Effects of strength training on functional ambulation following knee replacement: a systematic review, meta-analysis, and meta-regression.

Strength training is recommended by the American Physical Therapy Association to improve muscle strength, mobility, and balance following knee replacement. Few studies have focused on the direct effects of strength training on functional ambulation, and potential dose-response relationships between strength training parameters and the effect remain unclear. The aim of this systematic review, meta-analysis, and meta-regression was to evaluate the effects of strength training on functional ambulation following knee replacement (KR). We also aimed to explore potential dose-response relationships between strength training parameters and performance in functional ambulation. A systematic literature search of eight online databases was performed on March 12, 2023, for randomized controlled trials evaluating the effects of strength training on functional ambulation by six-minute walk test (6MWT) or timed-up and go test (TUG) after KR. Data were pooled by random-effect meta-analyses and presented as weighted mean difference (WMD). A random-effect meta-regression was performed for four predetermined training parameters, namely, duration (weeks), frequency (sessions per week), volume (time per session), and initial time (after surgery) separately to explore dose-response relationships with WMD. Fourteen trials encompassing 956 participants were included in our study. Meta-analyses showed an improvement in 6MWT performance after strength training (WMD: 32.15, 95% CI 19.44-44.85) and a decrease in time to complete TUG (WMD: - 1.92, 95% CI - 3.43 to - 0.41). Meta-regression revealed a dose-response relationship only between volume and 6MWT, with a decreasing trend (P = 0.019, 95% CI - 1.63 to - 0.20). Increasing trends of improvement in 6MWT and TUG were observed with increasing training duration and frequency. A slight decreasing trend of improvement was observed in 6MWT with postponed initial time, while an opposite trend was observed in TUG. Based on existing studies, moderate-certainty evidence suggests that strength training could increase 6MWT distance, and low-certainty evidence shows that strength training could decrease the time to complete TUG after KR. Meta-regression results only suggested a dose-response relationship between volume and 6MWT with a decreasing trend.Registration: PROSPERO: CRD42022329006.

Exosomes in malignant pleural effusion from lung cancer patients impaired the cytotoxicity of double-negative T cells.

CD3+CD4-CD8- double-negative T (DNT) cells are new weapons in cancer immunotherapy. Here, we explored DNT cells in malignant pleural effusions (MPEs) from lung cancer patients. DNT cells, especially TCRαß+CD56- DNT cells, were increased in MPE from lung cancer patients. DNT cells highly expressed PD-1, TRAIL, NKG2D and DNAM-1. In contrast, FasL was barely detected in DNT cells. Compared with non-MPE cells, MPE-derived DNT cells expressed much higher levels of PD-1 and TRAIL. DNT cells from healthy peripheral blood donors potentially killed lung cancers, which was decreased by MPE supernatant. Exosomes from MPE supernatant expressed PD-1 and CEACAM1 and impaired the cytotoxicity of DNT cells. Blocking PD-1 and TIM3 rescued the cytotoxicity of DNT cells treated with MPE-derived exosomes. Overall, we demonstrated that the frequency of DNT cells in MPE from lung cancer patients was increased and that MPE-derived exosomes impaired the cytotoxicity of DNT cells via the PD-1/PD-L1 and CEACAM1/TIM3 pathways.

Design, Synthesis, Biological Evaluation, and Molecular Modeling of 2-Difluoromethylbenzimidazole Derivatives as Potential PI3Kα Inhibitors.

PI3Kα is one of the potential targets for novel anticancer drugs. In this study, a series of 2-difluoromethylbenzimidazole derivatives were studied based on the combination of molecular modeling techniques 3D-QSAR, molecular docking, and molecular dynamics. The results showed that the best comparative molecular field analysis (CoMFA) model had q2 = 0.797 and r2 = 0.996 and the best comparative molecular similarity indices analysis (CoMSIA) model had q2 = 0.567 and r2 = 0.960. It was indicated that these 3D-QSAR models have good verification and excellent prediction capabilities. The binding mode of the compound 29 and 4YKN was explored using molecular docking and a molecular dynamics simulation. Ultimately, five new PI3Kα inhibitors were designed and screened by these models. Then, two of them (86, 87) were selected to be synthesized and biologically evaluated, with a satisfying result (22.8 nM for 86 and 33.6 nM for 87).

MiR-181c sensitizes ovarian cancer cells to paclitaxel by targeting GRP78 through the PI3K/Akt pathway.

Primary cytoreductive surgery with platinum-taxane-based chemotherapy is the standard treatment for ovarian cancer (OC) patients; however, resistance to chemotherapy is a contributing factor to OC mortality. Paclitaxel (PTX), the most widely used taxane, has become the first-line drug against OC. The molecular mechanism of PTX resistance is different from that of platinum-based agents and is still not completely elucidated. Our previous study showed that glucose-regulated protein 78 (GRP78) is involved in the resistance of OC cells to PTX. However, little is known regarding endogenous inhibitors of this gene. MicroRNAs (miRNAs) play critical roles in the regulation of gene expression; therefore, we sought to identify miRNA(s) with potential to target GRP78 under the hypothesis that miRNA(s) could serve as potential therapeutic targets. Here, we show that miR-181c, predicted to target GRP78, was downregulated in PTX-resistant OC cells and tissues. MiR-181c downregulated GRP78 expression and induced apoptosis by directly targeting its 3'-untranslated region (UTR). Overexpression of miR-181c sensitized resistant OC to PTX by inhibiting the PI3K/Akt pathway in vitro and in vivo. Taken together, our findings indicate that the delivery of miR-181c can efficiently suppress GRP78 expression and GRP78-mediated PTX resistance in OC and suggest that this strategy has therapeutic potential.

Epithelial-Mesenchymal Transition in Asthma Airway Remodeling Is Regulated by the IL-33/CD146 Axis.

Epithelial-mesenchymal transition (EMT) is essential in asthma airway remodeling. IL-33 from epithelial cells is involved in pulmonary fibrosis. CD146 has been extensively explored in cancer-associated EMT. Whether IL-33 regulates CD146 in the EMT process associated with asthma airway remodeling is still largely unknown. We hypothesized that EMT in airway remodeling was regulated by the IL-33/CD146 axis. House dust mite (HDM) extract increased the expression of IL-33 and CD146 in epithelial cells. Increased expression of CD146 in HDM-treated epithelial cells could be blocked with an ST2-neutralizing antibody. Moreover, HDM-induced EMT was dependent on the CD146 and TGF-ß/SMAD-3 signaling pathways. IL-33 deficiency decreased CD146 expression and alleviated asthma severity. Similarly, CD146 deficiency mitigated EMT and airway remodeling in a murine model of chronic allergic airway inflammation. Furthermore, CD146 expression was significantly elevated in asthma patients. We concluded that IL-33 from HDM extract-treated alveolar epithelial cells stimulated CD146 expression, promoting EMT in airway remodeling in chronic allergic inflammation.

Airway invasive aspergillosis with organizing pneumonia: a case report and review of literature.

Organizing pneumonia (OP) is a distinct clinical and pathologic entity. This condition can be cryptogenic (COP) or secondary to other known causes (secondary OP, SOP). Concomitant occurrence of invasive pulmonary aspergillosis (IPA) with SOP is unusual. Here, we report a case where SOP was a presenting feature in a patient with diagnosed IPA. A previously healthy 62-year-old man presented to the hospital with a month of intermittent fever accompanied by cough and expectoration. According to computed tomography (CT), sputum culture, and transbronchial lung biopsy, he was diagnosed as IPA. Despite undergoing voriconazole and dexamethasone therapy, the patient's condition did not improve after three weeks of therapy. CT-guided percutaneous lung biopsy performed in the left upper lung showed invasive airway aspergillosis with organizing pneumonia. Two months after the combination therapy of voriconazole and methylprednisolone, the CT scan indicated the pulmonary consolidations were almost entirely resolved. To the best of our knowledge, this is the first case of successful non-surgical treatment of IPA with SOP. In a review of the literature, we aimed to highlight the possibility of invasive airway aspergillosis concurrent with secondary organizing pneumonia. Physicians should be aware of the possibility of SOP in the case of IPA.

Astragaloside IV inhibits oxidized low­density lipoprotein­induced endothelial damage via upregulation of miR­140­3p.

Oxidized low­density lipoprotein (ox­LDL)­mediated endothelial cell injury has an important role in the vascular complications of type 2 diabetes. Astragaloside IV (ASV) is an active component of Radix Astragali, which has been demonstrated to exert protective effects against endothelial damage. The present study explored whether microRNAs (miRNAs) are involved in mediating the protective effects of ASV on ox­LDL­induced damage in human umbilical vein endothelial cells (HUVECs). RNA sequencing and reverse transcription­quantitative PCR analyses revealed that ox­LDL treatment significantly downregulated miR­140­3p expression in HUVECs. miR­140­3p overexpression promoted cell proliferation and inhibited apoptosis in ox­LDL­induced HUVECs. However, inhibition of miR­140­3p expression could reverse the effects of ASV on ox­LDL­induced HUVECs and reactivate ASV­inhibited PI3K/Akt signaling in ox­LDL­induced HUVECs. In addition, Krüppel­like factor 4 (KLF4) was identified as a target of miR­140­3p in ox­LDL­treated HUVECs. Subsequent experiments revealed that KLF4 overexpression partially counteracted the protective effects of miR­140­3p or ASV treatment in ox­LDL­induced HUVECs. Taken together, the current findings demonstrated that the protective effects of ASV on HUVECs were dependent on miR­140­3p upregulation and subsequent inhibition of KLF4 expression, which in turn suppressed the PI3K/Akt signaling pathway. The present results shed light to the molecular mechanism by which ASV alleviated ox­LDL­induced endothelial cell damage.

Dual antifungal properties of cationic antimicrobial peptides polybia-MPI: membrane integrity disruption and inhibition of biofilm formation.

With the increasing emergence of resistant fungi, the discovery and development of novel antifungal therapeutics were urgently needed. Compared with conventional antibiotics, the limited propensity of AMPs to induce resistance in pathogens has attracted great interest. In the present study, the antifungal activity and its mechanism-of-action of polybia-MPI, a cationic peptide from the venom of Social wasp Polybia Paulista was investigated. We demonstrated that polybia-MPI could potently inhibit the growth of Candida albicans (C. albicans) and Candida glabrata (C. glabrata). The 50% inhibitory concentrations (IC50) of Polybia-MPI against cancer cells were much higher than the MICs against the tested C. albicans and C. glabrata cells, indicating that polybia-MPI had high selectivity between the fungal and mammalian cells. Our results also indicated that membrane disturbance mechanism was involved in the antifungal activity. Furthermore, polybia-MPI could inhibit the bio film forming of C. glabrata, which was frequently associated with clinically significant biofilm. These results suggest that polybia-MPI has great advantages in the development of antifungal agents.

[Expressions and clinical significance of OX40 and OX40L in peripheral blood of patients with primary Sjogren's syndrome].

OBJECTIVE: To investigate the expressions of costimulatory molecules OX40 and OX40L on peripheral blood mononuclear cells (PBMC) and their relationship with clinical characteristics of patients with primary Sjogren's syndrome (pSS). METHODS: Peripheral blood samples were collected from 51 pSS patients and 36 healthy subjects (HC). The expressions of OX40 and OX40L on PBMC were detected by immunofluorescence and flow cytometry. In addition, we observed the changes in the levels of OX40 and OX40L after treatment in 11 patients with primary pSS and searched for the relationship between their expression levels and patients' clinical manifestations. RESULTS: The expression of OX40 on CD4(+);T cells in pSS patients was significantly higher than that in the HC group (8.65%±3.51% vs 5.68%±1.68%, P<0.01). However, there was no significant difference in OX40 expression on CD8(+);T cells between patient group and HC group. In comparison with HC group, the expression of OX40L on CD14(+); monocytes (6.76%±3.60% vs 3.15%±1.89%, P<0.01) and CD19(+);B cells (4.69%±2.40% vs 2.76%±1.33%, P<0.01) significantly increased in pSS patients. Moreover, OX40 expression on CD4(+);T cells and OX40L expression on monocytes and B cells rose significantly in active pSS patients compared with those in inactive patients. The expression levels of OX40 and OX40L were higher in pSS patients with multiple system damage than in patients with simple exocrine gland injury. In addition, immunosuppressive therapy significantly reduced the expressions of OX40 and OX40L. CONCLUSION: The expressions of OX40 and OX40L on peripheral lymphocytes was upregulated in pSS patients. The high levels of OX40 and OX40L expression were significantly correlated with clinical outcome and therapeutic response, suggesting that OX40/OX40L pathway may play a critical role in pSS pathogenesis.