NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance.

The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically1,2. This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells3. However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the 'writer' of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy.

The dePARylase NUDT16 promotes radiation resistance of cancer cells by blocking SETD3 for degradation via reversing its ADP-ribosylation.

Poly(ADP-ribosyl)ation (PARylation) is a critical posttranslational modification that plays a vital role in maintaining genomic stability via a variety of molecular mechanisms, including activation of replication stress and the DNA damage response. The nudix hydrolase NUDT16 was recently identified as a phosphodiesterase that is responsible for removing ADP-ribose units and that plays an important role in DNA repair. However, the roles of NUDT16 in coordinating replication stress and cell cycle progression remain elusive. Here, we report that SETD3, which is a member of the SET-domain containing protein (SETD) family, is a novel substrate for NUDT16, that its protein levels fluctuate during cell cycle progression, and that its stability is strictly regulated by NUDT16-mediated dePARylation. Moreover, our data indicated that the E3 ligase CHFR is responsible for the recognition and degradation of endogenous SETD3 in a PARP1-mediated PARylation-dependent manner. Mechanistically, we revealed that SETD3 associates with BRCA2 and promotes its recruitment to stalled replication fork and DNA damage sites upon replication stress or DNA double-strand breaks, respectively. Importantly, depletion of SETD3 in NUDT16-deficient cells did not further exacerbate DNA breaks or enhance the sensitivity of cancer cells to IR exposure, suggesting that the NUDT16-SETD3 pathway may play critical roles in the induction of tolerance to radiotherapy. Collectively, these data showed that NUDT16 functions as a key upstream regulator of SETD3 protein stability by reversing the ADP-ribosylation of SETD3, and NUDT16 participates in the resolution of replication stress and facilitates HR repair.

Adolescent administration of ketamine impairs excitatory synapse formation onto parvalbumin-positive GABAergic interneurons in mouse prefrontal cortex.

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, induces deficits in cognition and information processing following chronic abuse. Adolescent ketamine misuse represents a significant global public health issue; however, the neurodevelopmental mechanisms underlying this phenomenon remain largely elusive. This study investigated the long-term effects of sub-chronic ketamine (Ket) administration on the medial prefrontal cortex (mPFC) and associated behaviors. In this study, Ket administration during early adolescence displayed a reduced density of excitatory synapses on parvalbumin (PV) neurons persisting into adulthood. However, the synaptic development of excitatory pyramidal neurons was not affected by ketamine administration. Furthermore, the adult Ket group exhibited hyperexcitability and impaired socialization and working memory compared to the saline (Sal) administration group. These results strongly suggest that sub-chronic ketamine administration during adolescence results in functional deficits that persist into adulthood. Bioinformatic analysis indicated that the gene co-expression module1 (M1) decreased expression after ketamine exposure, which is crucial for synapse development in inhibitory neurons during adolescence. Collectively, these findings demonstrate that sub-chronic ketamine administration irreversibly impairs synaptic development, offering insights into potential new therapeutic strategies.

A rat model of cerebral small vascular disease induced by ultrasound and protoporphyrin.

Cerebral small vascular disease (CSVD) has a high incidence worldwide, but its pathological mechanisms remain poorly understood due to the lack of proper animal models. The current animal models of CSVD have several limitations such as high mortality rates and large-sized lesions, and thus it is urgent to develop new animal models of CSVD. Ultrasound can activate protoporphyrin to produce reactive oxygen species in a liquid environment. Here we delivered protoporphyrin into cerebral small vessels of rat brain through polystyrene microspheres with a diameter of 15 µm, and then performed transcranial ultrasound stimulation (TUS) on the model rats. We found that TUS did not affect the large vessels or cause large infarctions in the brain of model rats. The mortality rates were also comparable between the sham and model rats. Strikingly, TUS induced several CSVD-like phenotypes such as cerebral microinfarction, white matter injuries and impaired integrity of endothelial cells in the model rats. Additionally, these effects could be alleviated by antioxidant treatment with N-acetylcysteine (NAC). As control experiments, TUS did not lead to cerebral microinfarction in the rat brain when injected with the polystyrene microspheres not conjugated with protoporphyrin. In sum, we generated a rat model of CSVD that may be useful for the mechanistic study and drug development for CSVD.

Impact of Relative Improvement in Quantitative Flow Ratio on Clinical Outcomes After Percutaneous Coronary Intervention　- A Subanalysis of the PANDA III Trial.

BACKGROUND: The clinical impact of relative improvements in coronary physiology in patients receiving percutaneous coronary intervention (PCI) for coronary artery disease (CAD) remains undetermined. METHODS AND RESULTS: The quantitative flow ratio (QFR) recovery ratio (QRR) was calculated in 1,424 vessels in the PANDA III trial as (post-PCI QFR-pre-PCI QFR)/(1-pre-PCI QFR). The primary endpoint was the 2-year vessel-oriented composite endpoint (VOCE; a composite of vessel-related cardiac death, vessel-related non-procedural myocardial infarction, and ischemia-driven target vessel revascularization). Study vessels were dichotomously stratified according to the optimal QRR cut-off value. During the 2-year follow-up, 41 (2.9%) VOCEs occurred. Low (<0.86) QRR was associated with significantly higher rates of 2-year VOCEs than high (≥0.86) QRR (6.6% vs. 1.4%; adjusted hazard ratio [aHR] 5.05; 95% confidence interval [CI] 2.53-10.08; P<0.001). Notably, among vessels with satisfactory post-procedural physiological results (post-PCI QFR >0.89), low QRR also conferred an increased risk of 2-year VOCEs (3.7% vs. 1.4%; aHR 3.01; 95% CI 1.30-6.94; P=0.010). Significantly better discriminant and reclassification performance was observed after integrating risk stratification by QRR and post-PCI QFR to clinical risk factors (area under the curve 0.80 vs. 0.71 [P=0.010]; integrated discrimination improvement 0.05 [P<0.001]; net reclassification index 0.64 [P<0.001]). CONCLUSIONS: Relative improvement of coronary physiology assessed by QRR showed applicability in prognostication. Categorical classification of coronary physiology could provide information for risk stratification of CAD patients.

Genome-centric metagenomics and methanogenic pathway analysis for acclimated anaerobic digestion of chicken manure with high ammonia stressed under thermophilic condition.

Thermophilic anaerobic digestion (AD) of animal manure offers various environmental benefits but the process requires a microbial community acclimatized to high ammonia. In current study, a lab-scale continuous stirred tank reactor (CSTR) fed with chicken manure was operated under thermophilic condition for 450 days in total. Results showed that the volumetric methane production decreased from 445 to 328 and sharply declined to 153 mL L-1·d-1 with feeding total solid (TS) step increased from 5% to 7.5% and 10%, respectively. While, after a long-term stop feeding for 80 days, highly disturbed reactor was able to recover methane generation to 739 mL L-1·d-1 at feeding TS of 10%. Isotope analysis indicted acetate converted to methane through the syntrophic acetate oxidation and hydrogenotrophic methanogenesis (SAO-HM) pathway increased from 33% to 63% as the concentration of ammonium increased from 2493 to 6258 mg L-1. Significant different in the genome expression of the SAO bacterial from 0.09% to 1.23%, combining with main hydrogenotrophic partners (Methanoculleus spp. and Methanothermobacter spp.) contented of 2.1% and 99.9% during inhibitory and recovery stages, respectively. The highly expressed KEGG pathway in level 3 (enzyme genes) for the Recovery sludge combining with the extraordinary high abundance of genera Halocella sp. suggested that Halocella sp. might be a highly efficient hydrolytic and acidogenic microorganism and enhance the process of SAO during carbon metabolic flow to methane. This report will be a basis for further study of AD studies on high nitrogen content of poultry manure.

Renal thrombotic microangiopathy is associated with poor renal survival in children with immunoglobulin A nephropathy.

AIM: The aim of this study was to examine the clinical and pathological characteristics as well as the prognosis of immunoglobulin A nephropathy (IgAN) accompanied by renal thrombotic microangiopathy (rTMA) in paediatric patients. METHODS: After balancing epidemiological characteristics and pathological types between groups, 427 patients (rTMA group: 23, non-rTMA group: 46) were included. The clinical and pathological features, prognosis and clinical risk factors of the two groups were analysed. RESULTS: IgAN-rTMA children showed more severe clinical and pathological manifestations. The findings from the logistic regression analysis indicated that hypercellularity 1 (E1) (HR: 0.805, 95% CI: 0.763 ~ 1.452, P = .016), endocapillary proliferation (HR: 1.214, 95% CI: 0.093 ~ 4.815, P = .025) and C3 staining (HR: 7.554, 95% CI: 2.563 ~ 15.729, P = .037) were the risk factors for rTMA in children with IgAN. The renal survival in rTMA group was lower than non-rTMA group (χ2 = 18.467, P = .000). Cox regression analysis showed that E1 (HR: 7.441, 95% CI: 1.095 ~ 10.768, P = .037), C3 disposition (HR: 3.414, 95% CI: 0.834 ~ 11.578, P = .027) and rTMA (HR: 8.918, 95% CI: 1.032 ~ 16.754, P = .041) were identified as independent risk factors for the development of end-stage renal disease (ESRD). CONCLUSION: The presence of rTMA had a significant impact on the severity and prognosis of IgAN. And rTMA has been identified as an independent risk factor for the development of renal failure in children diagnosed with IgAN.

Efficacy of Botulinum Toxin in the Treatment of Facial and Cervical Hypertrophic Scar: A Meta-Analysis.

Objective: Maxillofacial-neck hyperplastic scars have long been a persistent concern among individuals in both Western and Eastern countries. These scars exhibit rapid growth within 3-6 months following wound healing, subsequently receding at a slower pace, leading to skin redness, tension, and potential itching. The lack of comprehensive understanding regarding the formation mechanism and biological attributes of these scars has made them a prominent subject of research both domestically and internationally. Methods: Research data from 2010 to 2023 was selected, and relevant literature on the efficacy of botulinum toxin in the treatment of facial and neck hypertrophic scars was searched until August 2023. The literature on the incidence of facial-neck hypertrophic scars included in PubMed, the Cochrane Library, EMbase, and Web of Science was searched. Two researchers independently screened and extracted the data according to strict inclusion and exclusion criteria.Risk bias in Review Manager 5.4, provided by the Cochrane Collaboration, was used for methodological quality assessment and meta-analysis of the included literature. In case of any disagreement, the decision shall be made through consultation with the third party. Scar width, patient satisfaction, and visual analogue scale (VAS) were evaluated. Weighted mean difference (WMD), odds ratio (OR), and 95% confidence interval (95%CI) were used for evaluation. Publication bias was intuitively determined by funnel plot, and sensitivity analysis was conducted by removing literatures one by one for risk assessment. Results: After reading the title, abstract, and full text, a total of 237 patients were included in 7 articles. Scar width was only studied in 6 literatures, and the heterogeneity test of the included studies (χ2 = 148.95, P < .001, I2 = 98%) showed significant heterogeneity among the studies. Therefore, the random effects model was used to merge the data. Combined effect value WMD =-2.85 [95% CI :(-6.51, 0.81), P < .001], the difference between the two groups was statistically significant. The combined OR of the random-effects model was 8.52 [95%CI: (7.96, 9.08), P < .001], and the difference between the two groups was statistically significant. Among them, the heterogeneity test (χ2 = 2.69, P = .44, I² = 0%) was carried out in two studies, indicating good homogeneity among the studies, so the combined WMD was 0.68 [95%CI: (0.38, 0.99), P < .001] by using the fixed-effect model. The median VAS was described in the other two literatures, and the mean scores in the experimental group were 8.9 and 8.25, respectively, while the mean scores in the control group were 7.2 and 6.28, respectively, indicating that local injection of botulinum A toxin at the early stage of wound healing can significantly improve scar quality. Sensitivity analysis suggested that the meta-analysis results were stable and reliable, and publication bias was not analyzed using funnel plots. Conclusion: Botulinum toxin has a positive effect on preventing hyperplastic scars in the maxillofacial and neck areas, and it can also help fade existing scars.

Efficacy of Dexamethasone in Reducing Pain and Inflammation and Accelerating Total Hip Arthroplasty Postoperative Recovery: A Randomized Controlled Trial.

PURPOSE: To evaluate the efficacy of dexamethasone in reducing pain and accelerating recovery after total hip arthroplasty (THA). DESIGN: A prospective randomized controlled trial. METHODS: A total of 98 patients who underwent THA received either low-dose (10 mg) dexamethasone (dexa group) or isotonic saline (placebo group). C-reactive protein and interleukin-6 levels were recorded at 24, 48, and 72 hours after surgery. Pain visual analog scale (VAS) score at rest and walking, the incidence of postoperative nausea and vomiting (PONV), nausea VAS score, postoperative identity-consequence fatigue scale rating, antiemetic use, postoperative length of stay (PLOS), and complications were also recorded and compared. FINDINGS: Inflammatory marker (C-reactive protein and interleukin-6) levels at 24, 48, and 72 hours postoperatively in the dexa group were lower than that in the placebo group (P < .05). After 24 hours of rest, the dynamic pain VAS scores in the dexa group were lower than those in the placebo group (P < .05). The incidence of PONV, nausea VAS score, and identity-consequence fatigue scale score in the dexa group were lower than those in the placebo group (P < .05), and the dosages of analgesics and antiemetics were also lower (P < .05). In addition, PLOS in the dexa group was shorter than that in the placebo group (P < .05). No significant difference in perioperative complications between the two groups was observed (P > .05). CONCLUSIONS: Low-dose dexamethasone in the THA perioperative period can effectively reduce inflammatory marker levels, pain, nausea, postoperative fatigue, opioid analgesic use, and shorten PLOS without increasing complications.

Impacts of Diabetes Mellitus on Cardiovascular Outcomes and Differential Effects of Direct Oral Anticoagulants in Patients with Left Ventricular Thrombus.

Background: The focus of this investigation into the impact of type 2 diabetes mellitus (T2DM) on left ventricular thrombus (LVT) is (a) the differences in LVT characteristics, (b) long-term clinical outcomes, and (c) differential effects of direct oral anticoagulants (DOAC) among patients with T2DM and without diabetes. Methods: Patients with confirmed LVT from 2009 to 2021 were included. The primary endpoints were major adverse cardiac and cerebrovascular events (MACCE), composite of cardiovascular death, ischemic stroke, and acute myocardial infarction (AMI). The secondary endpoints were all-cause death and cardiovascular death. Multivariable competing-risk regression and cumulative incidence functions (CIF) were used to evaluate the adverse consequences. Results: In total, 1675 patients were assessed initially. Follow-up data were available for 91.1% of the participants. Median follow-up was 3.8 years. This retrospective study ultimately comprised 1068 participants, of which 429 had T2DM. Significantly higher proportions of comorbidities were observed in the T2DM group. The location, morphology, and size of LVT were similar in the two groups. Multivariable analysis suggested a higher risk of MACCE among patients with T2DM. The difference in risk between the two groups after matching and weighting was not statistically significant. Among the whole sample (n = 638) or the just the non-diabetic patients with LVT and anticoagulation (n = 382), the incidence of MACCE did not differ between DOAC treatment and warfarin treatment. In the diabetic LVT population with anticoagulation (n = 256), DOAC treatment was associated with a significantly higher risk of MACCE than was warfarin treatment. Conclusions: The location and morphology of LVT are similar in T2DM and non-diabetic patients. A higher risk of MACCE was found among patients with diabetes.

Feasibility and Safety of Drug-Coated Balloon for Treatment of De Novo Coronary Artery Lesions in Large Vessel Disease: A Large-Scale Multicenter Prospective Study.

Background: Drug-coated balloons (DCB) have been evaluated to be safe and practical in treating coronary small vessel disease (SVD). However, evidence about the practicality and safety of DCB in treating coronary lesions with diameters greater than 3.0 mm is limited. Methods: 1166 patients who received DCB angioplasty were enrolled and divided into groups of SVD or large vessel disease (LVD) according to the target vessel diameters ( < 3.0 mm for SVD; ≥ 3.0 mm for LVD). All participants received a 2-year follow-up. The two main outcomes were patient-oriented composite endpoint (patient-oriented composite endpoint (POCE), all-cause mortality, all myocardial infarctions [MI], or any revascularization), and target lesion failure (target lesion failure (TLF), cardiac death, target vessel MI, or ischemia-driven target lesion revascularization). Results: In these patients, a total of 30 (2.6%) TLF and 82 (7.0%) POCE were recorded. Patients in the LVD group showed statistically greater rates of lesion success compared to the SVD group (752 [96.0%] vs. 380 [99.2%], p = 0.004) and procedural success (751 [95.9%] vs. 380 [99.2%], p = 0.003). No significant difference was found in the 2-year risk of TLF (hazard ratio (HR) 1.41, 95% CI 0.58-3.44; p = 0.455), POCE (HR 1.29, 95% CI 0.76-2.20; p = 0.354), MI (HR 0.88, 95% CI 0.24-3.13; p = 0.837), revascularization (HR 1.22, 95% CI 0.68-2.21; p = 0.506), and stroke (HR 0.78, 95% CI 0.03-15.26; p = 0.784) between the SVD and LVD groups. Conclusions: There was no discernible inferiority of the DCB intervention in the LVD group as compared to the SVD group. The DCB intervention is practical for coronary lesions with diameters higher than 3.0 mm.

Time Trends of Etiology, Treatment, and Long-Term Outcomes Among Patients with Left Ventricular Thrombus.

Background: Recommendations for drug treatment of left ventricular thrombus (LVT) are based on the ST-segment elevation myocardial infarction (STEMI) guidelines; however, the etiology of LVT has changed. Due to the lack of evidence regarding LVT treatment in the heart failure population, current heart failure guidelines do not cover LVT treatment. We sought to review the etiology of LVT and changes in antithrombotic therapy over the previous 12 years and explore the impact of anticoagulation treatment from a single center's experience. Methods: From January 2009 to June 2021, we studied 1675 patients with a discharge diagnosis of LVT at a single center to investigate the clinical characteristics, incidence of all-cause death, cardiovascular death, ischemic stroke, major adverse cardiac and cerebrovascular events (MACCE), systemic embolism (SE), and major bleeding events. Patients were divided into an anticoagulant group and a non-anticoagulant group according to whether they received oral anticoagulant therapy at discharge. Results: The study included 909 patients (anticoagulation, 510; no anticoagulation, 399). While overall antiplatelet therapy dramatically decreased, more patients with LVT received oral anticoagulation in 2021 (74.0%) than in 2009 (29.6%). In addition, more than half of the patients had heart failure with reduced ejection fraction (HFrEF) each year. The all-cause mortality was 17.3% during 3.8 years of follow-up. The incidences of cardiovascular death, stroke, MACCE, SE, and major bleeding were 16.0%, 3.3%, 19.8%, 5.1%, and 1.7%, respectively. The anticoagulation group had a significantly higher proportion of dilated cardiomyopathy than the non-anticoagulation group (24.7% vs. 5.5%, p < 0.001), and a lower LVEF (34.0 vs. 41.0, p < 0.001). The anticoagulation group also had a higher probability of adverse events on long-term follow-up (p > 0.05). A multivariable competing risk regression model found no significant difference in all six endpoints between the groups (all p > 0.05). Similar results were found by matched and weighted data analysis. Diabetes mellitus (hazard ratio (HR), 1.42; 95% confidence interval (CI), 1.04-1.93; p = 0.027), renal insufficiency (HR, 2.36; 95% CI, 1.60-3.50; p < 0.001), history of previous stroke (HR, 1.60; 95% CI, 1.13-2.29; p = 0.009), and HFrEF (HR, 2.54; 95% CI, 1.78-3.64; p < 0.001) were predictors of increased risk of MACCE. Conclusions: Heart failure, rather than acute myocardial infarction, is currently the primary cause of LVT. A trend towards better prognosis in the no anticoagulation group was noted. Multivariable, matching and weighting analysis showed no improvement in prognosis with anticoagulant therapy. Our study does not negate the efficacy of anticoagulation but suggests the need to strengthen the management of anticoagulation in order to achieve better efficacy.

Effect of Thin-Walled Radial Sheath for Large-Bore Access On Reducing Periprocedural Radial Artery Occlusion Following Complex PCI: The REDUCE-RAO Randomized Trial.

Background: Transradial artery (TRA) access for percutaneous coronary intervention (PCI) was associated with lower risks of major bleeding and vascular complications compared to transfemoral artery access. Use of large-bore ( ≥ 7-Fr) guiding catheters through TRA approach increased the likelihood of radial artery occlusion (RAO). This study aimed to investigate whether use of the thin-walled 7-Fr Glidesheath Slender, allowing PCI with large-caliber guiding catheters, is superior to standard 7-Fr Cordis sheath with respect to periprocedural RAO within 24 hours after transradial coronary intervention (TRI) in complex lesions. Methods: A prospective randomized, controlled, single-blinded (patient-blinded) trial was conducted, randomizing 504 patients with TRI for complex lesions to either 7-Fr Glidesheath Slender or conventional 7-Fr Cordis sheath. The primary outcome was defined as the incidence of periprocedural RAO with Doppler ultrasound during the first 24 hours after TRI. Results: The incidence of early RAO was 10.3% for 7-Fr Glidesheath Slender and 13.5% for conventional 7-Fr sheath (p = 0.271). The procedural success rate for Glidesheath Slender was 92.9% and for Cordis sheath was 93.7% (p = 0.722). There was no signficiant difference between treatment arms in terms of local hematoma and radial spasm, whereas use of the Glidesheath Slender was associated with significantly less pain during the procedure (numeric rating scale [NRS], 2.27 ± 0.75 vs. 2.45 ± 0.95, p = 0.017). The assessment of radial artery in ultrasound parameters after complex TRI was improved with Glidesheath Slender. Conclusions: Among patients with complex coronary lesions undergoing TRI, 7-Fr Glidesheath Slender was not superior to conventional 7-Fr in the prevention of periprocedural RAO within 24 hours following complex PCI, without reducing RAO occurrence. Clinical Trial Registration: NCT04748068.

Cyclic cryotherapy with vitamin D facilitates early rehabilitation after total knee arthroplasty.

Objective: This study aimed to evaluate the efficacy of cyclic cryotherapy and vitamin D administration on early rehabilitation after total knee arthroplasty (TKA), as its efficacy remains unclear. Methods: We divided 150 patients (three groups) who underwent TKA into those treated with or without cyclic cryotherapy and vitamin D. Results: Compared with patients who did not receive cyclic cryotherapy, those who received postoperative cyclic cryotherapy and vitamin D supplementation had significantly higher American Knee Society Scores (AKSS) on postoperative day (POD) 7 and at 1 month postoperatively; higher visual analogue scale (VAS) values on POD1-3 and POD7; reduced thigh swelling on POD3 and POD7; increased range of motion (ROM) on POD3, POD7, and at 1 month postoperatively; and reduced postoperative length of stay (PLOS). However, no significant difference in patient satisfaction was observed between the patient groups. At 1 and 3 months postoperatively, patients administered cyclic cryotherapy and vitamin D had significantly higher AKSS, ROM, and vitamin D levels than those who did not receive vitamin D. No perioperative complications such as surgical site infection, skin frostbite, or vitamin D intoxication were observed. Conclusion: Cyclic cryotherapy post-TKA had short-term advantages in terms of AKSS, VAS, thigh swelling, ROM, PLOS, and accelerated rehabilitation, but did not improve patient satisfaction. Cyclic cryotherapy combined with vitamin D improved AKSS and ROM at 1 and 3 months postoperatively.

Analgesic effects of pectoserratus plane block and intermediate cervical plexus block for transaxillary endoscopic thyroidectomy: a prospective randomized controlled trial.

BACKGROUND: Transaxillary endoscopic thyroidectomy (TAET) is favored for its favorable cosmetic outcomes and the preservation of anterior cervical function. Despite these benefits, postoperative analgesia has traditionally relied on pharmacological interventions, and regional anesthetic procedures may be an alternative method. This study aimed to evaluate the efficacy of an ultrasound-guided pectoserratus plane block (PSPB) combined with an intermediate cervical plexus block (ICPB) for TAET. METHODS: Forty patients undergoing TAET were randomized into two groups: the nerve block group (N.=20) received ultrasound guided PSPB with 20 ml of 0.375% ropivacaine and ICPB with 8 mL of 0.3% ropivacaine, while the control group (N.=20) received no block. The primary outcome was the Visual Analog Scale (VAS) scores for postoperative neck and axillary pain at different time points (1, 6, 12, 24 h) during rest and movement post-TAET. The secondary outcomes included intraoperative remifentanil consumption, incidence of postoperative nausea and vomiting (PONV), number of remedial analgesic requirements, and patient satisfaction postoperatively. RESULTS: Compared to the control group, patients in the nerve block had significantly lower VAS scores of the neck and axilla whether at rest or movement, and 1, 6, 12, and 24 h postoperatively (P<0.0125). The nerve block group showed higher patient satisfaction (P<0.001). No difference was observed in intraoperative remifentanil consumption, need for rescue analgesics, or other adverse effects 48 h postoperatively. CONCLUSIONS: Ultrasound-guided PSPB with ICPB significantly alleviated postoperative pain and improved patient satisfaction with TAET.

Effects of Nanoparticle-Mediated Dihydromyricetin to Diabetic Wounds: An In Vivo Study.

Diabetic wound is one of the serious complications of diabetes, and the wound is persistent and easily recurring, which seriously endangers the health and life of patients. How to effectively promote the healing of diabetic wounds has been a hot spot and difficult area of clinical research. Some previous studies have shown that dihydromyricetin has the effects of regulating blood glucose, controlling the severity, and inhibiting scarring. In the present study, we used polylactic-co-glycolic acid nanoparticles as a carrier to load dihydromyricetin to make drug-loaded nanoparticles and applied them dropwise (200 µL) to diabetic mice wounds by topical application to observe the healing and scar formation of diabetic wounds. We found that the healing rate of the diabetic mice was faster and the scar formation was less obvious. In addition, the elevated blood glucose level and weight loss of the mice in the treatment group were also reduced. Therefore, nanoparticle-mediated dihydromyricetin may be an effective treatment for diabetic wounds.

Geniposide effectively safeguards HT22 cells against Aß-induced damage by activating mitophagy via the PINK1/Parkin signaling pathway.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the significant involvement of amyloid-beta (Aß) peptide in its pathogenesis. Geniposide, derived from the versatile medicinal of Gardenia jasminoides, is one of the active compounds studied extensively. The objective was to explore the impact of geniposide on Aß25-35-induced damage in HT22 cells, specifically focusing on its modulation of PINK1/Parkin-mediated mitophagy. In our investigation, geniposide exhibited remarkable restorative effects by enhancing cell viability and preserving the mitochondrial membrane potential. Moreover, it effectively reduced and mitigated the oxidative stress and apoptosis rates induced by Aß25-35. Notably, geniposide exhibited the capacity to enhance autophagic flux, upregulate LC3II and Beclin-1 expression, and downregulate the expression of p62. Furthermore, geniposide positively influenced the expression of PINK1 and Parkin proteins, with molecular docking substantiating a strong interaction between geniposide and PINK1/Parkin proteins. Intriguingly, the beneficial outcomes of geniposide on alleviating the pronounced apoptosis rates, the overproduction of reactive oxygen species, and diminished the PINK1 and Parkin expression induced by Aß25-35 were compromised by the mitophagy inhibitor cyclosporine A (CsA). Collectively, these findings suggested that geniposide potentially shields HT22 cells against neurodegenerative damage triggered by Aß25-35 through the activation of mitophagy. The insights contribute valuable references to the defensive consequences against neurological damage of geniposide, thereby highlighting its potential as a therapeutic intervention in AD.

Salidroside pretreatment alleviates ferroptosis induced by myocardial ischemia/reperfusion through mitochondrial superoxide-dependent AMPKα2 activation.

BACKGROUND: Ferroptosis, a form of regulated cell death (RCD) that relies on excessive reactive oxygen species (ROS) generation, Fe2+accumulation, abnormal lipid metabolism and is involved in various organ ischemia/reperfusion (I/R) injury, expecially in myocardium. Mitochondria are the powerhouses of eukaryotic cells and essential in regulating multiple RCD. However, the links between mitochondria and ferroptosis are still poorly understood. Salidroside (Sal), a natural phenylpropanoid glycoside isolated from Rhodiola rosea, has mult-bioactivities. However, the effects and mechanism in alleviating ferroptosis caused by myocardial I/R injury remains unclear. PURPOSE: This study aimed to investigate whether pretreated with Sal could protect the myocardium against I/R damage and the underlying mechanisms. In particular, the relationship between Sal pretreatment, AMPKα2 activity, mitochondria and ROS generation was explored. STUDY DESIGN AND METHODS: Firstly, A/R or I/R injury models were employed in H9c2 cells and Sprague-Dawley rats. And then the anti-ferroptotic effects and mechanism of Sal pretreatment was detected using multi-relevant indexes in H9c2 cells. Further, how does Sal pretreatment in AMPKα2 phosphorylation was explored. Finally, these results were validated by I/R injury in rats. RESULTS: Similar to Ferrostatin-1 (a ferroptosis inhibitor) and MitoTEMPO, a mitochondrial free radical scavenger, Sal pretreatment effectively alleviated Fe2+ accumulation, redox disequilibrium and maintained mitochondrial energy production and function in I/R-induced myocardial injury, as demonstrated using multifunctional, enzymatic, and morphological indices. However, these effects were abolished by downregulation of AMPKα2 using an adenovirus, both in vivo and in vitro. Moreover, the results also provided a non-canonical mechanism that, under mild mitochondrial ROS generation, Sal pretreatment upregulated and phosphorylated AMPKα2, which enhanced mitochondrial complex I activity to activate innate adaptive responses and increase cellular tolerance to A/R injury. CONCLUSION: Overall, our work highlighted mitochondria are of great impotance in myocardial I/R-induced ferroptosis and demonstrated that Sal pretreatment activated AMPKα2 against I/R injury, indicating that Sal could become a candidate phytochemical for the treatment of myocardial I/R injury.

nNOS in Erbb4-positive neurons regulates GABAergic transmission in mouse hippocampus.

Neuronal nitric oxide synthase (nNOS, gene name Nos1) orchestrates the synthesis of nitric oxide (NO) within neurons, pivotal for diverse neural processes encompassing synaptic transmission, plasticity, neuronal excitability, learning, memory, and neurogenesis. Despite its significance, the precise regulation of nNOS activity across distinct neuronal types remains incompletely understood. Erb-b2 receptor tyrosine kinase 4 (ErbB4), selectively expressed in GABAergic interneurons and activated by its ligand neuregulin 1 (NRG1), modulates GABA release in the brain. Our investigation reveals the presence of nNOS in a subset of GABAergic interneurons expressing ErbB4. Notably, NRG1 activates nNOS via ErbB4 and its downstream phosphatidylinositol 3-kinase (PI3K), critical for NRG1-induced GABA release. Genetic removal of nNos from Erbb4-positive neurons impairs GABAergic transmission, partially rescued by the NO donor sodium nitroprusside (SNP). Intriguingly, the genetic deletion of nNos from Erbb4-positive neurons induces schizophrenia-relevant behavioral deficits, including hyperactivity, impaired sensorimotor gating, and deficient working memory and social interaction. These deficits are ameliorated by the atypical antipsychotic clozapine. This study underscores the role and regulation of nNOS within a specific subset of GABAergic interneurons, offering insights into the pathophysiological mechanisms of schizophrenia, given the association of Nrg1, Erbb4, Pi3k, and Nos1 genes with this mental disorder.

HDAC9-mediated calmodulin deacetylation induces memory impairment in Alzheimer's disease.

AIMS: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. AD pathology involves protein acetylation. Previous studies have mainly focused on histone acetylation in AD, however, the roles of nonhistone acetylation in AD are less explored. METHODS: The protein acetylation and expression levels were detected by western blotting and co-immunoprecipitation. The stoichiometry of acetylation was measured by home-made and site-specific antibodies against acetylated-CaM (Ac-CaM) at K22, K95, and K116. Hippocampus-dependent learning and memory were evaluated by using the Morris water maze, novel object recognition, and contextual fear conditioning tests. RESULTS: We showed that calmodulin (CaM) acetylation is reduced in plasma of AD patients and mice. CaM acetylation and its target Ca2+ /CaM-dependent kinase II α (CaMKIIα) activity were severely impaired in AD mouse brain. The stoichiometry showed that Ac-K22, K95-CaM acetylation were decreased in AD patients and mice. Moreover, we screened and identified that lysine deacetylase 9 (HDAC9) was the main deacetylase for CaM. In addition, HDAC9 inhibition increased CaM acetylation and CaMKIIα activity, and hippocampus-dependent memory in AD mice. CONCLUSIONS: HDAC9-mediated CaM deacetylation induces memory impairment in AD, HDAC9, or CaM acetylation may become potential therapeutic targets for AD.