Association of pre-stroke frailty and health-related factors with post-stroke functional independence among community-dwelling Chinese older adults.

OBJECTIVES: Frailty is associated with a range of poor post-stroke outcomes. There is still a lack of comprehensive understanding of the temporal relationship between pre-stroke frailty status and other related factors with functional recovery after stroke. This study aims to evaluate pre-stroke frailty status and health-related factors associated with functional independence among community-dwelling Chinese older adults. MATERIALS AND METHODS: The dataset based on the China Health and Retirement Longitudinal Study (CHARLS) conducted in 28 provinces across China was used. The pre-stroke frailty status was assessed using the Physical Frailty Phenotype (PFP) scale with the 2015 wave data. The PFP scale consisted of five criteria with a total score of 5, and categorized into non-frail (0 point), prefrail (1 and 2 points), and frail (3 or more points). Covariates included demographic factors (age, sex, marital status, residence, and education level) and health-related variables (comorbidities, self-reported health status and cognition). Activities of daily living (ADL) and instrumental activities of daily living (IADL) were assessed as the functional outcomes, with difficulties in at least one of the 6 ADL items and 5 IADL items defined as ADL/IADL limitation respectively. A logistic regression model was used to estimate the associations. RESULTS: A total of 666 participants who were newly diagnosed with stroke during the 2018 wave were included. 234 (35.1%) participants were classified as non-frail, 380 (57.1%) participants were classified as prefrail, and 52 (7.8%) participants were classified as frail. Pre-stroke frailty was significantly associated with ADL and IADL limitations post stroke. Additional significant variables with ADL limitation were age, female and more comorbidities. Additional significant variables with IADL limitation were age, female, married or cohabitating, more comorbidities and pre-stroke lower global cognitive score. CONCLUSION: Frailty status was associated with ADL and IADL limitations after stroke. A more comprehensive assessment of frailty in older people may help to identify those with most significant risk for declining functional capacities after stroke and to develop appropriate intervention strategies.

Gastrodin attenuates angiotensin II-induced vascular contraction and MLCK/p-MLC2 pathway activation.

CONTEXT: Gastrodin has been used as antihypertension therapy in China; however, the mechanisms underlying the effects of gastrodin have yet to be fully elucidated. OBJECTIVE: To explore the therapeutic efficiency of gastrodin as an antihypertensive and determine the mechanisms underlying this effect. MATERIALS AND METHODS: C57BL/6 mice were continuously administered angiotensin II (Ang II) (500 ng/kg/min) to induce hypertension. Mice were randomly divided into control, Ang II and Ang II + gastrodin groups. Mice received intragastric administration of gastrodin (5 mg/kg) or double distilled water once a day for 4 weeks. Blood pressure, pulse wave velocity (PWV), thickness of the abdominal aorta, pathological morphology and differential expression transcripts (DETs) were assessed. Abdominal aorta rings and primary isolated vascular smooth muscle cells were subjected to Ang II stimulation to induce hypertension as ex vivo and in vitro models, respectively. Vascular ring tension, release of Ca2+ and levels of proteins involved in the myosin light chain kinase (MLCK)/phospho-myosin light chain 2 (p-MLC2) pathway were determined. RESULTS: Gastrodin treatment attenuated increases in blood pressure, PWV and thickness of the abdominal aorta. Treatment with gastrodin resulted in 2785 DETs and the enrichment of vascular contraction and calcium signalling pathways. Gastrodin treatment attenuated Ang II-induced vasoconstriction, produced a norepinephrine-precontracted vasodilation effect (attenuated by verapamil), and reduced intracellular Ca2+ release. Furthermore, gastrodin suppressed activation of the MLCK/p-MLC2 pathway in vivo and in vitro. CONCLUSIONS: Gastrodin treatment lowers blood pressure, suppresses Ang II-induced vascular contraction and MLCK/p-MLC2 pathway activation, thereby demonstrating the mechanisms underlying the therapeutic efficacy of gastrodin as an antihypertensive.

Role of MicroRNAs and their corresponding ACE2/Apelin signaling pathways in hypertension.

Hypertension is controlled via the alteration of microRNAs (miRNAs), their therapeutic targets angiotensin II type I receptor (AT1R) and cross talk of signaling pathways. The stimulation of the Ang II/AT1R pathway by deregulation of miRNAs, has also been linked to cardiac remodeling as well as the pathophysiology of high blood pressure. As miRNAs have been associated to ACE2/Apelin and Mitogen-activated protein kinases (MAPK) signaling, it has revealed an utmost protective impact over hypertension and cardiovascular system. The ACE2-coupled intermodulation between RAAS, Apelin system, MAPK signaling pathways, and miRNAs reveal the practicalities of high blood pressure. The research of miRNAs may ultimately lead to the expansion of an innovative treatment strategy for hypertension, which indicates the need to explore them further at the molecular level. Therefore, here we have focused on the mechanistic importance of miRNAs in hypertension, ACE2/Apelin signaling as well as their biological functions, with a focus on interplay and crosstalk between ACE2/Apelin signaling, miRNAs, and hypertension, and the progress in miRNA-based diagnostic techniques with the goal of facilitating the development of new hypertension-controlling therapeutics.

FgSpa2 recruits FgMsb3, a Rab8 GAP, to the polarisome to regulate polarized trafficking, growth and pathogenicity in Fusarium graminearum.

In filamentous fungi, hyphal growth depends on the continuous delivery of vesicles to the growing tips. It is unclear how fast-growing hyphae coordinate simultaneous cell extension and expansion in the tip cells. We have functionally characterized 12 TBC (Tre-2/Bub2/Cdc16) domain-containing proteins in Fusarium graminearum. Among them, FgMsb3 is found to regulate hyphal tip expansion and to be required for pathogenicity. The regulatory mechanism of FgMsb3 has been further investigated by genetic, high-resolution microscopy and high-throughput co-immunoprecipitation strategies. The FgMsb3 protein localizes at the polarisome and the hyphal apical dome (HAD) where it acts as a GTPase-activating protein for FgRab8 which is required for apical secretion-mediated growth and pathogenicity. Deletion of FgMSB3 causes excessive polarized trafficking but blocks the fusion of FgSnc1-associated vesicles to the plasma membrane. Moreover, we establish that FgSpa2 interacts with FgMsb3, enabling FgMsb3 tethering to the polarisome. Loss of FgSpa2 or other polarisome components (FgBud6 and FgPea2) causes complete shifting of FgMsb3 to the HAD and this affects the polarized growth and pathogenicity of the fungus. In summary, we conclude that FgSpa2 regulates FgMsb3-FgRab8 cascade and this is crucial for creating a steady-state equilibrium that maintains continuous polarized growth and contributes to the pathogenicity of F. graminearum.

Upregulation of SNTB1 correlates with poor prognosis and promotes cell growth by negative regulating PKN2 in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most highly malignant tumors and has a complicated pathogenesis. A preliminary study identified syntrophin beta 1 (SNTB1) as a potential oncogene in CRC. However, the clinical significance, biological function, and underlying mechanisms of SNTB1 in CRC remain largely unknown. Thus, the present study aimed to investigate the role of SNTB1 in CRC. METHODS: The expression profile of SNTB1 in CRC samples was evaluated by database analysis, cDNA array, tissue microarray, quantitative real-time PCR (qPCR), and immunohistochemistry. SNTB1 expression in human CRC cells was silenced using short hairpin RNAs (shRNA)/small interfering RNAs (siRNA) and its mRNA and protein levels were assessed by qPCR and/or western blotting. Cell viability, survival, cell cycle, and apoptosis were determined by the CCK-8 assay, colony formation, and flow cytometry assays, respectively. A xenograft nude mouse model of CRC was established to validate the roles of SNTB1 in vivo. Immunohistochemistry and TUNEL staining were used to determine the expression of SNTB1, PCNA, and cell apoptosis in tissue samples. Isobaric tag for relative and absolute quantification (iTRAQ) was used to analyze the differentially expressed proteins after knockdown of SNTB1 in CRC cells. Silence of protein kinase N2 (PKN2) using si-PNK2 was performed for rescue experiments. RESULTS: SNTB1 expression was increased in CRC tissues compared with adjacent noncancerous tissues and the increased SNTB1 expression was associated with shorter overall survival of CRC patients. Silencing of SNTB1 suppressed cell viability and survival, induced cell cycle arrest and apoptosis in vitro, and inhibited the growth of CRC cells in vivo. Further elucidation of the regulation of STNB1 on CRC growth by iTRAQ analysis identified 210 up-regulated and 55 down-regulated proteins in CRC cells after SNTB knockdown. A PPI network analysis identified PKN2 as a hub protein and was up-regulated in CRC cells after SNTB1 knockdown. Western-blot analysis further confirmed that SNTB1 knockdown significantly up-regulated PKN2 protein expression in CRC cells and decreased the phosphorylation of both ERK1/2 and AKT. Moreover, rescue experiments indicated that PKN2 knockdown significantly rescued SNTB1 knockdown-mediated decrease in cell viability, survival, and increase of cell cycle arrest at G0/G1 phase and apoptosis of CRC cells. CONCLUSIONS: These findings indicate that SNTB1 is overexpressed in CRC. Elevated SNTB1 levels are correlated with shorter patient survival. Importantly, SNTB1 promotes tumor growth and progression of CRC, possibly by reducing the expression of PKN2 and activating the ERK and AKT signaling pathway. Our study highlights the potential of SNTB1 as a new prognostic factor and therapeutic target for CRC.

Dumbbell shaped craniorbital cavernous hemangioma.

BACKGROUND: Cavernous hemangioma of the orbit is a benign tumor mostly located behind the eye globe, but it rarely spread into the brain, which is called cerebral cavernous malformation as well, the lesion in the brain is irregular and enlarged blood. Here we report one particular case of craniorbital cavernous hemangioma. CASE PRESENTATION: A 53-year-old woman presented with exophthalmos of the right eye and reduced vision. Computerized tomographical (CT) scan showed osteolytic honeycomb radial changes of the outer plate of the skull. A magnetic resonance imaging (MRI) scan was performed to obtain further details. T1-weighted (T1W) imaging showed slightly low signal mixed with small patchy high signal. T2-weighted (T2W) imaging showed uneven high signal. There was obvious enhancement in the middle and no enhancement in the peripheral bars. A surgically manage was performed using a left frontotemporal approach, the tumor excised fully, and the histopathology results revealed a cavernous hemangioma. The patient recovered well in the follow-up. Post-operative CT scan identified the lesion was successfully resected, MRI scan also showed full resection and enhanced signal from the presence of fat. CONCLUSIONS: Craniorbital cavernous hemangioma is uncommon, however within the cranium, they can lead to numerous complications particularly if affecting the visual apparatus. it could be diagnosed by imaging, which CT scan shows osteolytic honeycomb radial changes of the outer plate of the skull, T1W imaging shows slightly low signal mixed with small patchy high signal, T2W imaging shows uneven high signal, it is obvious enhancement in the middle and no enhancement in the peripheral bars. The surgically manage is the ideally treatment when there are some symptoms.

ESCRT-III accessory proteins regulate fungal development and plant infection in Fusarium graminearum.

Ubiquitinated biosynthetic and surface proteins destined for degradation are sorted into the lysosome/vacuole via the multivesicular body sorting pathway, which depends on the function of ESCRT machinery. Fusarium head blight (FHB) caused by Fusarium graminearum is one of the most devastating diseases for wheat and barley worldwide. To better understand the role of ESCRT machinery in F. graminearum, we investigated the function of ESCRT-III accessory proteins FgVps60, FgDid2 and FgIst1 in this study. FgVps60-GFP, FgDid2-GFP and FgIst1-GFP are localized to punctate structures adjacent to the vacuolar membrane except for FgIst1-GFP that is also found in the nucleus. Then, the gene deletion mutants ΔFgvps60, ΔFgdid2 and ΔFgist1 displayed defective growth to a different extent. ΔFgvps60 and ΔFgdid2 but not ΔFgist1 also showed significant reduction in hydrophobicity on cell surface, conidiation, perithecia production and virulence. Interestingly, ΔFgist1 mutant produced a significantly higher level of DON while showing a minor reduction in pathogenicity. Microscopic analyses revealed that FgVps60 but not FgIst1 and FgDid2 is necessary for endocytosis. Moreover, spontaneous mutations were identified in the ΔFgvps60 mutant that partially rescued its defects in growth and conidiation. Taken together, we conclude that ESCRT-III accessory proteins play critical roles in growth, reproduction and plant infection in F. graminearum.

MicroRNA-26b/PTEN Signaling Pathway Mediates Glycine-Induced Neuroprotection in SAH Injury.

Subarachnoid hemorrhage (SAH) is a form of stroke associated with high mortality and morbidity. Despite advances in treatment for SAH, the prognosis remains poor. We have previously demonstrated that glycine, a non-essential amino acid is involved in neuroprotection following intracerebral hemorrhage via the Phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) signaling pathway. However, whether it has a role in inducing neuroprotection in SAH is not known. The present study was designed to investigate the role of glycine in SAH. In this study, we show that glycine can reduce brain edema and protect neurons in SAH via a novel pathway. Following a hemorrhagic episode, there is evidence of downregulation of S473 phosphorylation of AKT (p-AKT), and this can be reversed with glycine treatment. We also found that administration of glycine can reduce neuronal cell death in SAH by activating the AKT pathway. Glycine was shown to upregulate miRNA-26b, which led to PTEN downregulation followed by AKT activation, resulting in inhibition of neuronal death. Inhibition of miRNA-26b, PTEN or AKT activation suppressed the neuroprotective effects of glycine. Glycine treatment also suppressed SAH-induced M1 microglial polarization and thereby inflammation. Taken together, we conclude that glycine has neuroprotective effects in SAH and is mediated by the miRNA-26b/PTEN/AKT signaling pathway, which may be a therapeutic target for treatment of SAH injury.

Retromer Is Essential for Autophagy-Dependent Plant Infection by the Rice Blast Fungus.

The retromer mediates protein trafficking through recycling cargo from endosomes to the trans-Golgi network in eukaryotes. However, the role of such trafficking events during pathogen-host interaction remains unclear. Here, we report that the cargo-recognition complex (MoVps35, MoVps26 and MoVps29) of the retromer is essential for appressorium-mediated host penetration by Magnaporthe oryzae, the causal pathogen of the blast disease in rice. Loss of retromer function blocked glycogen distribution and turnover of lipid bodies, delayed nuclear degeneration and reduced turgor during appressorial development. Cytological observation revealed dynamic MoVps35-GFP foci co-localized with autophagy-related protein RFP-MoAtg8 at the periphery of autolysosomes. Furthermore, RFP-MoAtg8 interacted with MoVps35-GFP in vivo, RFP-MoAtg8 was mislocalized to the vacuole and failed to recycle from the autolysosome in the absence of the retromer function, leading to impaired biogenesis of autophagosomes. We therefore conclude that retromer is essential for autophagy-dependent plant infection by the rice blast fungus.

Endosomal sorting complexes required for transport-0 is essential for fungal development and pathogenicity in Fusarium graminearum.

Fusarium graminearum is an important plant pathogen that causes head blight of major cereal crops. The vacuolar protein sorting (Vps) protein Vps27 is a component of ESCRT-0 involved in the multivesicular body (MVB) sorting pathway during endocytosis. In this study, we investigated the function of FgVps27 using a gene replacement strategy. The FgVPS27 deletion mutant (ΔFgvps27) exhibited a reduction in growth rate, aerial hyphae formation and hydrophobicity. It also showed increased sensitivity to cell wall-damaging agents and to osmotic stresses. In addition, FgHog1, the critical component of high osmolarity glycerol response pathway, was mis-localized in the ΔFgvps27 mutant upon NaCl treatment. Furthermore, the ΔFgvps27 mutant was defective in conidial production and was unable to generate perithecium in sexual reproduction. The depletion of FgVPS27 also caused a significant reduction in virulence. Further analysis by domain-specific deletion revealed that the FYVE domain was essential for the FgVps27 function and was necessary for the proper localization of FgVps27-GFP and endocytosis. Another component of ESCRT-0, the FgVps27-interacting partner FgHse1, also played an important role in F. graminearum development and pathogenesis. Overall, our results indicate that ESCRT-0 components play critical roles in a variety of cellular and biological processes.

Septins are involved in nuclear division, morphogenesis and pathogenicity in Fusarium graminearum.

Septins are GTP-binding proteins that regulate cell polarity, cytokinesis and cell morphogenesis. Fusarium head blight (FHB), caused by Fusarium graminearum, is one of the most devastating diseases worldwide. In this study, we have functionally characterized the core septins, Cdc3, Cdc10, Cdc11 and Cdc12 in F. graminearum. The loss of FgCdc3, FgCdc11, FgCdc12, but not FgCdc10, mutants showed significant reduction in growth, conidiation and virulence. Microscopic analyses revealed that all of them were involved in septum formation and nuclear division. Moreover, disruption of septin genes resulted in morphological defects in ascospores and conidia. Interestingly, conidia produced by ΔFgcdc3, ΔFgcdc11 and ΔFgcdc12 mutants exhibited deformation with interconnecting conidia in contrast to their parent wild-type strain PH-1 and the ΔFgcdc10 mutant that produced normal conidia. Using yeast two-hybrid assays, we determined the interactions among FgCdc3, FgCdc10, FgCdc11 and FgCdc12. Taken together, our results indicate that septins play important roles in the nuclear division, morphogenesis and pathogenicity in F. graminearum.

Retrograde trafficking from the endosome to the trans-Golgi network mediated by the retromer is required for fungal development and pathogenicity in Fusarium graminearum.

In eukaryotes, the retromer is an endosome-localized complex involved in protein retrograde transport. However, the role of such intracellular trafficking events in pathogenic fungal development and pathogenicity remains unclear. The role of the retromer complex in Fusarium graminearum was investigated using cell biological and genetic methods. We observed the retromer core component FgVps35 (Vacuolar Protein Sorting 35) in the cytoplasm as fast-moving puncta. FgVps35-GFP co-localized with both early and late endosomes, and associated with the trans-Golgi network (TGN), suggesting that FgVps35 functions at the donor endosome membrane to mediate TGN trafficking. Disruption of microtubules with nocodazole significantly restricted the transportation of FgVps35-GFP and resulted in severe germination and growth defects. Mutation of FgVPS35 not only mimicked growth defects induced by pharmacological treatment, but also affected conidiation, ascospore formation and pathogenicity. Using yeast two-hybrid assays, we determined the interactions among FgVps35, FgVps26, FgVps29, FgVps17 and FgVps5 which are analogous to the yeast retromer complex components. Deletion of any one of these genes resulted in similar phenotypic defects to those of the ΔFgvps35 mutant and disrupted the stability of the complex. Overall, our results provide the first clear evidence of linkage between the retrograde transport mediated by the retromer complex and virulence in F. graminearum.

Rab GTPases are essential for membrane trafficking-dependent growth and pathogenicity in Fusarium graminearum.

Rab GTPases represent the largest subfamily of Ras-related small GTPases and regulate membrane trafficking. Vesicular transport is a general mechanism that governs intracellular membrane trafficking along the endocytic and exocytic pathways in all eukaryotic cells. Fusarium graminearum is a filamentous fungus and causes the devastating and economically important head blight of wheat and related species. The mechanism of vesicular transport is not well understood, and little is known about Rab GTPases in F. graminearum. In this study, we systematically characterized all eleven FgRabs by live cell imaging and genetic analysis. We find that FgRab51 and FgRab52 are important for the endocytosis, FgRab7 localizes to the vacuolar membrane and regulates the fusion of vacuoles and autophagosomes, and FgRab8 and FgRab11 are important for polarized growth and/or exocytosis. Furthermore, both endocytic and exocytic FgRabs are required for vegetative growth, conidiogenesis, sexual reproduction, as well as pathogenesis and deoxynivalenol metabolism in F. graminearum. Thus, we conclude that Rab GTPases are essential for membrane trafficking-dependent growth and pathogenicity in F. graminearum.

Reference Standards of Cardiorespiratory Fitness Measured With the Cardiopulmonary Exercise Test Using the Treadmill in Chinese Adults Younger Than 60 Years.

PURPOSE: Cardiorespiratory fitness (CRF) is a strong predictor of cardiorespiratory diseases and varies by race. The purpose of this study was to provide CRF reference standards and a prediction equation for peak oxygen uptake (V˙O 2peak ) from treadmill-based cardiopulmonary exercise testing (CPX) in Chinese individuals. METHODS: Healthy participants (n = 4199) who completed a CPX using a treadmill were studied. The percentiles of V˙O 2peak were determined for four age groups (decades). A regression prediction model was developed from the derivation cohort (n = 3361), validated in the independent validation cohort (n = 838), and compared with the widely used Wasserman equation and the Fitness Registry and the Importance of Exercise National Database (FRIEND) equation. RESULTS: The mean V˙O 2peak values of four age groups (20-29, 30-39, 40-49, and 50-59 yr) were 42.6, 41.2, 38.7, and 35.9 mL/kg/min, respectively, for men, and 37.1, 34.7, 32.0, and 30.3 mL/kg/min, respectively, for women. The 50th percentiles of relative V˙O 2peak decreased with age for both sexes. The prediction equation was: Absolute V˙O 2peak (mL/min) = 236.68 - (504.64 × sex [male = 0; female = 1]) + (21.23× weight [kg]) - (14.31 × age [yr]) + (9.46 × height [cm]) (standard error of the estimate = 379.59 mL/min, R2 = 0.66, P < .001).Percentage predicted V˙O 2peak for the validation sample was 100.2%. The novel equation performed better than the other two equations. CONCLUSION: This study reports the first CRF reference standards and prediction equation generated from treadmill CPX in China. These reference standards provide a framework for interpreting the CRF of the Chinese population and could be useful information for a global CRF database.

Neurobiomechanical mechanism of Tai Chi to improve upper limb coordination function in post-stroke patients: a study protocol for a randomized controlled trial.

BACKGROUND: Upper limb dysfunction seriously affects the ability of stroke patients to perform activities of daily living. As a popular exercise therapy, Tai Chi may become an alternative intervention. However, the neurophysiological mechanism by which Tai Chi improves upper limb dysfunction in stroke patients is still unclear, which limits its further promotion and application. Therefore, conducting a strict randomized clinical trial is necessary to observe how Tai Chi affects upper limb dysfunction in stroke patients and to explore its neurophysiological mechanism. METHODS/DESIGN: This report describes a randomized, parallel-controlled trial with distributive concealment and evaluator blinding. A total of 84 eligible participants will be randomly assigned to the Tai Chi group or the control group in a 1:1 ratio. The participants in the Tai Chi group will receive 4 weeks of Tai Chi training: five 60-min sessions a week for a total of 20 sessions. The participants in the control group will not receive Tai Chi training. Both groups will receive medical treatment and routine rehabilitation training. The primary outcome measure is the mean change in the Fugl-Meyer Assessment Upper Extremity (FMA-UE) scale score between baseline and 4 weeks; the secondary outcomes are the mean changes in kinematic characteristics and the Wolf Motor Function Test (WMFT) and Stroke Impact Scale (SIS) scores. In addition, the corticomuscular coupling level and near-infrared brain functional imaging will be monitored to explore the mechanism by which Tai Chi improves upper limb function of stroke patients. DISCUSSION: This randomized controlled trial will examine the effectiveness of Tai Chi in stroke patients with upper limb dysfunction and explore the neurophysiological mechanism. Positive results will verify that Tai Chi can improve upper limb function of stroke patients. TRIAL REGISTRATION: Chinese Clinical Trial Registration Center, ChiCTR2200061376 (retrospectively registered). Registered June 22, 2022. http://www.chictr.org.cn/listbycreater.aspx . Manuscript Version: 3.0 Manuscript Date: October 10, 2023.

Neferine ameliorates hypertensive vascular remodeling modulating multiple signaling pathways in spontaneously hypertensive rats.

BACKGROUND: Neferine exhibits therapeutic effects on anti-hypertension. However, the effect of neferine on hypertensive vascular remodeling remains unexplored. Therefore, the current study was to investigate the effect of neferine on hypertensive vascular remodeling and its underlying mechanisms. METHODS: Total 30 male spontaneously hypertensive rats (SHRs) were divided randomly into five groups, including SHR, Neferine-L (2.5 mg/kg/day), Neferine-M (5 mg/kg/day), Neferine-H (10 mg/kg/day), and Valsartan (10 mg/kg/day) groups (n = 6 for each group). Wistar Kyoto (WKY) rats were set as control group (n = 6). Noninvasive blood pressure system, ultrasound, hematoxylin and eosin staining, masson trichrome staining were used to detect the blood pressure, pulse wave velocity (PWV), pathological changes and collagen content in abdominal aortas of SHRs. RNA-sequencing and immunohistochemistry(IHC) analyses were used to identify and verify the differentially expressed transcripts and activation of associated signaling pathways in SHRs. RESULTS: Various concentrations of neferine or valsartan treatment substantially reduced the elevation of blood pressure, PWV, and abdominal aortic thickening of SHRs. RNA-sequencing and KEGG analyses recognized 441 differentially expressed transcripts and several enriched pathways (including PI3K/AKT and TGF-ß/Smad2/3 signaling pathways) after neferine treatment. Masson trichromatic staining and IHC analysis demonstrated that neferine treatment decreased the collagen content and down-regulated the protein expression of PCNA, collagen I & III, and fibronectin, as well as p-PI3K, p-AKT, TGF-ß1 and p-Smad2/3 in abdominal aortic tissues of SHRs. CONCLUSION: Neferine treatment exhibits therapeutic effects on anti-hypertension and reduces vascular remodeling, as well as suppresses the abnormal activation of multiple signaling pathways, including PI3K/AKT and TGF-ß1/Smad2/3 pathways.

A Pilot Study of Compensatory Strategies for Reach-to-Grasp-Pen in Patients with Stroke.

Coordinated reaching and grasping movements may be impaired in patients with poststroke hemiplegia. Patients frequently adopt compensatory strategies, which require investigation. This pilot study used kinematic parameters to examine compensatory strategies by assessing the reach-to-grasp-pen movements in patients with stroke and unaffected participants. Twelve patients with stroke with mild impairment (45.16 ± 12.62 years, 2.41 ± 1.97 months), twelve with moderate impairment (50.41 ± 12.92 years, 3.83 ± 3.58 months), and ten healthy individuals (20.6 ± 0.69 years) performed a reach-to-grasp-pen task. Kinematics parameters of upper limb and fingers, such as movement time, number of movement units, index of curvature, spectral arc length, trunk forward transition, trunk lateral transition, elbow extension, shoulder flexion, shoulder abduction, trunk rotation, arm-plane angle, the joint angles of interphalangeal joints of the thumb, index, middle, ring, and little fingers were examined in the study. These parameters were evaluated with two Microsoft Azure Kinect and Leap Motion, which belong to markerless motion capture systems. Patients with stroke showed longer reaching movement time, less smooth movement trajectories, and more trunk rotation (P < 0.05). In patients with stroke, the metacarpophalangeal joint (MCP) and proximal interphalangeal joint (PIP) of the thumb were flexed in the starting position; the MCP and PIP joints of the index finger in the stroke group were more extended during pen grasp; the range of motion of the MCP of the middle finger and the PIP joints of the middle, ring, and little fingers became greater, suggesting a larger peak aperture (P < 0.05). The more significant extension was observed in the index finger at the end of the grasp, suggesting inadequate flexion (P < 0.05). In clinical practice, the reach-to-grasp-pen task using markless sensing technology can effectively distinguish patients with stroke from healthy individuals and evaluate the recovery and compensation strategies of upper limb and hand functions. It can potentially become an evaluation tool in hospital and community scenes. Accurate identification of abnormal trunk, arm, and finger strategies is crucial for therapists to develop targeted upper limb treatment methods and evaluate treatment effects.

Swimming attenuates tumor growth in CT-26 tumor-bearing mice and suppresses angiogenesis by mediating the HIF-1α/VEGFA pathway.

Low physical activity correlates with increased cancer risk in various cancer types, including colorectal cancer (CRC). However, the ways in which swimming can benefit CRC remain largely unknown. In this study, mice bearing tumors derived from CT-26 cells were randomly divided into the control and swimming groups. Mice in the swimming group were subjected to physical training (swimming) for 3 weeks. Compared with the control group, swimming clearly attenuated tumor volume and tumor weight in CT-26 tumor-bearing mice. RNA sequencing (RNA-seq) identified 715 upregulated and 629 downregulated transcripts (including VEGFA) in tumor tissues of mice in the swimming group. KEGG pathway analysis based on differentially expressed transcripts identified multiple enriched signaling pathways, including angiogenesis, hypoxia, and vascular endothelial growth factor (VEGF) pathways. Consistently, IHC analysis revealed that swimming significantly downregulated CD31, HIF-1α, VEGFA, and VEGFR2 protein expression in tumor tissues. In conclusion, swimming significantly attenuates tumor growth in CT-26 tumor-bearing mice by inhibiting tumor angiogenesis via the suppression of the HIF-1α/VEGFA pathway.

Quercetin inhibits angiotensin II-induced vascular smooth muscle cell proliferation and activation of JAK2/STAT3 pathway: A target based networking pharmacology approach.

The rapid growth of vascular smooth muscle cells (VSMCs) represents crucial pathological changes during the development of hypertensive vascular remodeling. Although quercetin exhibits significantly therapeutic effects on antihypertension, the systematic role of quercetin and its exact mode of action in relation to the VSMCs growth and its hypertension-related networking pharmacology is not well-documented. Therefore, the effect of quercetin was investigated using networking pharmacology followed by in vitro strategies to explore its efficacy against angiotensin II (Ang II)-induced cell proliferation. Putative genes of hypertension and quercetin were collected using database mining, and their correlation was investigated. Subsequently, a network of protein-protein interactions was constructed and gene ontology (GO) analysis was performed to identify the role of important genes (including CCND1) and key signaling pathways [including cell proliferation and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway]. We therefore further investigated the effects of quercetin in Ang II-stimulated VSMCs. This current research revealed that quercetin significantly reduced the cell confluency, cell number, and cell viability, as well as expression of proliferating cell nuclear antigen (PCNA) in Ang II-stimulated VSMCs. Mechanistic study by western blotting confirmed that quercetin treatment attenuated the activation of JAK2 and STAT3 by reducing its phosphorylation in Ang II stimulated VSMCs. Collectively, the current study revealed the inhibitory effects of quercetin on proliferation of Ang II stimulated VSMCs, by inhibiting the activation of JAK2/STAT3 signaling might be one of underlying mechanisms.

CCT6A knockdown suppresses osteosarcoma cell growth and Akt pathway activation in vitro.

We assessed the role of the protein-coding gene chaperonin-containing TCP1 subunit 6A (CCT6A) in osteosarcoma, as this is currently unknown. Using data from the R2 online genomic analysis and visualization application, we found that CCT6A messenger ribonucleic acid (RNA) expression is increased in osteosarcoma tissue and cells. Transfection of CCT6A small interfering RNA into cultured osteosarcoma cells revealed that CCT6A knockdown attenuates cell growth, cell viability, cell survival, and induced apoptosis and cell cycle progression at the G0/G1 phases. Moreover, CCT6A knockdown downregulated phospho-protein kinase B (p-Akt), cyclinD1 and B-cell lymphoma-2, whereas upregulated Bcl-2-associated X-protein expression. Thus, CCT6A knockdown inhibits cell proliferation, induces cell apoptosis, and suppresses the Akt pathway.