OBJECTIVES: Whether vortioxetine has a utility as an adjuvant drug in the treatment of bipolar depression remains controversial. This study aimed to validate the efficacy and safety of vortioxetine in bipolar depression. METHODS: Patients with bipolar Ⅱ depression were enrolled in this prospective, two-center, randomized, 12-week pilot trial. The main indicator for assessing treatment effectiveness was a Montgomery-Asberg Depression Rating Scale (MADRS) of ≥50%. All eligible patients initially received four weeks of lurasidone monotherapy. Patients who responded well continued to receive this kind of monotherapy. However, no-response patients were randomly assigned to either valproate or vortioxetine treatment for eight weeks. By comprehensively comparing the results of MADRS over a period of 4‍‒‍12 weeks, a systematic analysis was conducted to determine whether vortioxetine could be used as an adjuvant drug for treating bipolar depression. RESULTS: Thirty-seven patients responded to lurasidone monotherapy, and 60 patients were randomly assigned to the valproate or vortioxetine group for eight weeks. After two weeks of combined valproate or vortioxetine treatment, the MADRS score in the vortioxetine group was significantly lower than that in the valproate group. There was no difference in the MADRS scores between the two groups at 8 and 12 weeks. The incidence of side effects did not significantly differ between the valproate and vortioxetine groups. Importantly, three patients in the vortioxetine group appeared to switch to mania or hypomania. CONCLUSIONS This study suggested that lurasidone combination with vortioxetine might have potential benefits to bipolar II depression in the early stage, while disease progression should be monitored closely for the risk of switching to mania.
Humans ; Bipolar Disorder/drug therapy* ; Vortioxetine/therapeutic use* ; Male ; Female ; Middle Aged ; Adult ; Valproic Acid/administration & dosage* ; Lurasidone Hydrochloride/administration & dosage* ; Prospective Studies ; Treatment Outcome ; Pilot Projects ; Drug Therapy, Combination ; Sulfides/therapeutic use* ; Antidepressive Agents/therapeutic use*

Cuproptosis, a recently discovered form of regulated cell death involving copper ion metabolism, has emerged as a promising approach for tumor therapy. This pathway not only directly eliminates tumor cells but also promotes immunogenic cell death (ICD), reshaping the tumor microenvironment (TME) and initiating robust anti-tumor immune responses. However, translating cuproptosis-based therapies into clinical applications is hindered by challenges, including complex metabolic regulation, TME heterogeneity, and the precision required for effective drug delivery. To address these limitations, nanoparticles offer transformative solutions by providing precise delivery of cuproptosis-inducing agents, controlled drug release, and enhanced therapeutic efficacy through simultaneous modulation of metabolic pathways and immune responses. This review systematically discusses recent advancements in nanoparticle-based cuproptosis delivery systems, highlighting nanoparticle design principles and their synergistic effects when integrated with other therapeutic modalities such as ICB, PTT, and CDT. Furthermore, we explore the potential of cuproptosis-based nanomedicine for personalized cancer treatment by emphasizing strategies for TME stratification and therapeutic optimization tailored to patient profiles. By integrating current insights from metabolic reprogramming, tumor immunotherapy, and nanotechnology, this review aims to facilitate the clinical translation of cuproptosis nanomedicine and significantly contribute to the advancement of precision oncology.

Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Rheumatoid arthritis (RA) represents a persistent autoimmune condition distinguished by a multifaceted etiology that encompasses both genetic and environmental factors. Recent progress in understanding the mechanisms behind RA pathogenesis has delved into the critical role of epigenetic regulatory processes, including DNA methylation, histone modifications, and the regulation by microRNAs (miRNAs). These findings provide new insights into the intricate nature of RA and pave the way for innovative therapeutic strategies. This review consolidates the latest developments in the epigenetic regulation of RA, concentrating on how these mechanisms affect the dysregulated signaling pathways associated with the disease. We analyze the roles of specific proteins that function as 'writers', 'erasers', and 'readers' in epigenetic modifications, highlighting their potential as targets for therapeutic intervention. Additionally, in view of the significance of miRNAs in the pathogenesis of RA, we deliberate on their involvement in disease progression and explore miRNA-based treatment strategies. By integrating these diverse epigenetic dimensions, this review offers a comprehensive epigenetic perspective on RA pathogenesis and identifies promising avenues for future research and therapeutic interventions.

OBJECTIVES: To investigate the protective effects of dexmedetomidine (DEX) against heat stress (HS)-induced oncosis in human skeletal muscle cells (HSKMCs) and its underlying mechanisms. METHODS: A HSKMC model of HS-induced oncosis were established by 43 ℃ water bath for 4 h, and the effects of treatments with 30 μmol/L DEX, ML385 (a Nrf2 inhibitor) +DEX, si-Nrf2+HS, and si-Nrf2+DEX prior to modeling on cell viability was assessed using CCK-8 assay. Oncosis characteristics were evaluated using transmission electron microscopy and Annexin V-FITC/PI flow cytometry. The oxidative stress markers (GSH, GSH-Px, MDA, SOD and ROS), mitochondrial membrane potential, energy metabolism, and inflammatory cytokines (TNF-α, IL-6 and IL-1β) in the cells were quantified using standard kits, and the expressions of porimin, caspase-3 and Nrf2 pathway proteins were analyzed using Western blotting and qRT-PCR. RESULTS: HS induced typical oncotic features in HSKMCs including organelle swelling and cytoplasmic vacuolization. DEX pretreatment significantly attenuated these changes, reduced Annexin V⁺/PI⁺ cell ratio and cellular porimin expression, and lowered the levels of ROS and MDA while restoring GSH and SOD levels. DEX pretreatment also significantly increased the mitochondrial membrane potential and ATP level, upregulated the expressions of Nrf2, p-Nrf2, HO-1 and NQO1, and suppressed the expressions of TNF-α, IL-6 and IL-1β. The protective effects of DEX were obviously attenuated by interventions with ML385 or si-Nrf2. CONCLUSIONS DEX mitigates HS-induced HSKMC oncosis by activating the Nrf2/HO-1 pathway to relieve oxidative stress, mitochondrial dysfunction, and inflammatory responses.
Humans ; Dexmedetomidine/pharmacology* ; NF-E2-Related Factor 2/metabolism* ; Oxidative Stress/drug effects* ; Heat-Shock Response/drug effects* ; Signal Transduction/drug effects* ; Membrane Potential, Mitochondrial ; Muscle, Skeletal/cytology* ; Heme Oxygenase-1/metabolism* ; Apoptosis/drug effects*

Hypoxic-ischemic (HI) brain damage poses a high risk of death or lifelong disability, yet effective treatments remain elusive. Here, we demonstrated that miR-100-5p levels in the lesioned cortex increased after HI insult in neonatal mice. Knockdown of miR-100-5p expression in the brain attenuated brain injury and promoted functional recovery, through inhibiting the cleaved-caspase-3 level, microglia activation, and the release of proinflammation cytokines following HI injury. Engineered extracellular vesicles (EVs) containing neuron-targeting rabies virus glycoprotein (RVG) and miR-100-5p antagonists (RVG-EVs-Antagomir) selectively targeted brain lesions and reduced miR-100-5p levels after intranasal delivery. Both pre- and post-HI administration showed therapeutic benefits. Mechanistically, we identified protein phosphatase 3 catalytic subunit alpha (Ppp3ca) as a novel candidate target gene of miR-100-5p, inhibiting c-Fos expression and neuronal apoptosis following HI insult. In conclusion, our non-invasive method using engineered EVs to deliver miR-100-5p antagomirs to the brain significantly improves functional recovery after HI injury by targeting Ppp3ca to suppress neuronal apoptosis.
Animals ; MicroRNAs/metabolism* ; Extracellular Vesicles/metabolism* ; Mice ; Recovery of Function/physiology* ; Hypoxia-Ischemia, Brain/therapy* ; Mice, Inbred C57BL ; Antagomirs/administration & dosage* ; Male ; Animals, Newborn ; Apoptosis/drug effects* ; Brain Injuries/metabolism* ; Glycoproteins ; Peptide Fragments ; Viral Proteins

Disruption of normal secretion or mucociliary clearance can impair airway defense mechanisms and lung function, and increase the risk of infection. Airway clearance techniques are recommended as part of a comprehensive treatment plan for patients. Among these, vibratory expectoration is an important method of airway clearance, which loosens and liquefies mucus and metabolites on the surface of the respiratory tract through chest wall oscillation, promoting ciliary movement to facilitate sputum expulsion. However, commonly used handheld vibrating head devices and vest-type vibration expectorators have several limitations in clinical practice, such as inconvenience of operation, limited treatment time, poor adaptability, and difficulty in disinfection. To address these issues, the research team from the department of critical care medicine at Ruijin Hospital, Shanghai Jiao Tong University, has designed a novel belt-type vibration expectorator, which has been granted a national utility model patent (Patent No.: ZL 2023 2 1610983.1). The device is mainly composed of a chest strap assembly, a sputum clearance component, and a fixed shoulder strap component. Several pockets are placed on the outer surface of the chest strap, with corresponding inner-side openings that allow the percussion head of the percussive expectorator placed inside the pocket to make contact with the patient's chest wall. Each pocket has markings indicating the percussion position, enabling the placement of the percussive expectorator according to the location of infection, thereby achieving multi-point, precise percussive vibration expectoration in different body positions. On the inner side of the chest strap, there are diagrams illustrating postural drainage, providing guidance on the body positions patients should assume based on the location of infection. The hook-and-loop fasteners on both sides of the chest strap can be wrapped around and secured according to the patient's body shape, ensuring that the sputum clearance components adhere tightly to the chest wall, allowing the vibrations generated by percussion to be effectively transmitted to the patient's airways. Additionally, to prevent the chest strap from slipping due to changes in the patient's position, a Y-shaped fixing strap can be selectively attached to the chest strap for further stabilization. This innovation not only simplifies the operation process, improves convenience and flexibility of use, but also supports the principle of "disinfection after each use by one person," which helps to reduce the risk of nosocomial infections and improve the efficiency of patients' respiratory rehabilitation.
Humans ; Vibration ; Equipment Design ; Chest Wall Oscillation/instrumentation* ; Sputum ; Expectorants ; Mucociliary Clearance

Objective To investigate the expression and clinical significance of serum microRNA-141-3p(miR-141-3p)and Kelch like epichlorohydrin associated protein 1(KEAP1)in neonatal acute respiratory dis-tress syndrome(NARDS).Methods A total of 121 children with NARDS admitted to the hospital from Janu-ary 2022 to March 2024(NARDS group)and 65 healthy neonates during the same period(control group)were selected.According to the degree of disease,the children with NARDS were divided into the mild NARDS group(4≤oxygen index<8,48 cases),the moderate NARDS group(8≤oxygen index<16,46 ca-ses),the severe NARDS group(oxygen index≥16,27 cases),and the children with NARDS were divided into the death group(18 cases)and the survival group(103 cases)according to the 28-day prognosis.Serum miR-141-3p and KEAP1 levels were detected by fluorescence quantitative polymerase chain reaction and enzyme-linked immunosorbent assay.The correlation between serum miR-141-3p and KEAP1 levels in children with NARDS was analyzed by Pearson correlation coefficient.The correlation between serum miR-141-3p and KEAP1 levels and oxygen index in children with NARDS was analyzed by Spearman correlation coefficient.Receiver operating characteristic(ROC)curve was plotted to analyze the predictive efficacy of serum miR-141-3p and KEAP1 levels on the death in children with NARDS.Results Serum miR-141-3p level in the NARDS group was lower than that in the control group,and KEAP1 level in the NARDS group was higher than that in the control group(t=14.288,12.596,P<0.001).There was a binding site between miR-141-3p and KEAP1 at the 3'-untranslated region 131-138.Pearson correlation showed that serum miR-141-3p was negatively correlated with KEAP1 level in children with NARDS(r=-0.745,P<0.001).The levels of ser-um miR-141-3p increased sequentially in the severe NARDS group,moderate NARDS group,and mild NARDS group,while the level of KEAP1 decreased sequentially(F=185.469,113.126,P<0.001).Spearman correla-tion coefficient showed that oxygen index in children with NARDS was negatively correlated with serum miR-141-3p level(r=-0.815,P<0.001)and positively correlated with serum KEAP1 level(r=0.827,P<0.001).Serum miR-141-3p level in the dead group was lower than that in the survival group,and KEAP1 level was higher than that in the surviving group(t=4.213,4.495,P<0.001).The area under the curve of the combined prediction of serum miR-141-3p and KEAP1 levels for the death in children with NARDS was 0.878(95%CI:0.806-0.930),which was greater than 0.783(95%CI:0.699-0.853)and 0.786(95%CI:0.702-0.855)predicted by serum miR-141-3p and KEAP1 levels alone(Z=2.963,2.021,P<0.05).Conclu-sion The serum miR-141-3p level is decreased and the KEAP1 level is increased in children with NARDS,which is associated with worsening of the disease and poor prognosis.The combination of serum miR-141-3p and KEAP1 levels has high predictive efficacy for death in children with NARDS.

Objective:To analyze the correlation between bone metabolism indicators,ultrasound quantitative parameters,and prediction of osteoporosis fracture risk assessment tool(FRAX)in elderly patients with osteoporosis(OP).Methods:A total of eighty elderly patients with OP who admitted to Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine from December 2023 to December 2024 were selected.Based on the results of measuring bone quality by dual energy X-ray absorptiometry(DXA),they were divided into bone loss group(26 cases),moderate group(41 cases),and severe group(13 cases).All patients underwent measurements for N-terminal osteocalcin(N-MID OCN),total type I collagen N-terminal extended peptide(TP1NP),25 hydroxyvitamin D(25-OH VitD),parathyroid hormone(PTH),and β-collagen specific sequence(CROSSL)bone metabolism indicators when they were enrolled in groups.They underwent examinations of ultrasonic quantitative parameters included ultrasonic bone density(T value),ultrasound conduction velocity(SOS)and bone quality index(BQI),as well as FRAX prediction.The results of bone metabolism indicators,the examination of ultrasound quantitative parameter,and FRAX prediction were compared among the three groups of elderly patients with OP.Using Pearson linear correlation analysis analyzed the relationship among the three factors.Results:The N-MID OCN and 25-OH VitD levels in the severe group were lower respectively than those in the moderate group and the bone loss group,while the TP1NP,PTH,and CROSSL levels were higher than those in the moderate group and the bone less group,and the differences among the three groups were statistically significant(F=31.646,75.055,110.274,93.321,59.246,P<0.05).The T value,SOS,and BQI in the severe group were lower than those in the moderate group and the bone loss group,and the differences among the three groups were statistically significant(F=81.980,108.985,76.327,P<0.05).The levels of proximal humeral fracture(PHF)and postmenopausal osteoporosis fracture(PMOF)in the severe group were higher than those in the moderate group and the bone loss group,and the differences among the three groups were statistically significant(F=57.086,118.079,P<0.05).Pearson linear correlation analysis showed that the N-MID OCN and 25-OH VitD levels were positively correlated with T value,SOS,and BQI in elderly patients with OP(r=0.398,0.617,0.769,0.752,0.500,0.654,P<0.05),and were negatively correlated with PHF and PMOF(r=-0.504,-0.534,-0.572,-0.662,P<0.05).The TP1NP,PTH,CROSSL levels were negatively correlated with T value,SOS and BQI(r=-0.745,-0.751,-0.634,-0.733,-0.728,-0.569,-0.709,-0.648,-0.611,P<0.05),and were positively correlated with PHF and PMOF(r=0.612,0.558,0.602,0.700,0.695,0.740,P<0.05).Conclusion:The bone metabolism indicators of elderly patients with OP are correlated significantly with ultrasound quantitative parameters and FRAX prediction,which can be used as an important scheme in clinical assessment for bone strength and fracture risk.

Objective:To investigate the efficacy and safety of different endovascular interventional treatments for extracranial carotid artery pseudoaneurysms.Method:The clinical data of 48 patients with extracranial carotid artery pseudoaneurysms treated with multiple endovascular procedures were retrospectively analyzed in the First Affiliated Hospital of Zhengzhou University from February 2012 to February 2024. The patients presented with a total of 48 extracranial carotid pseudoaneurysms, ranging in diameter from 2.5 to 34.2 mm [mean (12.0±9.6) mm]. The lesions were distributed as follows: 25 in the internal carotid artery, 16 in the external carotid artery and 7 in the common carotid artery. The selection of endovascular interventional techniques was tailored to individual cases according to the pseudoaneurysm size, anatomical location, morphological configuration, and specific features of the parent artery. Perioperative adverse events were monitored, and the efficacy of individualized endovascular interventional therapy was evaluated based on immediate postoperative and 6-month follow-up digital subtraction angiography (DSA) findings, including aneurysm occlusion and in-stent patency.Result:The treatment modalities included parent artery coiling occlusion ( n=16), overlapping braided carotid stent implantation ( n=3), covered stent placement ( n=23), combined implantation of covered stent and braided carotid stent implantation ( n=4) and flow-diverting stent implantation ( n=2) based on the characteristics of the pseudoaneurysms. Endovascular interventional procedures were successfully completed in 47 patients (technical success rate: 97.9%). Immediate postoperative DSA revealed residual pseudoaneurysm at the distal end of the stent in 1 case. Among the remaining cases, complete aneurysm obliteration or faint opacification was observed, with stent lumen patency confirmed in 31 cases and complete parent artery occlusion achieved in 16 cases. In one case involving a patient who underwent flow-diverting stent implantation, a pulsatile vascular murmur reappeared in the neck one week postoperatively. Follow-up DSA revealed stent migration into the aneurysm sac. After retrieval and removal of the displaced stent, combined implantation of a covered stent and a braided carotid artery stent was performed. Postoperative angiography confirmed complete aneurysm occlusion and patent parent artery blood flow. No severe perioperative adverse events (e.g., aneurysm rupture) were observed. During a postoperative follow-up period of 6.2-24.2 months, DSA at 6 months revealed mild in-stent or distal segment stenosis in 2 patients who underwent covered stent implantation. The remaining 46 patients exhibited complete aneurysm occlusion with no significant stenosis observed within the stent lumen. At the final follow-up, all patients demonstrated resolution or significant alleviation of clinical symptoms. Conclusion:Individualized endovascular interventional therapy demonstrates favorable safety and efficacy profiles in managing extracranial carotid artery pseudoaneurysms.