BAG5 regulates HSPA8-mediated protein folding required for sperm head-tail coupling apparatus assembly.

Teratozoospermia is a significant cause of male infertility, but the pathogenic mechanism of acephalic spermatozoa syndrome (ASS), one of the most severe teratozoospermia, remains elusive. We previously reported Spermatogenesis Associated 6 (SPATA6) as the component of the sperm head-tail coupling apparatus (HTCA) required for normal assembly of the sperm head-tail conjunction, but the underlying molecular mechanism has not been explored. Here, we find that the co-chaperone protein BAG5, expressed in step 9-16 spermatids, is essential for sperm HTCA assembly. BAG5-deficient male mice show abnormal assembly of HTCA, leading to ASS and male infertility, phenocopying SPATA6-deficient mice. In vivo and in vitro experiments demonstrate that SPATA6, cargo transport-related myosin proteins (MYO5A and MYL6) and dynein proteins (DYNLT1, DCTN1, and DNAL1) are misfolded upon BAG5 depletion. Mechanistically, we find that BAG5 forms a complex with HSPA8 and promotes the folding of SPATA6 by enhancing HSPA8's affinity for substrate proteins. Collectively, our findings reveal a novel protein-regulated network in sperm formation in which BAG5 governs the assembly of the HTCA by activating the protein-folding function of HSPA8.

Epigallocatechin-3-gallate protects sepsis-induced myocardial dysfunction by inhibiting the nuclear factor-κB signaling pathway.

Sepsis-induced myocardial dysfunction (SIMD) has become one of the most lethal complications of sepsis, while the treatment was limited by a shortage of pertinent drugs. Epigallocatechin-3-gallate (EGCG) is the highest content of active substances in green tea, and its application in cardiovascular diseases has broad prospects. This study was conducted to test the hypothesis that EGCG was able to inhibit lipopolysaccharide (LPS) induced myocardial dysfunction and investigate the underlying molecular mechanisms. The cardiac systolic function was assessed by echocardiography. The cardiomyocyte apoptosis was determined by TUNEL staining. The expression of inflammatory factors and apoptosis-related protein, cardiac markers were examined by Western Blot and qRT-PCR. EGCG effectively improve LPS-induced cardiac function damage, enhance left ventricular systolic function, and restore myocardial cell vitality. It can effectively inhibit the upregulation of TLR4 expression induced by LPS and inhibit IκB α/NF- κB/p65 signaling pathway, thereby inhibiting cardiomyocyte apoptosis and improving myocarditis. In conclusion, EGCG protects against SIMD through anti-inflammatory and anti-apoptosis effects; it was mediated by the inhibition of the TLR4/NF-κB signal pathway. Our results demonstrated that EGCG might be a possible medicine for SIMD prevention and treatment.

Roles and inhibitors of FAK in cancer: current advances and future directions.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that exhibits high expression in various tumors and is associated with a poor prognosis. FAK activation promotes tumor growth, invasion, metastasis, and angiogenesis via both kinase-dependent and kinase-independent pathways. Moreover, FAK is crucial for sustaining the tumor microenvironment. The inhibition of FAK impedes tumorigenesis, metastasis, and drug resistance in cancer. Therefore, developing targeted inhibitors against FAK presents a promising therapeutic strategy. To date, numerous FAK inhibitors, including IN10018, defactinib, GSK2256098, conteltinib, and APG-2449, have been developed, which have demonstrated positive anti-tumor effects in preclinical studies and are undergoing clinical trials for several types of tumors. Moreover, many novel FAK inhibitors are currently in preclinical studies to advance targeted therapy for tumors with aberrantly activated FAK. The benefits of FAK degraders, especially in terms of their scaffold function, are increasingly evident, holding promising potential for future clinical exploration and breakthroughs. This review aims to clarify FAK's role in cancer, offering a comprehensive overview of the current status and future prospects of FAK-targeted therapy and combination approaches. The goal is to provide valuable insights for advancing anti-cancer treatment strategies.

ATG5 attenuates inflammatory signaling in mouse embryonic stem cells to control differentiation.

Attenuated inflammatory response is a property of embryonic stem cells (ESCs). However, the underlying mechanisms are unclear. Moreover, whether the attenuated inflammatory status is involved in ESC differentiation is also unknown. Here, we found that autophagy-related protein ATG5 is essential for both attenuated inflammatory response and differentiation of mouse ESCs and that attenuation of inflammatory signaling is required for mouse ESC differentiation. Mechanistically, ATG5 recruits FBXW7 to promote ubiquitination and proteasome-mediated degradation of ß-TrCP1, resulting in the inhibition of nuclear factor κB (NF-κB) signaling and inflammatory response. Moreover, differentiation defects observed in ATG5-depleted mouse ESCs are due to ß-TrCP1 accumulation and hyperactivation of NF-κB signaling, as loss of ß-TrCP1 and inhibition of NF-κB signaling rescued the differentiation defects. Therefore, this study reveals a previously uncharacterized mechanism maintaining the attenuated inflammatory response in mouse ESCs and further expands the understanding of the biological roles of ATG5.

Publication Trends of Research on Adverse Event and Patient Safety in Nursing Research: A 8-Year Bibliometric Analysis.

BACKGROUND: Adverse events (AEs), which are associated with medical system instability, poor clinical outcomes, and increasing socioeconomic burden, represent a negative outcome of the healthcare system and profoundly influence patient safety. However, research into AEs remains at a developmental stage according to the existing literature, and no previous studies have systematically reviewed the current state of research in the field of AEs. Therefore, the aims of this study were to interpret the results of published research in the field of AEs through bibliometric analysis and to analyze the trends and patterns in the data, which will be important for subsequent innovations in the field. METHODS: A statistical and retrospective visualization bibliometric analysis was performed on July 28, 2022. The research data were extracted from the Web of Science Core Collection, and bibliometric citation analysis was performed using Microsoft Excel, VOSviewer 1.6.18, CiteSpace 6.1.R2, and the Online Analysis Platform of Literature Metrology (http://bibliometric.com/). RESULTS: A total of 1035 publications on AEs were included in the analysis. The number of articles increased annually from 2014 to 2022. Among them, the United States (n = 318) made the largest contribution, and Chung-Ang University (n = 20) was the affiliation with the greatest influence in this field. Despite notable international cooperation, a regional concentration of research literature production was observed in economically more developed countries. In terms of authors, Stone ND (n = 9) was the most productive author in the research of AEs. Most of the publications concerning AEs were cited from internationally influential nursing journals, and the Journal of Nursing Management (n = 62) was the most highly published journal. Regarding referencing, the article titled "Medical error-the third leading cause of death in the US" received the greatest attention on this topic (51 citations). CONCLUSIONS: After systematically reviewed the current state of research in the field of AEs through bibliometric analysis, and AEs highlighted medication errors, patient safety, according reporting, and quality improvement as essential developments and research hotspots in this field. Furthermore, thematic analysis identified 2 new directions in research, concerned with psychological safety, nurse burnout, and with important research value and broad application prospects in the future.

Emerging role of NEDD8-mediated neddylation in age-related metabolic diseases.

Aging in humans is associated with abdominal distribution and remodeling of body fat and a parallel gradual increase in the prevalence of metabolic diseases such as obesity, type 2 diabetes mellitus and fatty liver disease, as well as the risk of developing metabolic complications. Current treatments might be improved by understanding the detailed mechanisms underlying the onset of age-related metabolic disorders. Neddylation, a post-translational modification that adds the ubiquitin-like protein NEDD8 to substrate proteins, has recently been linked to age-related metabolic diseases, opening new avenues of investigation and raising a potential target for treatment of these diseases. In this review, we will focus on the potential role of NEDD8-mediated neddylation in age-related metabolic dysregulation, insulin resistance, obesity, type 2 diabetes mellitus and fatty liver. We propose that alterations in NEDD8-mediated neddylation contribute to triggering insulin resistance and the development of age-related metabolic dysregulation, thus highlighting NEDD8 as a promising therapeutic target for preventing age-related metabolic diseases.

Peptidic heterodimer-based radiotracer targeting fibroblast activation protein and integrin αvß3.

PURPOSE: Several studies have demonstrated the advantages of heterodimers over their corresponding monomers due to the multivalency effect. This effect leads to an increased number of effective targeted receptors and, consequently, improved tumor uptake. Fibroblast activation protein (FAP) and integrin αvß3 are found to be overexpressed in different components of the tumor microenvironment. In our pursuit of enhancing tumor uptake and retention, we designed and developed a novel peptidic heterodimer that synergistically targets both FAP and integrin αvß3. METHODS: FAP-RGD was synthesized from FAP-2286 and c(RGDfK) through a multi-step organic synthesis. The dual receptor binding property of 68Ga-FAP-RGD was investigated by cell uptake and competitive binding assays. Preclinical pharmacokinetics were determined in HT1080-FAP and U87MG tumor models using micro-positron emission tomography/computed tomography (micro-PET/CT) and biodistribution studies. The antitumor efficacy of 177Lu-FAP-RGD was assessed in U87MG tumor models. The radiation exposure and clinical diagnostic performance of 68 Ga-FAP-RGD were evaluated in healthy volunteers and cancer patients. RESULTS: Bi-specific radiotracer 68Ga-FAP-RGD exhibited high binding affinity for both FAP and integrin αvß3. In comparison to 68Ga-FAP-2286 and 68Ga-RGDfK, 68Ga-FAP-RGD displayed enhanced tumor uptake and longer tumor retention time in preclinical models. 177Lu-FAP-RGD could efficiently suppress the growth of U87MG tumor in vivo when applied at an activity of 18.5 and 29.6 MBq. The effective dose of 68Ga-FAP-RGD was 1.06 × 10-2 mSv/MBq. 68Ga-FAP-RGD demonstrated low background activity and stable accumulation in most neoplastic lesions up to 3 h. CONCLUSION: Taking the advantages of multivalency effect, the bi-specific radiotracer 68Ga-FAP-RGD showed superior tumor uptake and retention compared to its corresponding monomers. Preclinical studies with 68Ga- or 177Lu-labeled FAP-RGD showed favorable image contrast and effective antitumor responses. Despite the excellent performance of 68Ga-FAP-RGD in clinical diagnosis, experimental efforts are currently underway to optimize the structure of FAP-RGD to increase its potential for clinical application in endoradiotherapy.

Clinical study on low-frequency repetitive transcranial magnetic stimulation for the treatment of walking dysfunction following stroke through three-dimensional gait analysis.

BACKGROUND: The recovery of walking capacity is of great significance in stroke rehabilitation. We evaluated changes in post-stroke gait function after low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) treatment. METHODS: Stroke patients were randomly assigned to control (conventional treatment)/LF-rTMS (LF-rTMS treatment based on conventional treatment) groups. Gait spatiotemporal parameters/affected side joint motion angle/affected side dynamic parameters were analyzed by 3D gait analyses. Motor evoked potential (MEP)/central motor conduction time (CMCT) changes were detected. Correlations between MEP latency/CMCT and gait parameters after LF-rTMS were analyzed by Pearson analysis. RESULTS: The two groups exhibited boosted stride speed/frequency/length, affected side stride length/swing phase percentage/hip/knee/ankle joint plantar flexion angle, and affected side ahead ground reaction force/ upward ground reaction force (AGRF/UGRF)/ankle joint plantar flexion moment, along with reduced affected side gait period/stance phase percentage after treatment, and the LF-rTMS group manifested better efficacy. MEP latency/CMCT of stroke patients treated with LF-rTMS was adversely linked to stride speed, affected side stride length/swing phase percentage/knee flexion angle, AGRF and UGRF, and positively correlated with affected side stance phase percentage. CONCLUSION: LF-rTMS significantly improved gait spatiotemporal parameters/affected joint motion angles/neurophysiologic parameters (MEP latency/CMCT) in patients with post-stroke walking dysfunction. MEP latency/CMCT after LF-rTMS treatment were prominently correlated with gait parameters. Relative to the traditional scale assessment, we provided a more accurate, objective and reliable evaluation of the effects of LF-rTMS on lower limb mobility and functional recovery effects in stroke patients from the perspective of 3D gait analysis and neurophysiology, which provided more evidence to support the clinical application of LF-rTMS in post-stroke walking dysfunction treatment.

Isolation and Purification of Protamine from the Cultured Takifugu flavidus and Its Physicochemical Properties.

Protamine is a cationic peptide derived from fish sperm and has several important functional properties: antibacterial properties, acting as a carrier for injectable insulin and as a heparin antagonist, combatting fatigue, etc. Thus, it has been widely used in medicinal applications and food products. Cultured Takifugu flavidus is a type of pufferfish with a delicious taste that is popular in China, and its production is increasing significantly. Therefore, protamine was extracted via acid extraction from the sperm of Takifugu flavidus and further isolated and purified via sephadex gel chromatography, ion exchange chromatography, and desalination chromatography. Furthermore, the physicochemical properties of protamine were investigated. The results showed that the sperm of the cultured T. flavidus were non-toxic, and the extracted and purified protamine had high contents of arginine (36.90%) and lysine (27.02%), respectively. The secondary structure of protamine was mainly ß-folded and irregularly curled. Additionally, protamine exhibited high thermal stability with a denaturation temperature of 176 °C. This study would provide a theoretical basis for the structural analysis, bioactivity, and resource development of pufferfish protamine and help to promote the development of the pufferfish industry.

Methylglyoxal accumulation contributes to accelerated brain aging in spontaneously hypertensive rats.

While it is well-acknowledged that neurovascular dysfunction in hypertension is tightly associated with accelerated brain aging, we contend that the deleterious effects of hypertension may extend beyond affecting only the arteries. Methylglyoxal (MG) derived from glycolysis, is involved in the accumulation of advanced glycated end products (AGEs), which are the hallmarks of neurodegenerative disorders. Therefore, the present study aims to firstly investigate the role of MG metabolism in the hypertension-accelerated brain aging process. The results of our study indicate that the levels of MG increase with age in both the plasma and hippocampus of SHRs at 12, 16, and 30 weeks old. AGE methylglyoxal-hydro imidazoline-1 (MG-H1) is primarily localized in astrocytes, while its presence was not observed in neurons and microglia within the hypertensive hippocampus. Our observations also suggest that angiotensin II (Ang II) enhances glucose uptake and glycolysis while reducing the expression of Glo1 in cultured astrocytes. N-acetylcysteine (NAC) was found to counteract the increase in escape latency and inhibit the activation of the AGEs-RAGE axis in 30-week-old SHRs. NAC decreased Iba-1 immunofluorescence intensity, inhibited the levels of pro-inflammatory markers, and enhanced the abundance of anti-inflammatory markers in the hippocampus of SHRs. Moreover, NAC reduced the immunofluorescence signal of 4HNE and increased the content of GSH and SOD in SHRs. Finally, NAC was observed to inhibit apoptosis in the hippocampus of SHRs. Collectively, we firstly showed the enhanced accumulation of MG in the hypertensive brain, whereas the clearance of MG by NAC treatment mitigated the aging process and attenuated AGEs generation, neuroinflammation, and oxidative damage.

Global prevalence of depressive symptoms among people living with HIV/AIDS: a systematic review and meta-analysis of the past five years.

A clear and accurate assessment of depressive symptoms among people living with HIV/AIDS (PLWHA) in the past five years is essential to help develop reasonable and sound interventions to improve their depressive symptoms. PubMed, Web of Science, MEDLINE, Cochrane, Embase, CINAHL, and APA were searched from 1 January 2017 to 12 April 2022. The data were analyzed using STATA 15 Software to pool the global prevalence of depressive symptoms in PLWHA. Ultimately, 103785 PLWHA from 81 original studies were included. The pooled analysis showed that the global prevalence of depressive symptoms in PLWHA over the past five years was 0.35 (95% CI: 0.31-0.38), with differences in depressive symptoms in PLWHA by geographic location, gender, assessment instruments, alcohol use, smoking, marriage, co-morbid disease, financial situation, and educational level. Scientific and timely public health interventions should be developed among PLWHA to improve their depressive symptoms and thereby improve mental health and clinical outcomes.

1,3-Substituted ß-Carboline Derivatives as Potent Chemotherapy for the Treatment of Cystic Echinococcosis.

Echinococcosis is a global public health issue that generally occurs in areas with developed animal husbandry. In search of safe and effective therapeutic agents against echinococcosis, we designed and synthesized new 1,3-substituted ß-carboline derivatives based on harmine. Among them, compounds 1a, 1c, and 1e displayed potent inhibitory activity against Echinococcus granulosus in vitro, significantly better than albendazole and harmine. The morphological detection revealed that 1a, 1c, and 1e significantly changed the ultrastructure of Echinococcus granulosus protoscolices (PSCs). Furthermore, pharmacokinetic studies suggested that 1a possessed a better metabolic property. Encouragingly, 1a exhibited a highest cyst inhibition rate as 76.8% in vivo and did not display neurotoxicity in mice. Further mechanistic research illustrated that 1a has the potential to induce autophagy in PSCs, which may be responsible for the therapeutic effect of the drugs. Together, 1a could be a promising therapeutic agent against echinococcosis, warranting further study.

Advances in Research on Marine-Derived Lipid-Lowering Active Substances and Their Molecular Mechanisms.

Hyperlipidemia (HLP) is a metabolic disorder caused by abnormal lipid metabolism. Recently, the prevalence of HLP caused by poor dietary habits in the population has been increasing year by year. In addition, lipid-lowering drugs currently in clinical use have shown significant improvement in blood lipid levels, but are accompanied by certain side effects. However, bioactive marine substances have been shown to possess a variety of physiological activities such as hypoglycemic, antioxidant, antithrombotic and effects on blood pressure. Therefore, the hypolipidemic efficacy of marine bioactive substances with complex and diverse structures has also attracted attention. This paper focuses on the therapeutic role of marine-derived polysaccharides, unsaturated fatty acids, and bioactive peptides in HLP, and briefly discusses the main mechanisms by which these substances exert their hypolipidemic activity in vivo.

Aptamer-functionalized hydrogels promote bone healing by selectively recruiting endogenous bone marrow mesenchymal stem cells.

Bone regeneration heavily relies on bone marrow mesenchymal stem cells (BMSCs). However, recruiting endogenous BMSCs for in situ bone regeneration remains challenging. In this study, we developed a novel BMSC-aptamer (BMSC-apt) functionalized hydrogel (BMSC-aptgel) and evaluated its functions in recruiting BMSCs and promoting bone regeneration. The functional hydrogels were synthesized between maleimide-terminated 4-arm polyethylene glycols (PEG) and thiol-flanked PEG crosslinker, allowing rapid in situ gel formation. The aldehyde group-modified BMSC-apt was covalently bonded to a thiol-flanked PEG crosslinker to produce high-density aptamer coverage on the hydrogel surface. In vitro and in vivo studies demonstrated that the BMSC-aptgel significantly increased BMSC recruitment, migration, osteogenic differentiation, and biocompatibility. In vivo fluorescence tomography imaging demonstrated that functionalized hydrogels effectively recruited DiR-labeled BMSCs at the fracture site. Consequently, a mouse femur fracture model significantly enhanced new bone formation and mineralization. The aggregated BMSCs stimulated bone regeneration by balancing osteogenic and osteoclastic activities and reduced the local inflammatory response via paracrine effects. This study's findings suggest that the BMSC-aptgel can be a promising and effective strategy for promoting in situ bone regeneration.

The predictive value of 18F-FDG PET/CT combined with inflammatory index for major pathological reactions in resectable NSCLC receiving neoadjuvant immunochemotherapy.

OBJECTIVES: To investigate whether the combination of inflammatory biomarkers and metabolic parameters of 18F-FDG PET/CT could predict the major pathological reactions (MPR) in resectable NSCLC patients after neoadjuvant immunochemotherapy more accurately and screen out patients who may benefit from the neoadjuvant therapy. MATERIALS AND METHODS: 114 resectable NSCLC patients who underwent neoadjuvant immunochemotherapy and radical surgery were retrospectively enrolled. Detailed clinical characteristics, B-R and 18F-FDG PET/CT images were collected for analyzing their correlation with MPR. A metabolic-inflammation comprehensive prognostic index (MICPI) combined 18F-FDG PET/CT metabolic parameters and inflammatory index was proposed to predict MPR. RESULTS: 66.7 % patients achieved MPR. Smoking history, gender and ILO were influencing factors for MPR acquisition in NSCLC patients. High absolute neutrophils count (PreN ≥ 3.65), metabolic parameters (PreSUVmax ≥ 11.73) before treatment and ΔSUVmean (≥54.18) were significantly associated with MPR (P＜0.01, P＜0.05 and P＜0.001 respectively). MICPI-B based on PreN and PreSUVmax categorized NSCLC patients into three groups and among the groups of high, intermediate and low MICPI-B score, MPR accounted for 80.00 %, 51.72 % and 28.57 % respectively (P < 0.01). In high, intermediate and low MICPI-P groups which based on PreN and ΔSUVmean, MPR accounted for 92.31 %, 53.57 % and 11.11 %, respectively (P < 0.001). CONCLUSION: PreN and metabolic parameter of 18F-FDG PET/CT may be an accurate alternative biomarker for predicting MPR in NSCLC patients after neoadjuvant immunochemotherapy. Moreover, MICPI can stratify patients into different groups based on their likelihood of obtaining MPR, allowing clinicians to identify patients who may most likely benefit from neoadjuvant immunochemotherapy.

Extracorporeal shock wave therapy inhibits osteoclast differentiation by targeting NF-κB signaling pathway.

BACKGROUND: Extracorporeal shock wave therapy (ESWT) has been reported to promote osteoblast differentiation. However, the role of ESWT on osteoclast differentiation is still elusive. METHODS: This study analyzed the differentiation of osteoclasts in the shock wave group and the control group in vitro, and TRAP staining, RT-PCR, WB assays, and MTT assays were assessed between the two groups. Furthermore, we analyzed the bone formation in these two groups in vivo and micro-CT and trap staining were assessed between the two groups. RESULTS: We found that ESWT inhibited osteoclast maturation in vitro and ESW treatment of femur promoted bone formation in vivo. Mechanically, osteoclast differentiation was inhibited as the number of impulses increased and ESWT decreased endogenous levels of NTAFc1 and P65 protein. CONCLUSIONS: ESWT may be a potential therapy of osteoporosis through NF-κB signaling pathway.

Affinity Purification and Molecular Characterization of Angiotensin-Converting Enzyme (ACE)-Inhibitory Peptides from Takifugu flavidus.

An affinity chromatography filler of CNBr-activated Sepharose 4B-immobilized ACE was used to purify ACE-inhibitory peptides from Takifugu flavidus protein hydrolysate (<1 kDa). Twenty-four peptides with an average local confidence score (ALC) ≥ 80% from bounded components (eluted by 1 M NaCl) were identified by LC-MS/MS. Among them, a novel peptide, TLRFALHGME, with ACE-inhibitory activity (IC50 = 93.5 µmol·L-1) was selected. Molecular docking revealed that TLRFALHGME may interact with the active site of ACE through H-bond, hydrophobic, and electrostatic interactions. The total binding energy (ΔGbinding) of TLRFALHGME was estimated to be -82.7382 kJ·mol-1 by MD simulations, indicating the favorable binding of peptides with ACE. Furthermore, the binding affinity of TLRFALHGME to ACE was determined by surface plasmon resonance (SPR) with a Kd of 80.9 µmol, indicating that there was a direct molecular interaction between them. TLRFALHGME has great potential for the treatment of hypertension.

Severe thrombocytopenia induced by tirofiban after percutaneous coronary intervention: a case report.

BACKGROUND: Tirofiban is a nonpeptide glycoprotein IIb/IIIa receptor antagonist used widely in patients subjected to percutaneous coronary intervention. While the usage of tirofiban sets an important clinical benefit, severe thrombocytopenia can occur with use of this agent. CASE PRESENTATION: A 76-year-old Chinese man was admitted with 1-month history of sudden onset of chest tightness. He was diagnosed as having subacute inferior myocardial infarction, and percutaneous coronary intervention was performed. After the procedure, patient received tirofiban at 0.15 µg/kg/minute for 4 h. A blood sample was obtained for a complete blood count; severe thrombocytopenia was reported according to routine orders at our hospital. All antiplatelet drugs including tirofiban, aspirin, and clopidogrel were immediately discontinued. The patient received platelet transfusions and was treated with immunoglobulin G. Two days later, the patient's platelet count had increased to 75 × 109/L. There was a significant improvement after day 5, and the platelet count was 112 × 109/L. Seven days after the acute thrombocytopenia, he was discharged with normal platelet count. CONCLUSIONS: Clinicians should be particularly aware of tirofiban-induced thrombocytopenia in routine practice.

In vitro and in vivo Efficacies of Novel Harmine Derivatives in the Treatment of Cystic Echinococcosis.

Introduction: Cystic echinococcosis (CE) is a chronic zoonotic parasitic disease caused by the larvae of the Echinococcus granulosus sensu lato (s.l.) cluster. The current existing drugs have limited therapeutic efficacy against cystic echinococcosis, and thus, there is an urgent need to develop new drugs. Methods: In this study, 7 harmine (HM) derivatives were screened and the effects of HM derivatives on E. granulosus sensu stricto (s.s.) were evaluated by in vitro and mouse experiments. The safety of the HM derivatives was assessed by cytotoxicity assays, acute toxicity study in animals and subacute toxicity study. Results: These results show that the HM derivatives H-2-168 and DH-004 exhibited more significant antiparasitic effects at an initial concentration of 40 µM. The results of further studies showed that H-2-168 and DH-004 had dose-dependent effects against protoscoleces and had satisfactory therapeutic outcomes in vivo. Electron microscopy observations demonstrated that H-2-168 and DH-004 caused severe disruption of the parasite ultrastructure. Notably, the results of the acute toxicity and subchronic toxicity studies showed that H-2-168 and DH-004 had significantly improved safety. In addition, we found that H-2-168 and DH-004 induced DNA damage in E. granulosus s.s., which may be the mechanism by which these drugs produce their therapeutic effects. Discussion: Overall, the data from this work demonstrate that H-2-168 and DH-004 are highly effective candidate compounds with low toxicity for the treatment of CE and will provide a new therapeutic strategy for CE pharmacological treatment.

Self-immolative nanocapsules precisely regulate depressive neuronal microenvironment for synergistic antidepression therapy.

BACKGROUND: Pharmacotherapy constitutes the first-line treatment for depression. However, its clinical use is hindered by several limitations, such as time lag, side effects, and narrow therapeutic windows. Nanotechnology can be employed to shorten the onset time by ensuring permeation across the blood brain barrier (BBB) to precisely deliver more therapeutic agents; unfortunately, formidable challenges owing to the intrinsic shortcomings of commercial drugs remain. RESULTS: Based on the extraordinary capability of monoamines to regulate the neuronal environment, we engineer a network nanocapsule for delivering serotonin (5-hydroxytryptamine, 5-HT) and catalase (CAT) to the brain parenchyma for synergistic antidepression therapy. The nanoantidepressants are fabricated by the formation of 5-HT polymerization and simultaneous payload CAT, following by surface modifications using human serum albumin and rabies virus glycoprotein. The virus-inspired nanocapsules benefit from the surface-modifying strategies and exhibit pronounced BBB penetration. Once nanocapsules reach the brain parenchyma, the mildly acidic conditions trigger the release of 5-HT from the sacrificial nanocapsule. Releasing 5-HT further positively regulate moods, relieving depressive symptoms. Meanwhile, cargo CAT alleviates neuroinflammation and enhances therapeutic efficacy of 5-HT. CONCLUSION: Altogether, the results offer detailed information encouraging the rational designing of nanoantidepressants and highlighting the potential of nanotechnology in mental health disorder therapies.