Botulinum toxin A attenuates osteoarthritis development via inhibiting chondrocyte ferroptosis through SLC7Al1/GPX4 axis.

Osteoarthritis (OA) is a prevalent joint degenerative disease, resulting in a significant societal burden. However, there is currently a lack of effective treatment option available. Previous studies have suggested that Botulinum toxin A (BONT/A), a macromolecular protein extracted from Clostridium Botulinum, may improve the pain and joint function in OA patients, but the mechanism remains elusive. This study was to investigate the impact and potential mechanism of BONT/A on OA in vivo and in vitro experiment. LPS increased the levels of ROS, Fe2+and Fe3+, as well as decreased GSH levels, the ratio of GSH / GSSH and mitochondrial membrane potential. It also enhanced the degeneration of extracellular matrix (ECM) and altered the ferroptosis-related protein expression in chondrocytes. BONT/A rescued LPS-induced decrease in collagen type II (Collagen II) expression and increase in matrix metalloproteinase 13 (MMP13), mitigated LPS-induced cytotoxicity in chondrocytes, abolished the accumulation of ROS and iron, upregulated GSH and the ratio of GSH/ GSSH, improved mitochondrial function, and promoted SLC7A11/GPX4 anti-ferroptosis system activation. Additionally, intra-articular injection of BONT/A inhibited the degradation of cartilage in OA model rats. This chondroprotective effect of BONT/A was reversed by erastin (a classical ferroptosis agonist) and enhanced by liproxstatin-1 (a classic ferroptosis inhibitor). Our research confirms that BONT/A alleviates the OA development by inhibiting the ferroptosis of chondrocytes, which revealed to be a potential therapeutic mechanism for BONT/A treating the OA.

Macrophage migration inhibitor factor (MIF): Potential role in cognitive impairment disorders.

Macrophage migration inhibitory factor (MIF) is a cytokine in the immune system, participated in both innate and adaptive immune responses. Except from immune cells, MIF is also secreted by a variety of non-immune cells, including hematopoietic cells, endothelial cells (ECs), and neurons. MIF plays a crucial role in various diseases, such as sepsis, rheumatoid arthritis, acute kidney injury, and neurodegenerative diseases. The role of MIF in the neuropathogenesis of cognitive impairment disorders is emphasized, as it recruits multiple inflammatory mediators, leading to activating microglia or astrocyte-derived neuroinflammation. Furthermore, it contributes to the cell death of neurons and ECs with the binding of apoptosis-inducing factor (AIF) through parthanatos-associated apoptosis-inducing factor nuclease (PAAN) / MIF pathway. This review comprehensively delves into the relationship between MIF and the neuropathogenesis of cognitive impairment disorders, providing a series of emerging MIF-targeted pharmaceuticals as potential treatments for cognitive impairment disorders.

Neuro-bone tissue engineering: emerging mechanisms, potential strategies, and current challenges.

The skeleton is a highly innervated organ in which nerve fibers interact with various skeletal cells. Peripheral nerve endings release neurogenic factors and sense skeletal signals, which mediate bone metabolism and skeletal pain. In recent years, bone tissue engineering has increasingly focused on the effects of the nervous system on bone regeneration. Simultaneous regeneration of bone and nerves through the use of materials or by the enhancement of endogenous neurogenic repair signals has been proven to promote functional bone regeneration. Additionally, emerging information on the mechanisms of skeletal interoception and the central nervous system regulation of bone homeostasis provide an opportunity for advancing biomaterials. However, comprehensive reviews of this topic are lacking. Therefore, this review provides an overview of the relationship between nerves and bone regeneration, focusing on tissue engineering applications. We discuss novel regulatory mechanisms and explore innovative approaches based on nerve-bone interactions for bone regeneration. Finally, the challenges and future prospects of this field are briefly discussed.

Corrigendum to "Photocatalytic oxygen evolution and antibacterial biomimetic repair membrane for diabetes wound repair via HIF1-α pathway" [Mater. Today Bio 20 (2023) 100616].

[This corrects the article DOI: 10.1016/j.mtbio.2023.100616.].

Different doses of bevacizumab in combination with chemotherapy for advanced colorectal cancer: a meta-analysis and Bayesian analysis.

OBJECTIVE: The aim of the present study was to explore the incremental benefit of bevacizumab (Bev) in the treatment of advanced colorectal cancer (CRC) with different doses. METHODS: A literature search of eight electronic databases (China National Knowledge Infrastructure, Wanfang databases, Chinese Biomedical Database, VIP medicine information, Cochrane Library, MEDLINE, PubMed, and EMBASE) was conducted from database creation to December 2022. Randomized controlled trials (RCTs) that compared Bev at various dosages + chemotherapy (CT) versus placebo (or blank control) + CT were selected. The overall survival (OS), progression-free survival (PFS), overall response rate (ORR; complete response [CR] + partial response [PR]), and grade ≥ 3 adverse events (AEs) were integrated first by pooled analysis. The likelihood of ideal dosage of Bev was then ranked using random effects within Bayesian analysis. RESULTS: Twenty-six RCTs involving 18,261 patients met the inclusion criteria. OS increased significantly after using 5 mg (HR: 0.87, 95% CI 0.75 to 1.00) and 10 mg dosages of Bev (HR: 0.75, 95% CI 0.66 to 0.85) with CT, but statistical significance was not attained for the 7.5 mg dose (HR: 0.95, 95% CI 0.83 to 1.08). A significantly increased in PFS with doses of 5 mg (HR: 0.69, 95% CI 0.58 to 0.83), 7.5 mg (HR: 0.81, 95% CI 0.66 to 1.00), and 10 mg (HR: 0.60, 95% CI 0.53 to 0.68). ORR distinctly increased after 5 mg (RR: 1.34, 95% CI 1.15 to 1.55), 7.5 mg (RR: 1.25, 95% CI 1.05 to 1.50), and10 mg (RR: 2.27, 95% CI 1.82 to 2.84) doses were administered. Grade ≥ 3 AEs increased clearly in 5 mg (RR: 1.11, 95% CI 1.04 to 1.20) compared to 7.5 mg (RR: 1.05, 95% CI 0.82 to 1.35) and 10 mg (RR: 1.15, 95% CI 0.98 to 1.36). Bayesian analysis demonstrated that 10 mg Bev obtained the maximum time of OS (HR: 0.75, 95% CrI 0.58 to 0.97; probability rank = 0.05) indirectly compared to 5 mg and 7.5 mg Bev. Compared with 5 mg and 7.5 mg Bev, 10 mg Bev also holds the longest duration for PFS (HR: 0.59, 95% CrI 0.43 to 0.82; probability rank = 0.00). In terms of ORR, 10 mg Bev holds the maximum frequency (RR: 2.02, 95% CrI 1.52 to 2.66; probability rank = 0.98) in comparison to 5 mg and 7.5 mg Bev clearly. For grade ≥ 3 AEs, 10 mg Bev has the maximum incidence (RR: 1.15, 95% CrI 0.95 to 1.40, probability rank = 0.67) in comparison to other doses of Bev. CONCLUSION: The study suggests that 10 mg dose Bev could be more effective in treating advanced CRC in efficacy, but 5 mg Bev could be more safer in terms of safety.

Photocatalytic oxygen evolution and antibacterial biomimetic repair membrane for diabetes wound repair via HIF1-α pathway.

Diabetic wounds always have puzzled patients and caused serious social problems. Due to the lack of local blood vessels, severe hypoxia is generated in the defect area, which is an essential reason for the difficulty of wound healing. We have constructed a photocatalytic oxygen evolution and antibacterial biomimetic repair membrane to solve the problems of wound repair. A scanning electron microscope and transmission electron microscope characterized the biomimetic repair membrane. The oxygen evolution of the biomimetic membrane was tested by an oxygen meter. The excellent antibacterial performance of the biomimetic repair membrane was also verified by co-culture with Staphylococcus aureus and Escherichia coli. It was confirmed that the expression of collagen and HIF1-α in fibroblasts was significantly increased in vitro. And the mitochondrial activity of the vascular and nerve was increased considerably. In vivo, the healing time of diabetes wounds treated with the biomimetic repair membrane was significantly reduced, the collagen and the number of pores were increased considerably, and vascular regeneration was enhanced. The biomimetic repair membrane has an excellent performance in photocatalytic oxygen evolution and antibacterial and can significantly promote the repair of diabetes wounds. This will provide a promising treatment for diabetes wound repair.

[Role of histone posttranslational modifications in the regulation of ovarian function].

The ovary is the reproductive organ of female mammals, which is responsible for producing mature eggs and secreting sex hormones. The regulation of ovarian function involves the ordered activation and repression of genes related to cell growth and differentiation. In recent years, it has been found that histone posttranslational modification can affect DNA replication, damage repair and gene transcriptional activity. Some regulatory enzymes mediating histone modification are co-activators or co-inhibitors associated with transcription factors, which play important roles in the regulation of ovarian function and the development of ovary-related diseases. Therefore, this review outlines the dynamic patterns of common histone modifications (mainly acetylation and methylation) during the reproductive cycle and their regulation of gene expression for important molecular events, focusing on the mechanisms of follicle development and sex hormone secretion and function. For example, the specific dynamics of histone acetylation are important for the arrest and resumption of meiosis in oocytes, while histone (especially H3K4) methylation affects the maturation of oocytes by regulating their chromatin transcriptional activity and meiotic progression. Besides, histone acetylation or methylation can also promote the synthesis and secretion of steroid hormones before ovulation. Finally, the abnormal histone posttranslational modifications in the development of two common ovarian diseases (premature ovarian insufficiency and polycystic ovary syndrome) are briefly described. It will provide a reference basis for understanding the complex regulation mechanism of ovarian function and further exploring the potential therapeutic targets of related diseases.

Endogenous Electric Field-Coupled PD@BP Biomimetic Periosteum Promotes Bone Regeneration through Sensory Nerve via Fanconi Anemia Signaling Pathway.

To treat bone defects, repairing the nerve-rich periosteum is critical for repairing the local electric field. In this study, an endogenous electric field is coupled with 2D black phosphorus electroactive periosteum to explore its role in promoting bone regeneration through nerves. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) are used to characterize the electrically active biomimetic periosteum. Here, the in vitro effects exerted by the electrically active periosteum on the transformation of Schwann cells into the repair phenotype, axon initial segment (AIS) and dense core vesicle (DCV) of sensory neurons, and bone marrow mesenchymal stem cells are assessed using SEM, immunofluorescence, RNA-sequencing, and calcium ion probes. The electrically active periosteum stimulates Schwann cells into a neuroprotective phenotype via the Fanconi anemia pathway, enhances the AIS effect of sensory neurons, regulates DCV transport, and releases neurotransmitters, promoting the osteogenic transformation of bone marrow mesenchymal stem cells. Microcomputed tomography and other in vivo techniques are used to study the effects of the electrically active periosteum on bone regeneration. The results show that the electrically active periosteum promotes nerve-induced osteogenic repair, providing a potential clinical strategy for bone regeneration.

Photosensitive and Conductive Hydrogel Induced Innerved Bone Regeneration for Infected Bone Defect Repair.

Repairing infected bone defects is a challenge in the field of orthopedics because of the limited self-healing capacity of bone tissue and the susceptibility of refractory materials to bacterial activity. Innervation is the initiating factor for bone regeneration and plays a key regulatory role in subsequent vascularization, ossification, and mineralization processes. Infection leads to necrosis of local nerve fibers, impeding the repair of infected bone defects. Herein, a biomaterial that can induce skeletal-associated neural network reconstruction and bone regeneration with high antibacterial activity is proposed for the treatment of infected bone defects. A photosensitive conductive hydrogel is prepared by incorporating magnesium-modified black phosphorus (BP@Mg) into gelatin methacrylate (GelMA). The near-infrared irradiation-based photothermal and photodynamic treatment of black phosphorus endows it with strong antibacterial activity, improving the inflammatory microenvironment and reducing bacteria-induced bone tissue damage. The conductive nanosheets and bioactive ions released from BP@Mg synergistically improve the migration and secretion of Schwann cells, promote neurite outgrowth, and facilitate innerved bone regeneration. In an infected skull defect model, the GelMA-BP@Mg hydrogel shows efficient antibacterial activity and promotes bone and CGRP+ nerve fiber regeneration. The phototherapy conductive hydrogel provides a novel strategy based on skeletal-associated innervation for infected bone defect repair.

Guidelines for management of pediatric acute hyperextension spinal cord injury.

Pediatric acute hyperextension spinal cord injury (SCI) named as PAHSCI by us, is a special type of thoracolumbar SCI without radiographic abnormality and highly related to back-bend in dance training, which has been increasingly reported. At present, it has become the leading cause of SCI in children, and brings a heavy social and economic burden. Both domestic and foreign academic institutions and dance education organizations lack a correct understanding of PAHSCI and relevant standards, specifications or guidelines. In order to provide standardized guidance, the expert team formulated this guideline based on the principles of science and practicability, starting from the diagnosis, differential diagnosis, etiology, admission evaluation, treatment, complications and prevention. This guideline puts forward 23 recommendations for 14 related issues.

Aptamer engineering exosomes loaded on biomimetic periosteum to promote angiogenesis and bone regeneration by targeting injured nerves via JNK3 MAPK pathway.

Repairing critical bone defects is a complex problem in the clinic. The periosteum rich in nerve plays a vital role in initiating and regulating bone regeneration. However, current studies have paid little attention to repairing nerves in the periosteum to promote bone regeneration. Thus, it is essential to construct bionic periosteum with the targeted injured nerves in the periosteum. We coupled phosphatidylserine (PS) targeted aptamers with repair Schwann cell exosomes to construct exosome@aptamer (EA). Then through PEI, EA was successfully built on the surface of the electrospun fiber, which was PCL@PEI@exosome@aptamer (PPEA). Through SEM, TEM, and other technologies, PPEA was characterized. Experiments prove in vivo and in vitro that it has an excellent repair effect on damaged nerves and regeneration of vascular and bones. In vivo, we confirmed that biomimetic periosteum has an apparent ability to promote nerve and bone regeneration by using Microcomputer tomography, hematoxylin-eosin, Masson, and Immunofluorescence. In vitro, we used Immunofluorescence, Real-Time Quantitative PCR, Alkaline phosphatase staining, and other tests to confirm that it has central nerve, blood vessel, and bone regeneration ability. The PPEA biomimetic periosteum has apparent neurogenic, angiogenic, and osteogenic effects. The PPEA biomimetic periosteum will provide a promising method for treating bone defects.

Both-Column Acetabular Fractures: Should Pelvic Ring Reduction or Acetabulum be Performed First?

OBJECTIVE: Both-column acetabular fracture is a type that accumulates both the pelvis and acetabulum with complex fracture line alignment and has variant fracture fragments. The selection of different reduction landmarks and sequences produces different qualities of reduction. This study aims to compare the operation-related items, quality of reduction, and hip functional outcome by using different reduction landmarks and sequences for management of both-column acetabular fractures (BCAF). METHODS: A consecutive cohort of 42 patients from January 2013 to January 2019 with BCAF were treated operatively with different reduction landmarks and sequences: pelvic ring fractures reduction first (PRFRF group) and acetabular fractures reduction first (AFRF group). Preoperative computer visual surgical procedures were applied. There were 22 patients in PRFRF group and 20 patients in AFRF group. The surgical details, complications, radiographic and clinical results were recorded. The quality of reduction was assessed by the Matta scoring system. The functional outcome was evaluated by the modified Merle d'Aubigné and Postel scoring system. The measurement data were analyzed using the t-test of independent samples and rank-sum test of ranked data. RESULTS: The real reduction sequence in both groups was almost identical to the preoperative surgical procedures. The excellent/good quality of reduction in PRFRF group (21/22) was better than AFRF group (17/20). Operative time (152.3 ± 16.3 mins) and intra-operative blood loss (639.5 ± 109.9ml) were significantly reduced in PRFRF group (p < 0.05). The incidence of deep vein thrombosis in PRFRF group (2/22) was less than AFRF group (4/20), but without statistical signification. CONCLUSION: Selection of an appropriate reduction landmark and sequence could result in better quality of reduction, operative time, and decreased blood loss during treatment of BCAF.

Small Intestinal Submucosa Biomimetic Periosteum Promotes Bone Regeneration.

BACKGROUND: Critical bone defects are a significant problem in clinics. The periosteum plays a vital role in bone regeneration. A tissue-engineered periosteum (TEP) has received increasing attention as a novel strategy for bone defect repairs. METHODS: In this experiment, a biomimetic periosteum was fabricated by using coaxial electrospinning technology with decellularized porcine small intestinal submucosa (SIS) as the shell and polycaprolactone (PCL) as the core. In vitro, the effects of the biomimetic periosteum on Schwann cells, vascular endothelial cells, and bone marrow mesenchymal stem cells were detected by a scratch test, an EdU, a tube-forming test, and an osteogenesis test. In vivo, we used HE staining to evaluate the effect of the biomimetic periosteum on bone regeneration. RESULTS: In vitro experiments showed that the biomimetic periosteum could significantly promote the formation of angiogenesis, osteogenesis, and repaired Schwann cells (SCs). In vivo experiments showed that the biomimetic periosteum could promote the repair of bone defects. CONCLUSIONS: The biomimetic periosteum could simulate the structural function of the periosteum and promote bone repair. This strategy may provide a promising method for the clinical treatment of skull bone defects.

The novel infra-pectineal buttress plates used for internal fixation of elderly quadrilateral surface involved acetabular fractures.

OBJECTIVES: In geriatric acetabular fractures, the quadrilateral surface (QLS) was frequently involved in acetabular fracture patterns and accompanied by medial displacement. It was important to buttress the medial displaced QLS and reconstruct the congruity of the affected acetabulum. To evaluate the clinical effectiveness of the novel infra-pectineal quadrilateral surface buttress plates for the treatment of geriatric acetabular fractures. METHODS: Twenty-three geriatric patients who were treated for acetabular fractures involving QLS with the novel infra-pectineal buttress plates (NIBP) through a single supra-ilioinguinal approach between January 2015 and June 2019 were retrospectively analyzed; all patients received at least 1 year's follow-up. All patients were aged ≥60 years old and including 18 males and five females. Radiologic and clinical outcomes of patients involved in the study were collated and analyzed according to the Matta scoring system and the Merle D'Aubigné-Postel scoring system. The functional recovery scoring was compared using q-test. RESULTS: All 23 consecutive patients had relatively satisfactory clinical treatment effectiveness. Average ages, length of incision, operation time, and intraoperative blood loss were 69.8 ± 6.1 years, 12.1 ± 2.6 cm, 166.5 ± 43.5 min, and 500 (500,700) ml, respectively. According to the Matta scoring system, 14 cases of reduction were graded as excellent, five as good, and four as fair. At the last follow-up, the clinical outcome evaluation was excellent in 13 cases, good in seven cases, and poor in three cases with the use of the Merle D'Aubigné-Postel scoring system. The difference of modified Merle D'Aubigne-Postel score at 3 months, 6 months and last follow up was statistically significant (F = 21.56, p < 0.05). Postoperative lateral femoral cutaneous nerve injury occurred in three patients and heterotopic ossification occurred in one patient. CONCLUSIONS: For the treatment of geriatric acetabular fractures, the NIBP could provide stable and effective fixation to the QLS involved acetabular fractures, and related satisfactory clinical results with few complications were noted.

Assessment of acute traumatic cervical spinal cord injury using conventional magnetic resonance imaging in combination with diffusion tensor imaging-tractography: a retrospective comparative study.

PURPOSE: The application of conventional magnetic resonance imaging (MRI) in combination with diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) to diagnose acute traumatic cervical SCI has not been studied. This study explores the role of MRI with DTI-DTT in the diagnosis of acute traumatic cervical spinal cord injury (SCI). METHODS: Thirty patients with acute traumatic cervical SCI underwent conventional MRI and DTI-DTT. Conventional MRI was used to detect the intramedullary lesion length (IMLL) and intramedullary hemorrhage length (IMHL). DTI was used to detect the spinal cord's fractional anisotropy (FA) and apparent diffusion coefficient value, and DTT detected the imaginary white matter fiber volume and the connection rates of fiber tractography (CRFT). Patients' neurological outcome was determined using the American Spinal Injury Association (ASIA) Impairment Scale (AIS) grades. RESULTS: Patients were divided into group A (without AIS grade conversion) and group B (with AIS grade conversion). The IMLL and IMHL of group A were significantly higher than those of group B. The FA and CRFT of group A were significantly lower than those of group B. The final AIS grade was negatively correlated with the IMLL and IMHL, and positively correlated with the FA and CRFT. According to imaging features based on conventional MRI and DTI-DTT, we propose a novel classification and diagnostic procedure. CONCLUSIONS: The combination of conventional MRI with DTI-DTT is a valid diagnostic approach for SCI. Lower IMLL and IMHL, and higher FA value and CRFT are linked to better neurological outcomes.

Bioinspired Multifunctional Black Phosphorus Hydrogel with Antibacterial and Antioxidant Properties: A Stepwise Countermeasure for Diabetic Skin Wound Healing.

Cutaneous wound healing, especially diabetic wound healing, is a common clinical challenge. Reactive oxygen species (ROS) and bacterial infection are two major detrimental states that induce oxidative stress and inflammatory responses and impede angiogenesis and wound healing. A derivative of the metabolite itaconate, 4-octyl itaconate (4OI) has attracted increasing research interest in recent years due to its antioxidant and anti-inflammatory properties. In this study, 4OI-modified black phosphorus (BP) nanosheets are incorporated into a photosensitive, multifunctional gelatin methacrylamide hydrogel to produce a new photothermal therapy (PTT) and photodynamic therapy (PDT) system with antibacterial and antioxidant properties for diabetic wound regeneration. Under laser irradiation, the 4OI-BP-entrapped hydrogel enables rapid gelation, forming a membrane on wounds, and offers high PTT and PDT efficacy to eliminate bacterial infection. Without laser irradiation, BP acts as a carrier and controls the release of 4OI, with which it synergistically enhances antioxidant activity, thus alleviating excessive ROS damage to endothelial cells, promoting neovascularization, and facilitating faster diabetic wound closure. These findings indicate that 4OI-BP-entrapped multifunctional hydrogel provides a stepwise countermeasure with antibacterial and antioxidant properties for enhanced diabetic wound healing and may lead to novel therapeutic interventions for diabetic ulcers.

Acute hyperextension myelopathy in children: Radiographic predictors of clinical improvement.

STUDY DESIGN: Retrospective case series SETTING: Three hospitals in China. OBJECTIVE: Previous research indicates that only neurological status on admission determines prognosis of acute hyperextension myelopathy (AHM). The object of this study is to analyze other unfavorable predictors of AHM in children. METHODS: The clinical data of children with AHM were retrospectively analyzed. The ASIA impairment scale (AIS) grade was recorded upon admission and at last follow-up. Intramedullary lesion length (IMLL) was measured in the sagittal T2-weighted imaging (T2WI) within two weeks after onset; gadolinium enhancement in the cord was recorded for each patient. Relationships among AIS grade, IMLL, gadolinium enhancement in the cord, and clinical improvement were assessed. RESULTS: A total of 33 patients were included in this retrospective study. IMLL between complete and incomplete injury was significantly different (p < 0.01) in the subacute stage, and no difference was observed in the acute stage. Correlation analysis revealed that AIS grade on admission (r = 0.906, p < 0.001) was significantly positively correlated with clinical improvement. IMLL (r = -0.608, p < 0.001) and abnormal gadolinium enhancement (r = -0.816, p < 0.001) in the cord in the subacute stage were significantly negatively correlated with clinical improvement. There were no associations between IMLL in the acute stage and clinical improvement (r = -0.248, p = 0.242). The statistically significant predictors of clinical improvement were AIS grade on admission, IMLL in the subacute stage, and abnormal gadolinium enhancement. CONCLUSION: IMLL in the subacute stage and abnormal gadolinium enhancement in the cord are two other prognostic predictors of AHM in children.

Melatonin Attenuates Ropivacaine-Induced Apoptosis by Inhibiting Excessive Mitophagy Through the Parkin/PINK1 Pathway in PC12 and HT22 Cells.

Melatonin, as an endogenous circadian indoleamine secreted by the pineal gland, executes extensive biological functions, including antioxidant, anti-inflammatory, anti-tumor, and neuroprotective effects. Although melatonin has been reported to serve as a potential therapeutic against many nerve injury diseases, its effect on ropivacaine-induced neurotoxicity remains obscure. Our research aimed to explore the impact and mechanism of melatonin on ropivacaine-induced neurotoxicity. Our results showed that melatonin pretreatment protected the cell viability, morphology, and apoptosis of PC12 and HT22 cells, and it also improved ropivacaine-induced mitochondrial dysfunction and the activation of mitophagy. In addition, we found that autophagy activation with rapamycin significantly weakened the protective effect of melatonin against ropivacaine-induced apoptosis, whereas autophagy inhibition with 3-MA enhanced the effect of melatonin. We also detected the activation of Parkin and PINK1, a canonical mechanism for mitophagy regulation, and results shown that melatonin downregulated the expression of Parkin and PINK1, and upregulated Tomm20 and COXIV proteins, so that those results indicated that melatonin protected ropivacaine-induced apoptosis through suppressing excessive mitophagy by inhibiting the Parkin/PINK1 pathway. Melatonin may be a useful potential therapeutic agent against ropivacaine-induced neurotoxicity.

Combination multi-nitrogen with high heat of formation: theoretical studies on the performance of bridged 1,2,4,5-tetrazine derivatives.

A series of bridged tetrazine derivatives (BDDT) were designed by using different bridges to connect two molecules of 1,2,4, 5-tetrazine oxides and then combining different substituents. At the same time, we used DFT-wB97/6-31 + G** method to regularly predict the HOMO-LUMO, heats of formation (HOF), detonation properties, thermal stability, and thermodynamic property orbitals of BDDT compounds. By studying the comprehensive relationship between different substituents and bridging and performance, it is shown that -N(NO2)2 and -C(NO2)3 are not only excellent groups to improve the heat of formation and detonation properties, but also can cause the compound to have a superior oxygen balance. And that the incorporation of the -N = N- and -NH-N = N- is helpful to enhance their thermal stabilities and HOF. -CH2-CH2- and -CH2-NH- are good for improving the HOMO-LUMO energy gaps. Performances with positive HOF (1170-1590 kJ mol-1), remarkable density (1.88-1.93 g cm-3), outstanding detonation properties (D = 9.15-9.80 km s-1, P = 38.24-44.40 GPa), and acceptable impact sensitivity lead C5, D8, E5, E7, F5, and F7 to be the potential candidates of HEDMs.