Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

【Objective】 To explore the quality of autologous platelet-rich plasma prepared by manual and automatic method and to study the clinical injection therapeutic effects in patient with knee arthritis. 【Methods】 28 patients with knee arthritis in Orthopedics Department of our hospital were enrolled. PRP was prepared manually in 12 patients and automatically in 16. The whole blood of 50~70 mL was drawn from 12 patients and prepared into PRP of 10 mL manually by centrifugation. The 20~30 mL PRP was collected by automatic apheresis. Plt, RBC, WBC and other related indexes of PRP were detected after collection. Among the 28 patients, 12 in the manual group received injection twice, while 16 in the automatic group 4 episodes, with an interval of 15~20 days. The treatment effect was evaluated after the last treatment. 【Results】 The PRP prepared by two methods can both reach the required quality standard of platelet counts..The patient′s pain symptoms relieved significantly after injection treatment and the effect was remarkable. There was no significant difference in clinical efficacy between the two groups. 【Conclusion】 The PRP prepared by manual and automatic methods can be used for injection treatment for patient with knee arthritis. The clinical therapeutic effects were good and worth promotion and application.

BACKGROUND: The previous methods for the repair of tendon defect include end-to-end method, autologous tendon graft, tendon al ograft or artificial tendon transplantation, but each method has its advantages and disadvantages. OBJECTIVE: To investigate the feasibility of constructing tissue-engineered tendon by rabbit bone marrow mesenchymal stem cells as seed cells which were induced by bone morphogenetic protein 12 and with col agen-polyglycolic acid composite as frameworks in the repair of rabbit tendon defects. METHODS: Bone marrow was separated from rabbit proximal femur to harvest cells, and the cells were passaged to the second generation and induced with 10 μg/L bone morphogenetic protein 12. Then the passage 2 cells were implanted into the prefabricated tissue-engineered tendon on the polyglycolic acid stitch with certain percentage together with col agenⅠsolution. The rabbits were used to establish the Achil es tendon defect models, and different methods were used to repair Achil es tendon defect: tissue-engineered tendon, col agenⅠ-polyglycolic acid stitch and end-to-end suturing in silk. Morphology, mechanics and shistopathology of the tissue-engineered tendon were observed. RESULTS AND CONCLUSION: Pathomorphological observation of histological section after 12 weeks showed that multiple fusiform fibroblasts were homogeneously distributed in col agen in the direction of stress mechanics.Fibrocytes increased obviously, new smal vessels could be seen and col agen was found aligned compactedly. In col agen Ⅰ-polyglycolic acid stitch group, a part of fibroplasia hyperplasia accompanied by granulation tissue formation could be seen, the col age fibers were in loose filamentous network and the cells were distributed disorderly and unevenly. Granulation tissue formed around the fibrous tissue in the silk group. Biomechanics strength in bone morphogenetic protein 12+polyglycolic acid group was better than that in the col agen Ⅰ-polyglycolic acid group, and there was significant difference when compared with suture silk group. The biomechanics strength of the bone morphogenetic protein 12+polyglycolic acid group was lower than that of normal tendon. It is possible to construct a tissue-engineered tendon with autologous bone marrow mesenchymal stem cells as seed cells induced by bone morphogenetic protein 12 and with the col agen-polyglycolic acid as the framework. Constructed tissue-engineered tendon has biomechanics characteristics and can be used to repair Achil es tendon defect.

Neijing was a early medical classic existing in China and had a deep influence on the formation of traditional Chinese medicine. Besides, Neijing was also an ancient philosophic works, in which the severe view of heaven was recorded, laying a sound basis for the development of TCM. It would have great significance for health cultivation of patients with chronic liver diseases to analyze the theory on relation between human and nature recorded in Neijing and to absorb its rational contents.

Objective To explore into the superiority of the treatment of clavicle-hook plate for acromioclavicular dislocation and the fracture of the distal end of clavicle.Methods Select 35 clinical cases with the acromioclavicular dislocation and the fracture of the distal end of clavicle, and then evaluate the function of the joint and the union of fracture.Results All the fractures got fully union, no joint re-dislocation, and got 100% excellent and good result.Conclusion Clavicle-hook plate is the perfect fixation in the treatment of the acromioclavicular dislocation and the fracture of the distal end of clavicle.