Intervention in chronically activated microglia-mediated neuroinflammation is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood‒brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acid-cleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 peptides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improvements in late APP/PS1 mice.

The activation of the sirtuin1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing reactive oxygen species (ROS) levels. Clinical trials have demonstrated that Zhongfeng Xingnao Liquid (ZFXN) ameliorates post-stroke cognitive impairment (PSCI). However, the underlying mechanism, particularly whether it involves protecting mitochondria and inhibiting apoptosis through the SIRT1/Nrf2/HO-1 pathway, remains unclear. This study employed an oxygen-glucose deprivation (OGD) cell model using SH-SY5Y cells and induced PSCI in rats through modified bilateral carotid artery ligation (2VO). The effects of ZFXN on learning and memory, neuroprotective activity, mitochondrial function, oxidative stress, and the SIRT1/Nrf2/HO-1 pathway were evaluated both in vivo and in vitro. Results indicated that ZFXN significantly increased the B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax) ratio, reduced terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL)⁺ cells, and markedly improved cognition, synaptic plasticity, and neuronal function in the hippocampus and cortex. Furthermore, ZFXN exhibited potent antioxidant activity, evidenced by decreased ROS and malondialdehyde (MDA) content and increased superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels. ZFXN also demonstrated considerable enhancement of mitochondrial membrane potential (MMP), Tom20 fluorescence intensity, adenosine triphosphate (ATP) and energy charge (EC) levels, and mitochondrial complex I and III activity, thereby inhibiting mitochondrial damage. Additionally, ZFXN significantly increased SIRT1 activity and elevated SIRT1, nuclear Nrf2, and HO-1 levels. Notably, these effects were substantially counteracted when SIRT1 was suppressed by the inhibitor EX-527 in vitro. In conclusion, ZFXN alleviates PSCI by activating the SIRT1/Nrf2/HO-1 pathway and preventing mitochondrial damage.
Sirtuin 1/genetics* ; Animals ; NF-E2-Related Factor 2/genetics* ; Cognitive Dysfunction/genetics* ; Male ; Rats, Sprague-Dawley ; Rats ; Humans ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/administration & dosage* ; Heme Oxygenase-1/genetics* ; Stroke/complications* ; Oxidative Stress/drug effects* ; Apoptosis/drug effects* ; Mitochondria/metabolism* ; Reactive Oxygen Species/metabolism* ; Neuroprotective Agents

This article explores the construction and practice of the"Party Building+Health Science Popularization"model,using the"Yixian Health Science Popularization Guangdong Tour"campaign conducted by Sun Yat-sen Memorial Hospital as a case study.The initiative has achieved remarkable results.Additionally,it summarizes innovative measures,as well as uni-versal and exemplary experiences,providing new insights and pathway recommendations for public hospitals to develop the"Party Building+Health Science Popularization"model.

Objective:To explore the role of lactate in Superoxide dismutase 2 (SOD2) lactylation in cerebral ischemia-reperfusion injury in mice.Methods:Male C57BL/6 mice were randomLy (random number) divided into 4 groups: sham operation group (Sham group), Middle Cerebral Artery Occlusion/Reperfusion group (MCAO/R group), Middle Cerebral Artery Occlusion/Reperfusion+2-Deoxy-D-glucose group (MCAO/R+2-DG group), Middle Cerebral Artery Occlusion/Reperfusion+sodium lactate group (MCAO/R+Nala group). Cerebral ischemia reperfusion injury model was established in the mice of MCAO/R group using the thread occlusion. In the MCAO/R+2-DG group, mice received an intraperitoneal injection of 250 mg/kg of 2-DG 90 min before ischemia. Mice in the MCAO/R+ Nala group was given an intraventricular injection of 2 μL of 100 mmol/L Nala 24 h before ischemia. Commercial kits was used to detect lactate levels, Hematoxylin & Eosin Staining (HE) was employed to observe cell morphology, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed to assess cell apoptosis, and immunofluorescence was utilized to detect reactive oxygen species (ROS). Western blot was conducted to measure SOD2, Superoxide Dismutase 2 Lysine 114 Lactylation(SOD2-K114la), Iron regulatory protein 2(IRP2) and transferrin receptor protein 1(TFR1) levels. The above indicators were analyzed and compared by one-way variance.Results:Compared with the Sham group, the MCAO/R group showed increased levels of lactate, SOD2-K114la, TUNEL positive rate, ROS, IRP2 and TFR1[lactate: (0.608±0.064) vs. (0.376±0.030), P<0.005; SOD2-K114la: (2.311±0.146) vs. (1.009±0.073), P<0.0005; TUNEL positive rate: (35.420±2.832) vs. (0.294±0.147), P<0.0001; ROS: (3.415±0.229) vs. (1.166±0.155), P<0.0001; IRP2: (1.735±0.125) vs. (1.000±0.000), P<0.0001; TFR1: (1.611±0.058) vs. (1.000±0.000), P<0.0001], while SOD2 decreased[(0.545±0.062) vs. (1.082±0.088), P<0.0001]. HE staining indicated brain damage. Compared with the MCAO/R group, the MCAO/R+2-DG group showed reduced levels of lactate, SOD2-K114la, TUNEL positive rate, ROS, IRP2, and TFR1[lactate: (0.453±0.047) vs. (0.608±0.064), P<0.05; SOD2-K114la: (1.764±0.188) vs. (2.311±0.146), P<0.05; TUNEL positive rate: (23.800±3.168) vs. (35.420±2.832), P<0.005; ROS: (2.640±0.213) vs. (3.415±0.229), P<0.005; IRP2: (1.463±0.055) vs. (1.735±0.125), P<0.05; TFR1: (1.252±0.081) vs. (1.611±0.058), P<0.005], with higher level of SOD2 [(0.727±0.026) vs. (0.545±0.062), P<0.05]. Meanwhile, HE staining indicated reduced damage. Compared with the MCAO/R group, the MCAO/R+Nala group showed increased levels of lactate, SOD2-K114la, TUNEL positive rate, ROS, IRP2 and TFR1[lactate: (1.021±0.051) vs. (0.608±0.064), P<0.0001; SOD2-K114la: (3.479±0.275) vs. (2.311±0.146), P<0.0005; TUNEL positive rate: (53.430±3.551) vs. (35.420±2.832), P<0.0001; ROS: (4.687±0.253) vs. (3.415±0.229), P<0.0001; IRP2: (2.463±0.117) vs. (1.735±0.125), P<0.0001; TFR1: (2.209±0.094) vs. (1.611±0.058), P<0.0001], with decreased levels of SOD2 [(0.286±0.040) vs. (0.545±0.062), P<0.0001]. And HE staining revealed worsened braindamage. Conclusions:Increased lactate levels can enhance the lactylation of SOD2, exacerbating brain damage after Cerebral ischemia reperfusion injury(CIRI). Inhibiting lactate production may alleviate brain injury by regulating iron Metabolism.

This article explores the construction and practice of the"Party Building+Health Science Popularization"model,using the"Yixian Health Science Popularization Guangdong Tour"campaign conducted by Sun Yat-sen Memorial Hospital as a case study.The initiative has achieved remarkable results.Additionally,it summarizes innovative measures,as well as uni-versal and exemplary experiences,providing new insights and pathway recommendations for public hospitals to develop the"Party Building+Health Science Popularization"model.

The conventional identification and prediction for failures of medical equipment mainly depend on experience and knowledge of manager for equipment,which are not able to be quantified and have lower efficiency. Therefore,it is obvious that the prediction for the failure of medical equipment is not accurate. With the technical development of computer and machine learning,the conventional identification and prediction that depend on experiences can deal with characteristics of failures through machine learning method to improve efficiency,which are hopeful in filling the gap of discipline about the identification and prediction for failures of medical equipment. This article summarized the application situation of machine learning in identifying and predicting failures of the medical equipment and the similarly electric equipment at home and abroad. Based on the key technique of identification and prediction,this article proposed suggestion about corresponding design architecture. According to the characteristics of the failure of medical equipment,this article summarized a series of information about algorithms of various machine learning in scene and accurate rate of identification and prediction,so as to provide references for relevant research of this field.

The conventional identification and prediction for failures of medical equipment mainly depend on experience and knowledge of manager for equipment,which are not able to be quantified and have lower efficiency. Therefore,it is obvious that the prediction for the failure of medical equipment is not accurate. With the technical development of computer and machine learning,the conventional identification and prediction that depend on experiences can deal with characteristics of failures through machine learning method to improve efficiency,which are hopeful in filling the gap of discipline about the identification and prediction for failures of medical equipment. This article summarized the application situation of machine learning in identifying and predicting failures of the medical equipment and the similarly electric equipment at home and abroad. Based on the key technique of identification and prediction,this article proposed suggestion about corresponding design architecture. According to the characteristics of the failure of medical equipment,this article summarized a series of information about algorithms of various machine learning in scene and accurate rate of identification and prediction,so as to provide references for relevant research of this field.

The neurovascular unit (NVU) is highly responsible for cerebral homeostasis and its dysfunction emerges as a critical contributor to Alzheimer's disease (AD) pathology. Hence, rescuing NVU dysfunction might be a viable approach to AD treatments. Here, we fabricated a self-regulated muti-functional nano-modulator (siR/PIO@RP) that can intelligently navigate to damaged blood-brain barrier and release therapeutical cargoes for synergetic AD therapy. The resulting siR/PIO@RP enables self-regulation of its distribution in accordance with the physio/pathological state (low/high RAGE expression) of the target site via a feedback loop. siR/PIO@RP is capable of performing intricate tasks and goes beyond the capabilities of single-target therapeutic agents utilized in AD therapy, such as reducing cerebral Aβ load, relieving neuroinflammation, and alleviating the dysfunction of NVU. Overall, the current study provides proof of concept that normalizing NVU holds promise as a means of alleviating AD symptoms.

Significant research progress has been made in the development of antibody-drug conjugates (ADCs) for the treatment of ad-vanced breast cancer (ABC),ushering new hope for patients with this refractory disease. Through the conjugation of specific antibodies with highly potent cytotoxic drugs,tumor cells can be precisely targeted and killed while minimizing damage to normal tissues. ADCs such as trastuzumab-emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd),have shown excellent efficacy in the treatment of HER2-positive ABC,significantly prolonging patient survival. Furthermore,ADCs targeting triple-negative breast cancer (TNBC),such as sacituzumab govitecan (SG),have also achieved positive results in clinical trials. With the continuous research,development,and optimization of ADCs,as well as the exploration of combination treatment strategies,ADCs are expected to play an increasingly important role in the treatment of ABC in the future. This article provides an overview of the research progress of ADCs in the treatment of ABC,exploring their efficacy and safety. We aim to offer more treatment options and renewed hope for patients with ABC.

Objective To explore the role of the PPARα/HOXA10 signaling pathway in mediating the effect of adiponectin(APN)for improving endometrial receptivity in a rat model of polycystic ovary syndrome(PCOS).Methods Forty female SD rat models with letrozole-induced PCOS were randomized,with 10 normal rats as the control,into 4 equal groups for treatment with APN alone,APN combined with GW6471(a specific PPARα inhibitor)or the vehicle for 20 days,or no further treatment(PCOS model group).GW6471 treatment(daily dose of 1 mg/kg)and vehicle treatment were initiated on the 11th day following the start of APN treatment,all administered via intraperitoneal injection.The rats were observed for changes in estrous cycle,body weight,ovarian index and morphology,uterine index and morphology,serum hormone levels and lipid metabolism parameters.Endometrial expressions of PPARα and HOXA10 were detected with immunohistochemistry and Western blotting.The development of endometrial pinopodes was observed under electron microscope,and pregnancies of the rats were recorded.Results The rat models of PCOS exhibited obvious estrous cycle disorders with significantly prolonged estrous interval,increased body weight and ovarian index,decreased uterine index,disordered serum hormones and lipid metabolism(P<0.05),and polycystic ovarian changes,and these changes were significantly improved by APN treatment.Endometrial expressions of PPARα and HOXA10 were significantly lowered in PCOS rats and effectively up-regulated after APN treatment,but GW6471 treatment obviously blocked the effect of APN(P<0.05).APN showed strong protective effect against PCOS-induced impairment of endometrial pinopode development,and this effect was obviously attenuated by GW6471.APN also significantly increased the pregnancy rate and embryo number in PCOS rats,while GW6471 obviously reduced the embryo number and caused developmental retardation of the embryos.Conclusion APN can improve endometrial receptivity in PCOS rats by upregulating the PARα/HOXA10 pathway.