Effects of spinal mobilization on physical function in patients with stroke: a systematic review and meta-analysis.

This systematic review and meta-analysis aimed to identify, critically appraise, and synthesize current evidence regarding the effects of spinal mobilization on physical function in patients with stroke. Three databases, PubMed, Embase, and Scopus, were searched from inception to March 15, 2024. Randomized controlled trials comparing the effects of spinal mobilization to conventional therapy were eligible for inclusion. Methodological quality was assessed using the Physiotherapy Evidence Database scale. Meta-analyses were performed to determine the effects of spinal mobilization. Nine randomized controlled trials were included, with a total of 294 patients with stroke. All included studies were evaluated as good or above for quality assessment. No adverse events related to spinal mobilization were reported. Compared to conventional therapy, spinal mobilization demonstrated significantly improved forward head posture (SMD: 1.00, 95% CI: 0.53 to 1.46, p < 0.001); there were no between-group differences on forced vital capacity (SMD: 0.44, 95% CI: -0.01 to 0.88, p = 0.06), forced expiratory volume (SMD: 0.33, 95% CI: -0.12 to 0.77, p = 0.15), balance (SMD: 0.36, 95% CI: -0.04 to 0.77, p = 0.08), gait speed (SMD: 0.48, 95% CI: -0.44 to 1.40, p = 0.31), and trunk function (SMD: 0.79, 95% CI: -0.17 to 1.75, p = 0.11). Cervical mobilization significantly improved forward head posture; however, no significant differences were found in other outcomes. Clinicians may consider spinal mobilization as an adjunctive intervention in stroke rehabilitation to address posture-related impairments to expand treatment strategy and optimize quality of care.

Discovery of (2-(4-Substituted phenyl)quinolin-4-yl)(4-isopropylpiperazin-1-yl)methanone Derivatives as Potent Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors.

Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an increasingly important role in the treatment of hyperlipidemia. In pursuit of potent small molecules that block the PCSK9/low-density lipoprotein receptor (LDLR) protein-protein interaction (PPI), a series of 2-phenylquinoline-4-carboxylic acid derivatives were designed and synthesized based on previously derived molecules. In the in vitro PPI inhibition test, compounds M1, M12, M14, M18 and M27 exhibited potent activities with IC50 values of 6.25 µM, 0.91 µM, 2.81 µM, 4.26 µM and 0.76 µM, respectively, compared with SBC-115337 (IC50 value of 9.24 µM). Molecular docking and molecular dynamics simulations revealed the importance of hydrophobic interactions in the binding of inhibitors to the PPI interface of PCSK9. In LDLR expression and LDL uptake assays, the tested compounds M1, M12 and M14 were found to restore LDLR expression levels and to increase the extracellular LDL uptake capacity of HepG2 cells in the presence of exogenous PCSK9. Collectively, novel small-molecule PCSK9/LDLR PPI inhibitors (especially M12) with in vitro lipid lowering ability, were discovered as lead compounds for further development of hypolipidemic drugs.

Discovery of [5,5'-bibenzo[d][1,3]dioxol]-6-substituted amine derivatives as potent proprotein convertase subtilisin/kexin type 9 inhibitors.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hyperlipidemia. In discovery of novel small molecules that interfere PCSK9/LDLR protein-protein interaction (PPI), structural modification was performed based on our previously derived compounds. A series of [5,5'-bibenzo[d][1,3]dioxol]-6-amine analogs were designed and synthesized for the activity evaluation. In the PCSK9/LDLR PPI impairing test, molecules D28 and D29, exhibited remarkable inhibitory potency with IC50 values of 8.30 and 6.70 µM compared with SBC-115337 (17.89 µM), respectively. Molecular docking predicted the binding pattern of compounds D28 and D29 in the LDLR binding site of PCSK9. Hydrophobic interactions play an important role in the binding of aromatic molecular fragments to the pockets in the PCSK9/LDLR binding interface. Further LDLR expression and LDL uptake studies revealed that both D28 and D29 restored LDLR expression on the surface of hepatic HepG2 cells and improved extracellular LDL uptake in the presence of PCSK9. It is significant that molecules D28 and D29 exhibited potential for the treatment of hyperlipidemia in current in vitro investigations. Generally, lead compounds with novel structures were developed in the present study for further design of lipid-lowering molecules by targeting PCSK9/LDLR PPI.

Vibrations on mastoid process alter the gait characteristics during walking on different inclines.

Background: Eighty-eight percent of the persons with bilateral vestibular dysfunction have reported at least one fall within the past 5 years. The apparent alternations due to the bilateral vestibular dysfunctions (BVD) are the gait characteristics, such as slower walking speed, prolonged stance phase, and shorter step length. Unexpectedly, due to the prevalence of this BVD being relatively low, attention is not obtained as same as in other vestibular disorders. Moreover, how does walking on different inclines, part of daily activities, alter the gait characteristics under the unreliable bilateral vestibular systems? Previous studies used vibration-based stimulations (VS) as a perturbation to understand the postural control during walking while the bilateral vestibular systems were perturbed. Therefore, this study attempted to extend the knowledge to understand the alternations in spatial-temporal gait characteristics under perturbed bilateral vestibular systems while walking on different inclines. Methods: Nineteen healthy young adults participated in this study. Eight walking conditions were randomly assigned to each participant: 0%, 3%, 6%, and 9% grade of inclines with/without VS. The preferred walking speed was used for gait analysis. The dependent variables were stance time, double support time, step length, step time, step width, foot clearance, and respective variabilities. All dependent variables were defined by two critical gait events: heel-strike and toe-off. Pre-Hoc paired comparisons with Bonferroni corrections were used to prioritize the dependent variables. A two-way repeated measure was used to investigate the effect of VS and the effect of inclines on the selected dependent variables from Pre-Hoc analysis. Post-Hoc comparisons were also corrected by the Bonferroni method. Results: The step length, step time, foot clearance, and foot clearance variability were selected by the Pre-Hoc analysis because the corrected paired t-test demonstrated a significant VS effect (p < 0.05) on these gait parameters at least one of four inclines. The significant interaction between the effect of VS and the effect of inclines was found in step length (p = 0.005), step time (p = 0.028), and foot clearance variability (p = 0.003). The results revealed that implementing a VS increased step length and step time when walking on 0%, 3%, and 9% of grade inclines. In particular, the foot clearance variability was found when walking on 9% of grade inclines. Conclusion: The observations in the current study suggested that VS increased the step length, step time, foot clearance, and foot clearance variability while walking on inclines. These results suggested that these gait parameters might be promising targets for future clinical investigations in patients with BVD while walking on different inclines. Importantly, the increases in spatial-temporal gait performance under bilateral VS might be an indicator of gait improvement while walking on different inclines.

Targeting feedback activation of signaling transduction pathways to overcome drug resistance in cancer.

Dysregulation or aberrant signaling transduction contributes to tumorigenesis. Targeting these abnormal signaling pathways becomes an effective anticancer strategy. However, feedback activation or crosstalk between signaling pathways drives adaptive drug resistance which causes failure of cancer therapy. In this review article, we summarized treatments that cause feedback activation of AKT, ERK, STAT3, EGFR, FGFR, and HER2/3 signaling pathways and the combination therapy to enhance anti-tumor effect or to overcome drug resistance, to explore the underlying mechanisms that define the protein molecules participated or regulated the feedback activation. In addition, we reviewed clinical trials that employ combination treatments to suppress feedback activation and improve therapeutic efficacy of cancer treatments.

BC-02 eradicates liver cancer stem cells by upregulating the ROS-dependent DNA damage.

Cancer stem cells (CSCs) are responsible for chemoresistance, tumor recurrence and metastasis. Reportedly, aminopeptidase N (APN, also known as CD13) is a marker for semi-quiescent CSCs and a therapeutic target in human liver CSCs. In the present study, the effect of BC-02, a compound obtained by conjugating a CD13 inhibitor bestatin and fluorouracil (5-FU), was investigated toward liver CSCs. Tumor spheres formed in serum-free culture conditions have been successfully used to enrich CSCs. In this study, the sphere cells were shown to have several characteristics of CSCs, including drug resistance, high tumorigenicity, epithelial-mesenchymal transition (EMT) phenotype, lower reactive oxygen species (ROS) levels, greater colony-forming efficiency and increased proliferation capacity in vitro. Furthermore, BC-02 effectively suppressed self-renewal and malignant proliferation of CSCs compared with 5-FU, bestatin, and even the combination of 5-FU and bestatin. In addition, cell proliferation was effectively suppressed when exposed to 5-FU plus CD13-neutralizing antibody (CD13 Ab) compared with 5-FU alone. BC-02 can effectively inhibit the activity of CD13. Results demonstrated that CD13 inhibitor BC-02 impaired the properties of liver CSCs by targeting CD13 and upregulating the intracellular ROS and ROS-induced DNA damage. BC-02 might be a potential therapeutic agent for eradicating the liver CSCs and overcoming chemoresistance in liver cancer.