Transcutaneous spinal cord stimulation on motor function in patients with spinal cord injury: A meta-analysis.

BACKGROUND: It has been suggested that transcutaneous spinal cord stimulation (SCS) is effective in the rehabilitation of patients with spinal cord injury (SCI). However, the evidence is mainly based on case reports. OBJECTIVE: To summarize the influence of transcutaneous SCS on extremity motor function of patients with SCI in a meta-analysis. METHODS: A systematic literature search was performed in electronic databases including PubMed, Cochrane library, Embase, Web of Science, Wanfang, and CNKI to obtain relevant randomized controlled trials (RCTs). A random-effects model was used to pool the results by incorporating the impact of the potential heterogeneity. The most recent database search was conducted on December 31, 2023. RESULTS: Six small-scale open-label or single-blind RCTs were included. Transcutaneous SCS on the basis of conventional rehabilitation could significantly improve limb strength (mean difference: 4.82, p = 0.004; I2 = 0%) and attenuate spasticity (MD: -0.40, p = 0.02; I2 = 0%). The upper-extremity motor function was not significantly affected (p = 0.75). However, transcutaneous SCS significantly improved mobility as indicated by walking speed (MD: 0.13 m/s, p = 0.009; I2 = 0%) and walking distance (standardized MD: 0.62, I2 = 0%). CONCLUSION: Transcutaneous SCS is effective in improving limb strength, spasticity and mobility of patients with SCI.

High-Entropy Lanthanide-Organic Framework as an Efficient Heterogeneous Catalyst for Cycloaddition of CO2 with Epoxides and Knoevenagel Condensation.

Multimetallic synergistic effects have the potential to improve CO2 cycloesterification and Knoevenagel reaction processes, outperforming monometallic MOFs. The results demonstrate superior performance in these processes. To investigate this, we created and characterized a selection of single-component Ln(III)-MOFs (Ln=Eu, Tb, Gd, Dy, Ho) and high-entropy lanthanide-organic framework (HE-LnMOF) using solvent-thermal conditions. The experiments revealed that HE-LnMOF exhibited heightened catalytic efficiency in CO2 cycloesterification and Knoevenagel reactions compared to single-component Ln(III) MOFs. Moreover, the HE-LnMOF displayed significant stability, maintaining their structural integrity after five cycles while sustaining elevated conversion and selectivity rates. The feasible mechanisms of catalytic reactions were also discussed. HE-LnMOF possess multiple unsaturated metal centers, acting as Lewis acid sites, with oxygen atoms connecting the metal, and hydroxyl groups on the ligand serving as base sites. This study introduces a novel method for synthesizing HE-LnMOF and presents a fresh application of HE-LnMOF for converting CO2.

MCM5 is a Novel Therapeutic Target for Glioblastoma.

Objective: MCM5 is a DNA licensing factor involved in cell proliferation and has been previously established as an excellent biomarker in a number of malignancies. Nevertheless, the role of MCM5 in GBM has not been fully clarified. The present study aimed to investigate the potential roles of MCM5 in the treatment of GBM and to elucidate its underlying mechanism, which is beneficial for developing new therapeutic strategies and predicting prognosis. Methods: Firstly, we obtained transcriptomic and proteomic data from the TCGA and CPTAC databases on glioma patients. Employing the DeSeq2 R package, we then identified genes with joint differential expression in GBM tissues subjected to chemotherapy. To develop a prognostic risk score model, we performed univariate and multivariate Cox regression analyses. In vitro knockdown and overexpression of MCM5 were used to further investigate the biological functions of GBM cells. Additionally, we also delved into the upstream regulation of MCM5, revealing associations with several transcription factors. Finally, we investigated differences in immune cell infiltration and drug sensitivity across diverse risk groups identified in the prognostic risk model. Results: In this study, the chemotherapy-treated GBM samples exhibited consistent alterations in 46 upregulated and 94 downregulated genes at both the mRNA and protein levels. Notably, MCM5 emerged as a gene with prognostic significance as well as potential therapeutic relevance. In vitro experiments subsequently validated the role of increased MCM5 expression in promoting GBM cell proliferation and resistance to TMZ. Correlations with transcription factors such as CREB1, CTCF, NFYB, NRF1, PBX1, TEAD1, and USF1 were discovered during upstream regulatory analysis, enriching our understanding of MCM5 regulatory mechanisms. The study additionally delves into immune cell infiltration and drug sensitivity, providing valuable insights for personalized treatment approaches. Conclusion: This study identifies MCM5 as a key player in GBM, demonstrating its prognostic significance and potential therapeutic relevance by elucidating its role in promoting cell proliferation and resistance to chemotherapy.

Metabolism, Disposition, Excretion, and Potential Transporter Inhibition of 7-16, an Improving 5-HT2A Receptor Antagonist and Inverse Agonist for Parkinson's Disease.

Compound 7-16 was designed and synthesized in our previous study and was identified as a more potential selective 5-HT2A receptor antagonist and inverse agonist for treating Parkinson's disease psychosis (PDP). Then, the metabolism, disposition, and excretion properties of 7-16 and its potential inhibition on transporters were investigated in this study to highlight advancements in the understanding of its therapeutic mechanisms. The results indicate that a total of 10 metabolites of 7-16/[14C]7-16 were identified and determined in five species of liver microsomes and in rats using UPLC-Q Exactive high-resolution mass spectrometry combined with radioanalysis. Metabolites formed in human liver microsomes could be covered by animal species. 7-16 is mainly metabolized through mono-oxidation (M470-2) and N-demethylation (M440), and the CYP3A4 isozyme was responsible for both metabolic reactions. Based on the excretion data in bile and urine, the absorption rate of 7-16 was at least 74.7%. 7-16 had weak inhibition on P-glycoprotein and no effect on the transport activity of OATP1B1, OATP1B3, OAT1, OAT3, and OCT2 transporters. The comprehensive pharmacokinetic properties indicate that 7-16 deserves further development as a new treatment drug for PDP.

Novel selective agents for the degradation of AR/AR-V7 to treat advanced prostate cancer.

The androgen receptor AR antagonists, such as enzalutamide and apalutamide, are efficient therapeutics for the treatment of prostate cancer (PCa). Even though they are effective at first, resistance to both drugs occurs frequently. Resistance is mainly driven by aberrations of the AR signaling pathway including AR gene amplification and the expression of AR splice variants (e.g. AR-V7). This highlights the urgent need for alternative therapeutic strategies. Here, a total of 24 compounds were synthesized and biologically evaluated to disclose compound 20i, exhibiting potent AR antagonistic activities (IC50 = 172.85 ± 21.33 nM), promising AR/AR-V7 protein degradation potency, and dual targeting site of probably AR (ligand-binding domain, LBD and N-terminal domain, NTD). It potently inhibits cell growth with IC50 values of 4.87 ± 0.52 and 2.07 ± 0.34 µM in the LNCaP and 22RV1 cell lines, respectively, and exhibited effective tumor growth inhibition (TGI = 50.9 %) in the 22RV1 xenograft study. These data suggest that 20i has the potential for development as an AR/AR-V7 inhibitor with degradation ability to treat advanced prostate cancer.

Enhanced Electrocatalytic Oxygen Evolution by In Situ Growth of Tetrametallic Metal-Organic Framework Electrocatalyst FeCoNiMn-MOF on Nickel Foam.

Developing highly efficient, cost-effective, non-noble-metal-based electrocatalysts with superior performance and stability for oxygen evolution reactions is of immense challenge as well as great importance for the upcoming sustainable and green energy conversion technologies. The multivariate metal-organic frameworks with hierarchical porous structures and unsaturated coordination modes are considered to be promising emerging energy materials. In this work, a series of multimetallic MOFs were directly grown on nickel foam (NF) through the solvothermal method. Notably, the optimized tetrametallic FeCoNiMn-MOF/NF shows a low overpotential of 239 mV to achieve a current density of 50 mA cm-2 with a Tafel slope of 62.05 mV dec-1 for OER in 1 M KOH. It also exhibits excellent stability and durability over 100 h in chronoamperometric studies. The enhanced performance is closely tied to the high activity of iron and nickel ions and the decomposed and reconstructed Ni/Fe-OOH intermediates of the FeCoNiMn-MOF/NF during the OER process, which are revealed by XPS analysis and in situ Raman spectroscopy. This present work demonstrates the feasibility and advantage of utilizing highly efficient and durable multimetallic MOFs for electrocatalytic oxygen evolution.

1-Selector 1-Memristor Configuration with Multifunctional a-IGZO Memristive Devices Fabricated at Room Temperature.

Serving as neuromorphic hardware accelerators, memristors play a crucial role in large-scale neuromorphic computing. Herein, two-terminal memristors utilizing amorphous indium-gallium-zinc oxide (a-IGZO) are fabricated through room-temperature sputtering. The electrical characteristics of these memristors are effectively modulated by varying the oxygen flow during the deposition process. The optimized a-IGZO memristor, fabricated under 3 sccm oxygen flow, presents a 5 × 103 ratio between its high- and low-resistance states, which can be maintained over 1 × 104 s with minimal degradation. Meanwhile, desirable properties such as electroforming-free and self-compliance, crucial for low-energy consumption, are also obtained in the a-IGZO memristor. Moreover, analog conductance switching is observed, demonstrating an interface-type behavior, as evidenced by its device-size-dependent performance. The coexistence of negative differential resistance with analog switching is attributed to the migration of oxygen vacancies and the trapping/detrapping of charges. Furthermore, the device demonstrates optical storage capabilities by exploiting the optical properties of a-IGZO, which can stably operate for up to 50 sweep cycles. Various synaptic functions have been demonstrated, including paired-pulse facilitation and spike-timing-dependent plasticity. These functionalities contribute to a simulated recognition accuracy of 90% for handwritten digits. Importantly, a one-selector one-memristor (1S1M) architecture is successfully constructed at room temperature by integrating a-IGZO memristor on a TaOx-based selector. This architecture exhibits a 107 on/off ratio, demonstrating its potential to suppress sneak currents among adjacent units in a memristor crossbar.

Inverted U-shaped relationship between Barthel Index Score and falls in Chinese non-bedridden patients: a cross-sectional study.

BACKGROUND: Performing activities of daily living comprise an important risk factor for falls among non-bedridden stroke inpatients in rehabilitation departments. OBJECTIVES: To explore the correlation between Barthel Index score and the occurrence of falls in non-bedridden stroke rehabilitation inpatients. METHODS: In this cross-sectional study, information of patients grouped as non-bedridden patients by the Longshi Scale was collected. RESULTS: A total of 3097 patients were included in this study, with a fall incidence of 10.43%. After adjusting covariates, the total score of Barthel Index and falls in non-bedridden inpatients after stroke presented an inverted U-shaped curve relationship, in which inflection point was 60. The effect sizes on the left and right sides of infection point were 1.02 (95%CI 1.00-1.04) and 0.97 (95%CI 0.96-0.99), respectively. CONCLUSIONS: Non-bedridden stroke patients with moderate activities of daily living (ADL) capacity may be at particularly increased risk of falls in rehabilitation departments.

Inhibition of Pyruvate Dehydrogenase Kinase 4 Attenuates Myocardial and Mitochondrial Injury in Sepsis-Induced Cardiomyopathy.

BACKGROUND: Sepsis-induced cardiomyopathy (SIC) is a cardiac dysfunction caused by sepsis, with mitochondrial dysfunction being a critical contributor. Pyruvate dehydrogenase kinase 4 (PDK4) is a kinase of pyruvate dehydrogenase with multifaceted actions in mitochondrial metabolism. However, its role in SIC remains unknown. METHODS: Serum PDK4 levels were measured and analyzed in 27 children with SIC, 30 children with sepsis, and 29 healthy children. In addition, for mice exhibiting SIC, the effects of PDK4 knockdown or inhibition on the function and structure of the myocardium and mitochondria were assessed. RESULTS: The findings from the analysis of children with SIC revealed that PDK4 was significantly elevated and correlated with disease severity and organ injury. Nonsurvivors displayed higher serum PDK4 levels than survivors. Furthermore, mice with SIC benefited from PDK4 knockdown or inhibition, showing improved myocardial contractile function, reduced myocardial injury, and decreased mitochondrial structural injury and dysfunction. In addition, inhibition of PDK4 decreased the inhibitory phosphorylation of PDHE1α (pyruvate dehydrogenase complex E1 subunit α) and improved abnormal pyruvate metabolism and mitochondrial dysfunction. CONCLUSIONS: PDK4 is a potential biomarker for the diagnosis and prognosis of SIC. In experimental SIC, PDK4 promoted mitochondrial dysfunction with increased phosphorylation of PDHE1α and abnormal pyruvate metabolism.

A novel scaffold long-acting selective estrogen receptor antagonist and degrader with superior preclinical profile against ER+ breast cancer.

Breast cancer is one of the most common malignant tumors in women worldwide, with the majority of cases showing expression of estrogen receptors (ERs). Although drugs targeting ER have significantly improved survival rates in ER-positive patients, drug resistance remains an unmet clinical need. Fulvestrant, which overcomes selective estrogen receptor modulator (SERM) and AI (aromatase inhibitor) resistance, is currently the only long-acting selective estrogen receptor degrader (SERD) approved for both first and second-line settings. However, it fails to achieve satisfactory efficacy due to its poor solubility. Therefore, we designed and synthesized a series of novel scaffold (THC) derivatives, identifying their activities as ER antagonists and degraders. G-5b, the optimal compound, exhibited binding, antagonistic, degradation or anti-proliferative activities comparable to fulvestrant in ER+ wild type and mutants breast cancer cells. Notably, G-5b showed considerably improved stability and solubility. Research into the underlying mechanism indicated that G-5b engaged the proteasome pathway to degrade ER, subsequently inhibiting the ER signaling pathway and leading to the induction of apoptosis and cell cycle arrest events. Furthermore, G-5b displayed superior in vivo pharmacokinetics and pharmacodynamics properties, coupled with a favorable safety profile in the MCF-7 tamoxifen-resistant (MCF-7/TR) tumor xenograft model. Collectively, G-5b has emerged as a highly promising lead compound, offering potent antagonistic and degradation activities, positioning it as a novel long-acting SERD worthy of further refinement and optimization.

[Improvement of solubility of epimedium flavonoid secondary glycoside components by traditional Chinese medicine polysaccharides and its mechanism].

The poor solubility of insoluble components of traditional Chinese medicine(TCM) is an important factor restricting the development of its preparations. Natural polysaccharides of TCM can be used as functional components to increase the solubility of insoluble components. Epimedium flavonoid secondary glycoside components(EFSGC) have been shown to have positive effects on the prevention and treatment of osteoporosis, but they exhibit poor solubility. Therefore, the strategy of solubilizing EFSGC with TCM polysaccharides was adopted, and its effect on the permeability and stability of EFSGC was evaluated in this study. Based on the equilibrium solubility experiment of EFSGC, it was found that Panax notoginseng crude polysaccharide(PNCP) had the best solubilization effect on EFSGC among the ten kinds of TCM polysaccharides, which increased the solubility of EFSGC from 0.8 mg·mL~(-1) to 13.3 mg·mL~(-1). It should be noted that after the solubilization of EFSGC by preparation technology, the effects on permeability and stability should be considered. Therefore, this study also investigated these two properties. The results showed that PNCP increased the effective transmittance of EFSGC from 50.5% to 71.1%, which could increase the permeability of EFSGC significantly. At the same time, it could improve the stability of EFSGC in the simulated gastric juice environment. In order to explain the solubilization mechanism of PNCP on EGSGC, critical micelle concentration, particle size, potential, differential scanning calorimetry, and infrared spectroscopy were analyzed. It was preliminarily inferred that the mechanism was as follows: PNCP and EFSGC could self-assemble into aggregates for solubilization by intermolecular hydrogen bonding interaction in water. In summary, PNCP can not only improve the solubility of EFSGC but also improve its permeability and stability. This study lays the foundation for the application of TCM polysaccharides as a functional component to solubilize insoluble components.

Neuroimaging and artificial intelligence for assessment of chronic painful temporomandibular disorders-a comprehensive review.

Chronic Painful Temporomandibular Disorders (TMD) are challenging to diagnose and manage due to their complexity and lack of understanding of brain mechanism. In the past few decades' neural mechanisms of pain regulation and perception have been clarified by neuroimaging research. Advances in the neuroimaging have bridged the gap between brain activity and the subjective experience of pain. Neuroimaging has also made strides toward separating the neural mechanisms underlying the chronic painful TMD. Recently, Artificial Intelligence (AI) is transforming various sectors by automating tasks that previously required humans' intelligence to complete. AI has started to contribute to the recognition, assessment, and understanding of painful TMD. The application of AI and neuroimaging in understanding the pathophysiology and diagnosis of chronic painful TMD are still in its early stages. The objective of the present review is to identify the contemporary neuroimaging approaches such as structural, functional, and molecular techniques that have been used to investigate the brain of chronic painful TMD individuals. Furthermore, this review guides practitioners on relevant aspects of AI and how AI and neuroimaging methods can revolutionize our understanding on the mechanisms of painful TMD and aid in both diagnosis and management to enhance patient outcomes.

Visualization of Confined Electrons at Grain Boundaries in a Monolayer Charge-Density-Wave Metal.

1D grain boundaries in transition metal dichalcogenides (TMDs) are ideal for investigating the collective electron behavior in confined systems. However, clear identification of atomic structures at the grain boundaries, as well as precise characterization of the electronic ground states, have largely been elusive. Here, direct evidence for the confined electronic states and the charge density modulations at mirror twin boundaries (MTBs) of monolayer NbSe2 , a representative charge-density-wave (CDW) metal, is provided. The scanning tunneling microscopy (STM) measurements, accompanied by the first-principles calculations, reveal that there are two types of MTBs in monolayer NbSe2 , both of which exhibit band bending effect and 1D boundary states. Moreover, the intrinsic CDW signatures of monolayer NbSe2 are dramatically suppressed as approaching an isolated MTB but can be either enhanced or suppressed in the MTB-constituted confined wedges. Such a phenomenon can be well explained by the MTB-CDW interference interactions. The results reveal the underlying physics of the confined electrons at MTBs of CDW metals, paving the way for the grain boundary engineering of the functionality.

A Naïve Phage Display Library-Derived Nanobody Neutralizes SARS-CoV-2 and Three Variants of Concern.

Background: The emergence of the coronavirus disease 2019 (COVID-19) pandemic and the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VOCs) requires the continuous development of safe, effective, and affordable prevention and therapeutics. Nanobodies have demonstrated antiviral activity against a variety of viruses, providing a new candidate for the prevention and treatment of SARS-CoV-2 and its variants. Methods: SARS-CoV-2 glycoprotein spike 1 subunit (S1) was selected as the target antigen for nanobody screening of a naïve phage display library. We obtained a nanobody, named Nb-H6, and then determined its affinity, inhibition, and stability by ELISA, Competitive ELISA, and Biolayer Interferometry (BLI). Infection assays of authentic and pseudotyped SARS-CoV-2 were performed to evaluate the neutralization of Nb-H6. The structure and mechanism of action were investigated by AlphaFold, docking, and residue mutation assays. Results: We isolated and characterized a nanobody, Nb-H6, which exhibits a broad affinity for S1 and the receptor binding domain (RBD) of SARS-CoV-2, or Alpha (B.1.1.7), Delta (B.1.617.2), Lambda (C.37), and Omicron (BA.2 and BA.5), and blocks receptor angiotensin-converting enzyme 2 (ACE2) binding. Moreover, Nb-H6 can retain its binding capability after pH or thermal treatment and effectively neutralize both pseudotyped and authentic SARS-CoV-2, as well as VOC Alpha (B.1.1.7), Delta (B.1.617.2), and Omicron (BA.2 and BA.5) pseudoviruses. We also confirmed that Nb-H6 binds two distinct amino acid residues of the RBD, preventing SARS-CoV-2 from interacting with the host receptor. Conclusion: Our study highlights a novel nanobody, Nb-H6, that may be useful therapeutically in SARS-CoV-2 and VOC outbreaks and pandemics. These findings also provide a molecular foundation for further studies into how nanobodies neutralize SARS-CoV-2 and variants and imply potential therapeutic targets for the treatment of COVID-19.

Photoinduced Radical Cyclization of 2-Alkynylthioanisoles with Disulfides without an External Photocatalyst.

An efficient strategy for the synthesis of 3-arylthiobenzo[b]thiophenes via a photodriven radical cyclization of 2-alkynylthioanisoles with disulfide was developed. The reaction proceeded smoothly under visible-light irradiation without any external photocatalyst and generated the desired products in high yields with good functional group tolerance.

Complications of Mandibular Distraction Osteogenesis in Infants with Isolated Robin Sequence.

Mandibular Distraction Osteogenesis (MDO) is now the preferred procedure to alleviate airway obstruction in infants with severe Robin Sequence (RS). However, there have been very few studies investigating complications related to MDO surgery performed on patients affected by isolated RS. In this study, age at distraction, weight at distraction, preoperative intubation, repeat MDO and complications associated with MDO were included as variables. Minor, moderate and major problems were evaluated and recorded as surgical site infections (SSI), injuries to the facial nerve, self-extinction hypertrophic scars, temporomandibular joint ankylosis, device failures, early ossification and fibrous non-union. One hundred and fifty one patients with isolated RS were included. At distraction, the mean age was 72 days (12-540 days) and the mean weight was 4.05 kg (2.4-12.2 kg). Only one patient needed tracheostomy after MDO, and none required further distraction. Ultimately, the complication rate was 15.23%, and there was a total of 7.95% minor, 9.27% moderate and 0% major complications. Minor incidents included surgical site infection (SSI) managed with antibiotics taken orally (n = 8), neuropraxia in the VII cranial nerve (CN) (n = 1), and hypertrophic scarring (n = 3). Incidents reported as moderate were SSIs managed with intravenous antibiotics (n = 9), incision and drainage (n = 3) and self-extubation (n = 2). There was no case of TMJ ankylosis. There were no cases of early or premature ossification, fibrous non-union and device fracture. In conclusion, MDO is an effective and appropriate management technique for infants with isolated RS and severe airway obstruction. Infections at the surgery site accounted for the vast majority of the complications. Further investigations may be needed to determine the long-term consequences of MDO.

[Occurrence and Fate of Steroid Hormones in Sewage Treatment Plants].

Sewage treatment plants (STPs) are one of the crucial barriers for the environmental emission of steroid hormones. Insights into the occurrence and fate of different categories of steroid hormones in STPs could provide theoretical support for improving steroid removal by STPs. The present study investigated 22 steroid hormones in each treatment process of two STPs located in Wuxi via eight monthly sampling campaigns and compared the efficacy of Anaerobic-Anoxic-Aerobic (A2/O) and reversed A2/O treatments. The results showed that the total steroid concentrations in the influent and effluent were 27.7-256.8 ng·L-1 and 5.7-211.0 ng·L-1, respectively, and 36.3-123.6 ng·g-1 in the excess sludge. Androsterone, androstenedione, estrone, estriol, and progesterone were the main species detected in the STPs. The concentrations of most steroids increased with the rise of rainfall and temperature, whereas the removal rates were not significantly different between winter and summer. Secondary and tertiary treatment processes showed better performance in steroid removal compared with that in the primary treatment; however, reversed A2/O did not show advantages over traditional A2/O. The organic-normalized partition coefficients (lg Koc) of steroids ranged between 2 and 4.5. The values of lg Koc in STP A were slightly greater than those in STP B, indicating that the partition behavior of steroids may influence their treatment efficacies.

Subacute toxicity evaluations of LPM3480392 in rats, a full µ-opioid receptor biased agonist.

Opiates produce analgesia via G-protein signaling, and adverse effects, such as respiratory depression and decreased bowel motility, by ß-arrestin pathway. Oliceridine, a G protein-biased MOR agonist, only presents modest safety advantages as compared to other opiates in clinical trials, possibly due to its limited bias. Our previous study shown that LPM3480392, a full MOR biased agonist, is selective for the Gi pathway over the ß-arrestin-2. In the present article, we evaluated the subacute toxicity of LPM3480392 in rats. The rats were administered with control article or LPM3480392 0.6, 1.2 or 2.4 mg/kg/day for 4 consecutive weeks followed by a 4-week recovery phase. Intravenous infusion was conducted at tail vein at 0.2, 0.4 or 0.8 mg/kg/day with a dosing volume of 10 mL/kg and 5 min/rat/dose, three times a day with an interval of approximately 4 h. The concomitant toxicokinetics study was conducted. Two unscheduled rats at 2.4 mg/kg/day died with no clear cause. For the scheduled necropsy, the major effects were associated with the MOR agonist-related pharmacodynamic properties of LPM3480392 (e.g., increased activity, increased muscle tone; decreased food consumption and body weight gain; and clinical chemistry changes related with decreased food consumption) in three LPM3480392 groups. In addition, LPM3480392 at 2.4 mg/kg/day also induced deep respiration and histopathology changes in testis and epididymis in sporadic individual rats. However, different from other opiates, LPM3480392 presents weak/no immunosuppression and the decreased adrenal gland weight, which may be due to LPM3480392' full MOR bias. At the end of recovery phase, all findings were recovered to some extent or completely. In the toxicokinetics study, the dose-dependent elevation of drug exposure was observed, which partly explained the toxicity of high dose. In summary, LPM3480392 has exhibited good safety characteristics in this subacute toxicity study in rats.

Moringa oleifera Lam.: a comprehensive review on active components, health benefits and application.

Moringa oleifera Lam. is an edible therapeutic plant that is native to India and widely cultivated in tropical countries. In this paper, the current application of M. oleifera was discussed by summarizing its medicinal parts, active components and potential mechanism. The emerging products of various formats such as drug preparation and product application reported in the last years were also clarified. Based on literature reports, the unique components and biological activities of M. oleifera need to be further studied. In the future, a variety of new technologies should be applied to the development of M. oleifera products, to enrich the varieties of dosage forms, improve the bitter taste masking technology, and make it better for use in the fields of food and medicine.