanoscale imaging of protein fibrillation process using the fluorophores with aggregation-induced emission (AIE) activity. The AIE-active fluorophores exhibit the reversible capability of association and dissociation with ß-sheet structure and thus dynamic binding-induced emission, which causes the spontaneous switching of fluorescence. The entire HEWL denaturation process induced by sodium dodecyl sulfate (SDS) at ambient conditions was demonstrated in detail by using two AIE-active fluorophores (TPE-NaSO3 and PD-BZ-OH) through reversible electrostatic interaction and specific labeling between AIE probes and ß-sheet structures of amyloid fibrils, respectively. The results indicate that PD-BZ-OH is more specific AIE probe for amyloid fibrils than TPE-NaSO3. In comparison, the SEM and TEM results show the same denaturation process of protein fibrillation induced by SDS at different concentrations. The static super-resolution imaging of amyloid fibrils is performed with a resolution of 35 nm using PD-BZ-OH aqueous solution without additional auxiliary conditions. The dynamic evolution process of HEWL amyloid fibrillation is in situ visualized through super-resolution fluorescent microscopy with nanoscale resolution. Both static and dynamic super-resolution imaging of amyloid fibrillation provides detailed nanoscale structure information exceeding 50 nm resolution, which is of great significance in the exploration of amyloid fibrillation and related diseases.

Real-Time Fluorescence In Situ Visualization of Latent Fingerprints Exceeding Level 3 Details Based on Aggregation-Induced Emission.

A water-soluble probe, TPA-1OH, with aggregation-induced emission activity is synthesized and used for expedient real-time fluorescence in situ visualization of latent fingerprints (LFPs). A TPA-1OH aqueous solution exhibits nonfluorescence in pure water while strong fluorescence upon molecular aggregation induced by addition of poor solvent. Fluorescence images of LFPs on a variety of substrates, including rough surfaces such as walls, bricks, and paper, are developed under 405 nm light, by soaking in or spraying with a TPA-1OH aqueous solution (30 µM) without any necessity of organic cosolvents and post-treatment steps. The probe is noncytotoxic at a concentration lower than 50 µM. The development process of LFPs is demonstrated by real-time fluorescence in situ imaging. The exponential relationship between the relative fluorescence intensity and time is deduced from the fitting curve. The LFP images developed by TPA-1OH are evident and intact enough to allow that the level 1-3 details are displayed and analyzed. Noteworthily, the level 3 details of LFPs such as the fingerprint ridge width and the characteristics of the sweat pores are evidently visible under fluorescence microscopy. Even the nanoscopic details exceeding level 3 are visualized under super-resolution microscopy with sub-50 nm optical resolution.

Vitamin B1 and B12 mitigates neuron apoptosis in cerebral palsy by augmenting BDNF expression through MALAT1/miR-1 axis.

Through the roles of vitamin B1 and B12 in neuroprotection and in improving cerebral palsy symptoms have been previously noticed, the action mechanism is still unclear. This study aims to investigate the protective effect of vitamin B1 and B12 on neuron injury in cerebral palsy and to clarify the mechanism of vitamin B1 and B12 inhibiting neurons apoptosis, and to focus on the role of lncRNA MALAT1 in this process. In order to investigate the effect of vitamin B1 and B12 on neurons injury in vivo and on neuron apoptosis in vitro, we, respectively, introduced vitamin B1 and B12 into cerebral palsy rat and in apoptosis-induced N2A neurons by Oxygen Glucose Deprivation/reoxygenation (OGD/R). Our results demonstrated that vitamin B1 and B12 treatment improved the motor and memory functions and ameliorated the neurons injury in cerebral palsy rats. OGD/R treatment repressed the expression of MALAT1 and BDNF and the phosphorylation of PI3K and Akt, and enhanced the miR-1 expression, which were all reversed by vitamin B1 and B12 treatment in N2A neurons. Vitamin B1 and B12 inhibited miR-1 expression through MALAT1, promoted BDNF expression and activated PI3K/Akt signaling through the MALAT1/miR-1 axis. Vitamin B1 and B12 suppressed neuron apoptosis by up-regulating BDNF via MALAT1/miR-1 pathway. MALAT1 interference abolished the neuroprotective effect of vitamin B1 and B12 in cerebral palsy rats. Collectively, vitamin B1 and B12 up-regulates BDNF and its downstream PI3K/Akt signaling through MALAT1/miR-1 axis, thus suppressing neuron apoptosis and mitigating nerve injury in cerebral palsy rats.

Photoplastic Transformation Based on Dynamic Covalent Chemistry.

The magical fantasy of decades-old transformer characters is becoming closer to scientific reality, as transformable materials can change their shapes in response to thermal, mechanical, electrical, and chemical stimuli. However, precise and prompt control of plastic shaping remains to be wanted. Photoresponsive materials provide a promising alternative for rapid optomechanical shaping with limited success. Here, we report a new class of photoplastic transformation based on dynamic covalently crosslinked polytriazole (PTA) networks, in which crosslinking points are comprised of photocleaveable hexaarylbiimidazole (HABI). Upon sub-500 nm light irradiation, HABI is dissociated into two triphenylimidazole radicals (TPIRs) followed by spontaneous recombination back to the initial state. This photoswitching effect is demonstrated to generate nonthermal shape change in the PTA-HABI gel network at will upon light stimulus. A unique photoalignment phenomenon has also been discovered which can form oriented nanoscale patterning in the PTA-HABI gel network upon laser irradiation. The solvent-free PTA-HABI elastomer exhibits photoenhanced automatic self-healing properties at temperatures ranging from 25 °C to freezing points, which is attributed to the dynamic equilibrium between TPIRs and HABI. A photoplastic spring is fabricated and exhibits photoswitchable plastic behavior, i.e., a reversible transformation between plastic strain and elastic strain upon light irradiation. HABI-based polymer networks, including solvated gel and solvent-free elastomer, are promising as smart materials for nonthermal photoactivated shape changing, transformation, and self-healing applications.

LncRNA MIAT overexpression reduced neuron apoptosis in a neonatal rat model of hypoxic-ischemic injury through miR-211/GDNF.

OBJECTIVE: To investigate the underlying mechanism of lncRNA myocardial infarction-associated transcript (MIAT) in hypoxic-ischemic (HI)-induced neonatal cerebral palsy. MATERIALS AND METHODS: Neonatal rat model of HI injury was established to detect the motor function. LncRNA MIAT, miR-211, glial cell line-derived neurotrophic factor (GDNF) and caspase-3 expressions were measured by qRT-PCR or western blot. The apoptosis of Neuro2A cells was detected by flow cytometry. RNA immunoprecipitation (RIP) and RNA pull-down assays were performed to confirm the interaction between MIAT and miR-211. RESULTS: Compared with control group, lncRNA MIAT and GDNF were downregulated in striatal tissues of neonatal rats in HI group and oxygen glucose deprivation (OGD)-induced ischemic injury of Neuro2A cells, whereas miR-211 was up-regulated in striatal tissues of HI group and OGD-induced ischemic injury of Neuro2A cells. LncRNA MIAT interacted with miR-211, and lncRNA MIAT overexpression reduced neuron apoptosis through miR-211. Besides, GDNF expression was positively regulated by lncRNA MIAT and negatively regulated by miR-211 in Neuro2A cells. In vivo experiment proved MIAT promoted motor function and relieved HI injury. CONCLUSION: MIAT overexpression reduced apoptosis of Neuro2A cells through miR-211/GDNF, which relieved HI injury of neonatal rats.

Evaluation of efficacy and safety of sunitinib regimen in 22 patients with metastatic renal cell carcinoma: at least 12-month follow-up.

BACKGROUND: Sunitinib has been proved an effective new option for treatment of metastatic renal cell carcinoma (mRCC). Analysis of clinical data of 22 patients, who were exposed to sunitinib for at least 1 year, was conducted to evaluate the long-term efficacy and safety of sunitinib for the treatment of mRCC. METHODS: A total of 54 patients with mRCC were treated with sunitinib malate, 50 mg/d orally, on a 4-weeks-on and 2-weeks-off dosing schedule in Peking University First Hospital. Treatment continued until disease progression, unacceptable adverse events (AEs), or death. Among them, 22 patients continued treatment for at least 1 year. The clinical data of these 22 patients were prospectively collected for analysis. AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0. Tumor response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors. RESULTS: Median progression-free survival was 19.5 months until last follow-up. The best efficacy results achieved were complete response, partial response, and stable disease for 2, 9, and 11 patients, respectively. Objective response rate was 50%. The most common AEs were hand-foot syndrome (95%) and hypertension (91%). Other common AEs were thyroid-stimulating hormone elevation (82%), platelet decrease (77%), and loss of appetite (77%). Only one patient withdrew from treatment for cardiac infarction. Another nine patients experienced dose modifications or short-term suspensions. CONCLUSION: Long-term exposure to sunitinib malate showed encouraging efficacy in the treatment of mRCC. At the same time, the tolerability was good.

Chromophobe renal cell carcinoma: analysis of 53 cases.

PURPOSE: To discuss the pathological and clinical characteristics, treatments and prognosis of chromophobe renal cell carcinoma (CRCC). METHODS: We developed a database that contained 1,870 patients who were diagnosed with renal cell carcinoma (RCC) and who underwent surgery in our hospital between 2002 and 2010. Afterward, the clinical and pathological data of 53 CRCC cases were extracted and analyzed. RESULTS: The mean age of the 53 patients at diagnosis was 50.2 years (range, 21-88 years), and the ratio of male to female was 1:1. All tumors were unilateral and a majority of them (69.8%) were discovered incidentally. The mean tumor size was 5.8 ± 3.2 cm (range, 2-20 cm). Stage T1, T2, and T3 tumors, in accordance with 2004 TNM classification, accounted for 75.5, 13.2 and 11.3% of all cases, respectively. By histologic grading, 11.3, 73.6 and 15.1% of the tumors were G1, G2, and G3, respectively. Forty-one (77.4%) patients underwent radical nephrectomy, 12 (22.6%) underwent partial nephrectomy. Forty-five (84.9%) patients with follow-up results were alive after a mean follow-up of 34 months (range, 4-79 months). Tumor metastasis was discovered in 2 patients: one tumor metastasis was found in the liver 4 months postoperation, and the other was found in the lumbar vertebrae 47 months postoperation. No local recurrence was found. The overall survival rate was 100%. CONCLUSIONS: CRCC is an uncommon subtype of RCC, with a favorable prognosis. Chinese patients are seemingly younger at diagnosis. Prediction of prognosis is still difficult.

Efficacy and safety of sunitinib in the treatment of metastatic renal cell carcinoma.

BACKGROUND: The tyrosine kinase inhibitors (TKIs) sunitinib, the first targeted agent for the first line treatment of metastatic renal cell carcinoma (RCC), targets the vascular endothelial growth factor (VEGF) pathway. The objective of this study was to investigate the efficacy and safety of sunitinib in treating metastatic clear-cell RCC and to confirm if hypertension is an effective predictive factor. METHODS: A total of 36 patients with metastatic RCC were enrolled between June 2008 and December 2010. Among them 29 cases were first line therapy and 7 cases were in progression on first-line cytokine or sorafinib therapy. The pathology of all patients was confirmed predominant in clear cell type. Sunitinib mono-therapy was administered in repeated 6-week cycles of daily oral therapy for 4 weeks, followed by 2 weeks off in 34 patients; and 3 patients were administered with 37.5 mg/d continuously until disease progression or unacceptable toxicities occurred. Overall response rate and safety were evaluated. We divided patients into Group A and Group B according to the blood pressure level. RESULTS: The median follow-up was 15 months (10 cycles, range 1.5 - 30.0 months (1 - 20 cycles)). Ten patients (29.4%) achieved partial responses (PR); 23 patients (67.6%) demonstrated stable disease (SD) lasting ≥ 2 cycles. Seventeen patients (50%) developed progressive disease (PD) during follow-up. The median progression-free survival (PFS) was 15 months (range 3.0 - 28.5) months. A total of 9 patients died; the overall survival has not been reached; the median survival time of the deceased patients was 13 months (range 7 - 24) months. The most common adverse events were hand-foot syndrome (77.8%), thrombocytopenia (75.0%), hypertension (61.1%) and diarrhea (46.0%). Most adverse events were reversible by treatment interruption. Twenty-two patients (61.1%) developed hypertension; and hypertension was associated with a long time to disease progression and long overall survival (P = 0.004, 0.000, respectively). CONCLUSIONS: The results of this study demonstrate the efficacy and manageable adverse event profile of sunitinib as a single agent in first- or second-line therapy for patients with metastatic clear cell RCC. Further, sunitinib-associated hypertension may be a strong predictive marker for treatment efficacy in metastatic RCC.

[Complete transperitoneal laparoscopic nephroureterectomy for upper urinary tract urothelial carcinoma].

OBJECTIVE: To discuss the surgical skills and clinical value of complete transperitoneal laparoscopic nephroureterectomy. METHODS: We collected and analyzed the clinical data of 25 patients (14 renal pelvic carcinoma and 11 carcinoma of ulreter, right side 15 and left side 10) who underwent complete transperitoneal laparoscopic nephroureterectomy for the upper urinary tract urothelial carcinoma (UUT-UC) in Peking University First Hospital from May 2010 to April 2011. RESULTS: All the operations were successfully done by one surgeon with standard 4 or 5 trocars technique. The mean operative time was 150 min (120-180 min), the blood loss about 20-100 mL (mean 40 mL) and no severe complications observed. The postoperative hospital stay was 4-6 days with an average length of 5.5 days. The mean follow-up was 5.5 (1-11) months. One of 19 patients underwent trans urethral resection of bladder tumour (TURBT) for recurrent non-muscle invasive bladder tumor. CONCLUSION: Complete transperitoneal laparoscopic nephroureterectomy is a minimally invasive, safe and effective way to treat UUT-UC. The patients recover soon and have a shorter length of stay.