Discovery of Selective Proteolysis-Targeting Chimera Degraders Targeting PTP1B as Long-Term Hypoglycemic Agents.

PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 µM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75 with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC50 values of 250 nM and 50 nM, respectively. Compound 75 induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC0-2h to 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.

Reliability and validation of the Chinese version of the epilepsy surgery satisfaction questionnaire.

OBJECTIVE: To evaluate the reliability and validity the Chinese version of 19-item Epilepsy Surgery Satisfaction Questionnaire (C-ESSQ-19) in Chinese mainland patients. METHODS: Patients with epilepsy who had epilepsy surgery in our hospital one year earlier were included. Internal consistency and test-retest reliability were assessed by using Cronbach alpha and intraclass correlation coefficient (ICC). Confirmatory factor analysis was used for construct validity. Discriminant validity was assessed using receiver operating characteristic curve analysis. RESULTS: A total of 132 patients participated in our study, consisting of 59 females and 73 males. The C-ESSQ-19 yielded a median summary score of 86.5 (IQR=72.7-98.0). The Cronbach's alpha of the four domains of the C-ESSQ-19 ranged from 0.746 to 0.973. The test-retest reliability evaluated by ICC were good to excellent, ranging from 0.71 to 0.90 (P < 0.001). The C-ESSQ-19 demonstrated excellent construct validity, as indicated by the satisfactory goodness-of-fit of the data (SRMR = 0.046; CFI = 1.000). It exhibited acceptable discriminant validity for differentiating between patients excised or not (AUC = 0.72; 95% CI = 0.59-0.86) and self-rated severity of epilepsy (AUC = 0.76, 95% CI = 0.67-0.86), but poor discriminant validity for other factors, such as being seizure-free or not (AUC = 0.66, CI = 0.56-0.75), depressed or not (AUC = 0.66, 95% CI = 0.54-0.79), and self-rated disability related to seizures (AUC = 0.65, 95% CI = 0.50-0.80). CONCLUSIONS: The C-ESSQ-19 has proven to be a reliable and valid self-rated questionnaire for assessing the satisfaction of Chinese mainland epilepsy patients with surgery.

ChatGPT's potential role in non-English-speaking outpatient clinic settings.

Researchers recently utilized ChatGPT as a tool for composing clinic letters, highlighting its ability to generate accurate and empathetic communications. Here we demonstrated the potential application of ChatGPT as a medical assistant in Mandarin Chinese-speaking outpatient clinics, aiming to improve patient satisfaction in high-patient volume settings. ChatGPT achieved an average score of 72.4% in the Chinese Medical Licensing Examination's Clinical Knowledge section, ranking within the top 20th percentile. It also demonstrated its potential for clinical communication in non-English speaking environments. Our study suggests that ChatGPT could serve as an interface between physicians and patients in Chinese-speaking outpatient settings, possibly extending to other languages. However, further optimization is required, including training on medical-specific datasets, rigorous testing, privacy compliance, integration with existing systems, user-friendly interfaces, and the development of guidelines for medical professionals. Controlled clinical trials and regulatory approval are necessary before widespread implementation. As chatbots' integration into medical practice becomes more feasible, rigorous early investigations and pilot studies can help mitigate potential risks.

Individualized targeting is warranted in subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression: A tractography analysis.

Subcallosal cingulate gyrus (SCG) is a target of deep brain stimulation (DBS) for treatment-resistant depression. However, previous randomized controlled trials report that approximately 42% of patients are responders to this therapy of last resort, and suboptimal targeting of SCG is a potential underlying factor to this unsatisfactory efficacy. Tractography has been proposed as a supplementary method to enhance targeting strategy. We performed a connectivity-based segmentation in the SCG region via probabilistic tractography in 100 healthy volunteers from the Human Connectome Project. The SCG voxels with maximum connectivity to brain regions implicated in depression, including Brodmann Area 10 (BA10), cingulate cortex, thalamus, and nucleus accumbens were identified, and the conjunctions were deemed as tractography-based targets. We then performed deterministic tractography using these targets in additional 100 volunteers to calculate streamline counts compassing to relevant brain regions and fibers. We also evaluated the intra- and inter-subject variance using test-retest dataset. Two tractography-based targets were identified. Tractography-based target-1 had the highest streamline counts to right BA10 and bilateral cingulate cortex, while tractography-based target-2 had the highest streamline counts to bilateral nucleus accumbens and uncinate fasciculus. The mean linear distance from individual tractography-based target to anatomy-based target was 3.2 ± 1.8 mm and 2.5 ± 1.4 mm in left and right hemispheres. The mean ± SD of targets between intra- and inter-subjects were 2.2 ± 1.2 and 2.9 ± 1.4 in left hemisphere, and 2.3 ± 1.4 and 3.1 ± 1.7 in right hemisphere, respectively. Individual heterogeneity as well as inherent variability from diffusion imaging should be taken into account during SCG-DBS target planning procedure.

Evaluation of the knowledge, awareness, and attitudes toward epilepsy among nurses.

BACKGROUND: The standard of care provided to patients with chronic epilepsy might be affected by clinical nurses' understanding, awareness, and attitudes toward the condition. The objective of this study was to assess the knowledge, awareness, and attitudes toward chronic epilepsy among clinical nurses in the Second Affiliated Hospital of Zhejiang University School of Medicine, China. METHODS: Two hundred and thirty-eight nurses from the neurosurgery, neurology, epilepsy center, other internal medicine and other surgery department working at our hospital participated in this descriptive and cross-sectional study in 2022. The data were collected through an electronic questionnaire, which comprised four domains including demographic and clinical epilepsy-related questions, awareness of epilepsy section, 18 items for knowledge and a 15-item scale for attitudes. Mann-Whitney U tests, Kruskal-Wallis H tests, post hoc analysis, Pearson correlation analysis, and descriptive statistics were used to analyze the non-normal distribution of the dataset. RESULTS: The clinical nurses' average score on the awareness of epilepsy section was 14.93 ± 2.69 (maximum score: 20), the knowledge of epilepsy section scored 15.41 ± 2.30 (maximum score: 18), and the epilepsy attitude section scored 30.65 ± 7.40. The knowledge and awareness accuracy of the responses to the epilepsy-related questions were positively and significantly correlated (r = 0.251, p < 0.001). The multiple linear regression model found that the department (p < 0.001) and rank (p = 0.015) of nurses were independently associated with awareness toward epilepsy. Meanwhile, there was a statistically significant difference between the departments of nurses and accuracy on the Epilepsy Knowledge Scale (H = 18.340, p < 0.001). In addition, 92.77% of nurses agreed that people with chronic epilepsy have the same rights as all people. Unfortunately, over 30% of nurses maintained an uncertain attitude toward the employment, marriage, and emotion related to epilepsy. CONCLUSION: Our findings revealed that nurses had a general awareness and understanding of epilepsy, attitudes toward epilepsy. Specifically, nurses working in the Neurology Department and the Epilepsy Center were predisposed to have a considerably better level of awareness and knowledge of epilepsy. Additionally, as their understanding of epilepsy grew, so did their sensitivity to those who suffer from the condition. The study also recommends that epilepsy experts deliver additional lectures and training sessions to enhance nurses' knowledge of first-aid for seizures.

The Accuracy of Imaging Guided Targeting with Microelectrode Recoding in Subthalamic Nucleus for Parkinson's Disease: A Single-Center Experience.

BACKGROUND: Accurate electrode targeting was essential for the efficacy of deep brain stimulation (DBS). There is ongoing debate about the necessary of microelectrode recording (MER) in subthalamic nucleus (STN)-DBS surgery for accurate targeting. OBJECTIVE: This study aimed to analyze the accuracy of imaging-guided awake DBS with MER in STN for Parkinson's disease in a single center. METHODS: The authors performed a retrospective analysis of 161 Parkinson's disease patients undergoing STN-DBS at our center from March 2013 to June 2021. The implantation was performed by preoperative magnetic resonance imaging (MRI)-based direct targeting with intraoperative MER and macrostimulation testing. 285 electrode tracks with preoperative and postoperative coordinates were included to calculate the placement error in STN targeting. RESULTS: 85.9% of electrodes guided by preoperative MRI were implanted without intraoperative adjustment. 31 (10.2%) and 12 (3.9%) electrodes underwent intraoperative adjustment due to MER and intraoperative testing, respectively. We found 86.2% (245/285) of electrodes with trajectory error ≤2 mm. The MER physiological signals length < 4 mm and ≥4 mm group showed trajectory error > 2 mm in 38.0% and 8.8% of electrodes, respectively. Compared to non-adjustment electrodes, the final positioning of MER-adjusted electrodes deviated from the center of STN. CONCLUSION: The preoperative MRI guided STN targeting results in approximately 14% cases that require electrode repositioning. MER physiological signals length < 4 mm at first penetration implied deviation off planned target. MER combined with intraoperative awake testing served to rescue such deviation based on MRI alone.

Quantitative analysis of effects of salvianic acid a combined with hydroxy safflower yellow a on rat endothelial cells after hypoxic injury using the combination index method

Abstract Cerebrovascular disease is the second most serious disease in the world. It has the features of high morbidity, high mortality and recurrence rate. Numerous research on the compatibility of Chinese medicine with effective ingredients of cerebral ischemia has been made during the past decades. The purpose of this study is to quantitatively analyze the combined pharmacological effect of effective ingredients in Danshen and Honghua (Dan Hong) on rat microvascular endothelial cells after gradually oxygen-glucose deprivation. The experimental concentration range for the compatibility of two effective ingredients were determined in the preliminary experiments by Cell Counting kit-8 (CCK-8) method. Drugs were added to rat brain microvascular endothelial cells at a non-toxic dose level. After that, the cells were cultured for 12 h, and placed in a hypoxic environment. Finally, the cell survival rate was used as a measure of drug effect. In order to determine synergism or antagonism, the combination index (CI)-isobologram method was performed to analyze the data from the experiments. Based on this theory, the potencies of each drug and the shapes of their does-effect curves are both taken into account. The results show that the synergism or the antagonism between two effective ingredients compatibility change with different proportion and dosage. Furthermore, it can be seen from the results of these experiments that when these drugs are used in combination, the dosage required to achieve the same therapeutic effects is greatly reduced compared with the case of single one. It is worth mentioning that our experiments also prove that the median-effect equation and the CI method can be applied in the field of traditional Chinese medicine.

Gegen Qinlian Decoction Ameliorates Nonalcoholic Fatty Liver Disease in Rats via Oxidative Stress, Inflammation, and the NLRP3 Signal Axis.

Gegen Qinlian Decoction (GQD), a classic Chinese herbal formula, has been widely used in Chinese clinic for centuries and is well defined in treating nonalcoholic fatty liver disease (NAFLD). However, the mechanism action of GQD on NAFLD is still rarely evaluated. The present study aims to investigate the effect of GQD on treatment of NAFLD in rats and to further explore the underlying mechanism. The rat NAFLD model established by high-fat-diet feeding was used in the research. Our results exhibited the liver lesions and steatosis was significantly alleviated in NAFLD rats treated with GQD via Oil Red O and H&E staining. Body weight and liver index in GQD groups were reduced significantly (P < 0.05). Moreover, the biochemical analyzer test results showed that GQD significantly decreased blood lipid levels total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and liver injury indicators alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), while it increased the level of high-density lipoprotein cholesterol (HDL-C) (P < 0.05). The levels of interferon-ß (IFN-ß), tumor necrosis factor-α (TNF-α), and malondialdehyde (MDA) after the GQD treatment were significantly lower, and then interleukin-2 (IL-2), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels were lifted significantly (P < 0.05). Further, GQD blocked the expression of NLRP3, ASC, caspase-1 mRNA, and proteins in the liver tissues significantly (P < 0.05). These findings indicated that GQD can ameliorate the hepatic steatosis and injury of NAFLD. Its possible mechanism involves the modulation of inflammatory cytokines and antioxidative stress and the inhibition of NLRP3 signal axis activation. The results support that GQD may be a promising candidate in the treatment of NAFLD.

Pharmacokinetic-Pharmacodynamic Modeling of the Antioxidant Activity of Quzhou Fructus Aurantii Decoction in a Rat Model of Hyperlipidemia.

BACKGROUND: Quzhou Fructus Aurantii (QFA) is an herb that is commonly used to alleviate inflammation in individuals dealing with obesity.To date, however, no systematic pharmacokinetic (PK) or pharmacodynamic (PD) analyses of the clinical efficacy of QFA under hyperlipemia-associated oxidative stress conditions have been conducted. The present study, was therefore designed to construct a PK-PD model for this herb, with the goal of linking QFA PK profiles to key therapeutic outlines to guide the therapeutic use of this herb in clinical settings. METHODS: Rats were fed a high-fat diet in order to establish a model of hyperlipidemia, after which they were randomized into a normal control group (NCG), a normal treatment group (NTG), a model control group (MCG), and a model treated group (MTG) (n = 6 each). QAF decoction was used to treat rats in the NTG and MTG groups (25 g/kg), while equivalent volumes of physiological saline were administered to rats in the NCG and MCG groups. Plasma samples were collected from the mandibular vein for animals at appropriate time points and analyzed via high-performance liquid chromatography (HPLC). We evaluated PK properties for three QAF components and compared these dynamics between the NTG and MTG groups, while also measuring levels of lipid peroxidation (LPO) in the plasma of rats in all four treatment groups. We then constructed a PK-PD model based upon plasma neohesperidin, luteolin, and nobiletin concentrations and LPO levels using a three-compartment PK model together with a Sigmoid Emax PD model. This model thereby enabled us to assess the antioxidative impact of neohesperidin, luteolin, and nobiletin on hyperlipidemia in rats. RESULTS: When comparing the NTG and MTG groups, we detected significant differences in the following parameters pertaining to neohesperidin, luteolin, and nobiletin:t1/2ß, V1, t1/2γ, CL1 (p < 0.01) and AUC0-t, Tmax, Cmax (p < 0.05). Relative to NTG group rats, AUC0-t, TmaxandCmaxvalues significantly higher for MTG group rats (p < 0.01), while t1/2ß, V1, and t1/2γ values were significantly lower in MTG group rats (p < 0.01) in MTG rats. QAF decoction also exhibited excellent PD efficacy in MTG rats, with significant reductions in plasma LPO levels relative to NTG rats (p < 0.01) following treatment. This therapeutic efficacy may be attributable to the activity of neohesperidin, luteolin, and nobiletin, as LPO levels and plasma concentrations of these compounds were negatively correlated in treated rats. Based upon Akaike Information Criterion (AIC) values, we determined that neohesperidin, luteolin, and nobiletin PK processes were consistent with a three-compartment model. Together, these findings indicated that three active components in QAF decoction (neohesperidin, luteolin, and nobiletin) may exhibit antioxidant activity in vivo. CONCLUSION: Our in vivo data indicated that neohesperidin, luteolin and nobiletin components of QAF decoctions exhibit distinct PK and PD properties. Together, these findings suggest that hyperlipidemia-related oxidative stress can significantly impact QFA decoction PK and PD parameters. Our data additionally offer fundamental insights that can be used to design appropriate dosing regimens for individualized clinical QAF decoction treatment.

Sympodial bamboo species differ in carbon bio-sequestration and stocks within phytoliths of leaf litters and living leaves.

Phytolith-occluded carbon (PhytOC) with high resistance against decomposition is an important carbon (C) sink in many ecosystems. This study compared concentrations of phytolith in plants and the PhytOC production of seven sympodial bamboo species in southern China, aiming to provide the information for the managed bamboo plantation and selection of bamboo species to maximize phytolith C sequestration. Leaf litters and living leaves of seven sympodial bamboo species were collected from the field sites. Concentrations of phytoliths, silicon (Si), and PhytOC in leaf litters and living leaves were measured. Carbon sequestration as PhytOC was estimated. There was a considerable variation in the PhytOC concentrations in the leaf litters and living leaves among the seven bamboo species. The mean concentrations of PhytOC ranged from 3.4 to 6.9 g kg(-1) in leaf litters and from 1.6 to 5.9 g kg(-1) in living leaves, with the PhytOC production rates ranging from 5.7 to 52.3 kg e-CO2 ha(-1) year(-1) as leaf litters. Dendrocalamopsis oldhami (Munro) Keng f. had the highest PhytOC production rate. Based on a bio-sequestration rate of 52.3 kg e-CO2 ha(-1) year(-1), we estimated that the current 8 × 10(5) ha of sympodial bamboo stands in China could potentially acquire 4.2 × 10(4) t e-CO2 yearly via phytolith carbon. Furthermore, the seven sympodial bamboo species stored 5.38 × 10(5) t e-CO2 as PhytOC in living leaves and leaf litters in China. It is concluded that sympodial bamboos make a significant contribution to C sequestration and that to maximize the PhytOC accumulation, the bamboo species with the highest PhytOC production rate should be selected for plantation.

Production of carbon occluded in phytolith is season-dependent in a bamboo forest in subtropical China.

Carbon (C) occluded in phytolith (PhytOC) is a stable form of C; when PhytOC is returned to the soil through litterfall it is stored in the soil which can be an effective way for long-term C sequestration. However, few estimates on the rate of PhytOC input to the soil are available. To better understand the seasonal dynamics of PhytOC production and the annual rate of stable C sequestration through PhytOC input, we quantified the monthly litterfall, phytolith and PhytOC return to the soil over a year in a typical Lei bamboo (Phyllostachys praecox) forest in subtropical China. The monthly litterfall ranged between 14.81 and 131.18 g m(-2), and the phytolith concentration in the monthly litterfall samples ranged between 47.21 and 101.68 g kg(-1) of litter mass, with the PhytOC concentration in the phytolith ranged between 29.4 and 44.9 g kg(-1) of phytolith, equivalent to 1.8-3.6 g kg(-1) of PhytOC in the litterfall (based on litterfall dry mass). The amount of phytolith input to the soil system was 292.21 ± 69.12 (mean ± SD) kg ha(-1) yr(-1), sequestering 41.45 ± 9.32 kg CO2-e ha(-1) yr(-1) of C in the studied Lei bamboo forest. This rate of C sequestration through the formation of PhytOC found in this study falls within the range of rates for other grass-type species reported in the literature. We conclude that return of C occluded in phytolith to the soil can be a substantial source of stable soil C and finding means to increase PhytOC storage in the soil should be able to play a significant role in mitigating the rapidly increasing atmospheric CO2 concentration.