Fabric-Enhanced Vascular Graft with Hierarchical Structure for Promoting the Regeneration of Vascular Tissue.

Natural blood vessels have completed functions, including elasticity, compliance, and excellent antithrombotic properties because of their mature structure. To replace damaged blood vessels, vascular grafts should perform these functions by simulating the natural vascular structures. Although the structures of natural blood vessels are thoroughly explored, constructing a small-diameter vascular graft that matches the mechanical and biological properties of natural blood vessels remains a challenge. A hierarchical vascular graft is fabricated by Electrospinning, Braiding, and Thermally induced phase separation (EBT) processes, which could simulate the structure of natural blood vessels. The internal electrospun structure facilitates the adhesion of endothelial cells, thereby accelerating endothelialization. The intermediate PLGA fabric exhibits excellent mechanical properties, which allow it to maintain its shape during long-term transplantation and prevent graft expansion. The external macroporous structure is beneficial for cell growth and infiltration. Blood vessel remodeling aims to combine a structure that promotes tissue regeneration with anti-inflammatory materials. The results in vitro demonstrated that it EBT vascular graft (EBTVG) has matched the mechanical properties, reliable cytocompatibility, and the strongest endothelialization in situ. The results in vitro and replacement of the resected artery in vivo suggest that the EBTVG combines different structural advantages with biomechanical properties and reliable biocompatibility, significantly promoting the stabilization and regeneration of vascular endothelial cells and vascular smooth muscle cells, as well as stabilizing the blood microenvironment.

Comparison of structures and properties of gels formed by corn starch with fresh or dried Mesona chinensis polysaccharide.

Starch is a major dietary carbohydrate, but its digestion properties need to be improved. Mesona chinensis polysaccharides (MCPs) had a unique function in improving the flocculation performance of starch. This study investigated the effects of adding Mesona chinensis polysaccharide extracted from wet fresh and dry plants with one-year storage, namely WMCP and DMCP, on the physicochemical properties and digestion kinetics of corn starch(CS). The composition analysis showed both WMCP and DMCP were an acidic heteropolysaccharide rich in galacturonic acid and galactose, whereas showed different average main fraction molecular weights (Mw) of 47.36 kDa and 42.98 kDa, respectively. In addition, WMCP showed higher yield, purity and better physicochemical properties to CS than DWCP. Thermal analysis showed WMCP decreased more gelatinization temperatures and enthalpy of CS, and increased more freeze-thaw stability, water holding capacity, and textural parameters of CS gels than DMCP. Structural analysis revealed WMCP induced more changes in crystallinity, short-range order, and microstructure of CS, which inhibited retrogradation than DMCP. In vitro digestion assays demonstrated WMCP addition significantly increased higher resistant starch content by altering starch-starch and starch-MCP interactions than DWCP. Overall, MCPs addition beneficially modulated CS properties and digestion kinetics, providing a novel way to improve starch functionalities. Moreover, WMCP had more advantages to be chosen to form hydrocolloid with CS than DMCP.

Breastmilk microbiome changes associated with lactational mastitis and treatment with dandelion extract.

Introduction: Dandelion (Pugongying) is one of the most frequently used Chinese herbs for treating lactational mastitis (LM). Pugongying granules, a patented medication primarily comprised of dandelion extract, have been approved by CFDA for LM treatment in China. The aims of this study were to investigate the etiology of LM and the mechanism by which Pugongying granules decrease LM symptoms, with a particular focus on the microbial communities found in breastmilk. Methods: Participants were recruited from a previously performed randomized controlled trial (Identifier: NCT03756324, ClinicalTrials.gov). Between 2019 and 2020, women diagnosed with unilateral LM at the Beijing University of Chinese Medicine Third Affiliated Hospital were enrolled. In total, 42 paired breastmilk samples from the healthy and affected breasts of the participants were collected. Additionally, 37 paired pre- and post-treatment breastmilk samples from the affected breast were collected from women who received a 3-day course of either Pugongying granules (20 women) or cefdinir (17 women). Clinical outcomes [e.g., body temperature, visual analogue scale (VAS) score for breast pain, the percentage of neutrophils (NE%)] were analyzed pre- and post-treatment, and the breastmilk samples were subjected to 16S rRNA gene sequencing to analyze the alpha and beta diversities and identify significant bacteria. Finally, the relationship between microorganisms and clinical outcomes was analyzed. Results: There was no significant difference in fever and pain between the Pugongying group and cefdinir group. The most prevalent bacterial genera in breastmilk were Streptococcus and Staphylococcus. Compared to healthy breastmilk, microbial diversity was reduced in affected breastmilk, and there was a higher relative abundance of Streptococcus. After Pugongying treatment, there was an increase in microbial diversity with significantly higher abundance of Corynebacterium. A negative correlation was found between Corynebacterium, VAS score, and NE%. Treatment with cefdinir did not affect microbial diversity. Taken together, our results show a correlation between LM and reduced microbial diversity, as well as an increased abundance of Streptococcus in affected breastmilk. Conclusion: Pugongying granules enhanced microbial diversity in breastmilk samples. Given the substantial variation in individual microbiomes, identifying specific species of Streptococcus and Corynebacterium associated with LM may provide additional insight into LM pathogenesis and treatment.

Effectiveness and potential mechanism of Jiawei-Xiaoyao-San for hyperthyroidism: a systematic review.

Objectives: To evaluate the effectiveness and potential mechanism of traditional Chinese medicine Jiawei-Xiaoyao-San (JWXYS) as an adjunct or mono- therapy for antithyroid drugs (ATDs) in the treatment of hyperthyroidism. Methods: Eight databases and three trial registries were searched from inception until May 2023. Randomized controlled trials (RCTs) were included and meta-analysis was conducted using RevMan 5.4 and Stata 14.0. The Cochrane risk of bias (ROB) tool 1.0 and GRADE tool was used for quality appraisal. The findings from case reports using mono-JWXYS and pharmacological studies were summarized in tables. Results: Thirteen RCTs with 979 participants were included. The majority of the included studies were assessed as high risk of bias in one ROB domain. Compared with ATDs, JWXYS plus ATDs resulted in lower free triiodothyronine (FT3) (MD = -1.31 pmol/L, 95% CI [-1.85, -0.76]; low-certainty), lower free thyroxine (MD = -3.24 pmol/L, 95% CI [-5.06, -1.42]; low-certainty), higher thyroid stimulating hormone (MD = 0.42 mIU/L, 95% CI [0.26, 0.59]; low-certainty), higher effectiveness rate of traditional Chinese medicine syndrome (RR = 1.28, 95% CI [1.08, 1.52]; low-certainty), lower goiter score (MD = -0.66, 95% CI [-1.04, -0.29]; very low-certainty), lower thyrotrophin receptor antibody (SMD = -0.44, 95% CI [-0.73, -0.16]; low-certainty) and fewer adverse events (AEs) (RR = 0.34, 95% CI [0.18, 0.67]; moderate-certainty). Compared with regular dosage of ATDs, JWXYS plus half-dose ATDs resulted in fewer AEs (RR = 0.24, 95% CI [0.10, 0.59]; low-certainty). Compared with ATDs in 1 trial, JWXYS resulted in higher FT3, lower goiter score and fewer AEs. Three case reports showed that the reasons patients sought TCM-only treatment include severe AEs and multiple relapses. Three pharmacological studies demonstrated that JWXYS restored Th17/Treg balance, lowered deiodinases activity, regulated thyroid cell proliferation and apoptosis, and alleviated liver oxidative stress in mouse or rat models. Conclusion: JWXYS may enhance the effectiveness of ATDs for hyperthyroidism, particularly in relieving symptoms and reducing AEs. Mono-JWXYS is not recommended except in patients intolerant to ATDs. The findings should be interpreted with caution due to overall high risk of bias. Further pharmacological studies with more reliable models are needed. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023394923.

Efficacy and safety of Ophiocordyceps sinensis in the treatment of Hashimoto's thyroiditis: a systematic review and meta-analysis.

Objective: To evaluate the efficacy and safety of Ophiocordyceps sinensis (OS) preparations for the treatment of Hashimoto's thyroiditis (HT). Methods: We searched eight databases to collect randomized controlled trials (RCTs) of OS combined with a low-iodine diet or levothyroxine for HT. The search period was from inception to June 2023. Meta-analysis was performed using Revman 5.3 software after two evaluators independently screened the literature, extracted data, and evaluated the risk of bias of the included studies. The GRADE system was used to assess the certainty of evidence. Results: A total of 14 RCTs involving 1,014 patients with HT were included. Meta-analysis showed that OS preparations combined with a low-iodine diet were more effective in reducing thyroid peroxidase antibody (TPOAb) [SMD = -3.81, 95% CI (-5.07, -2.54), p < 0.00001] and thyroglobulin antibody (TgAb) [SMD = -4.73, 95% CI (-6.86, -2.61), p < 0.00001] compared to a low-iodine diet. Compared with levothyroxine treatment alone, OS preparations combined with levothyroxine further reduced TPOAb [SMD = -2.04, 95% CI (-2.82, -1.26), p < 0.00001], TgAb [SMD = -2.01, 95% CI (-2.68, -1.33), p < 0.00001], tumor necrosis factor alpha (TNF-α) [SMD = -3.40, 95% CI (-5.66, -1.14), p = 0.003], interleukin-2 (IL-2) [SMD = -2.31, 95% CI (-3.98, -0.65), p = 0.006], and interleukin-6 (IL-6) [MD = -4.16, 95% CI (-6.17, -2.15), p < 0.0001], and elevated free thyroxine (FT4) [SMD = 1.34, 95% CI (0.59, 2.08), p = 0.0004], but no significant effect on free triiodothyronine (FT3) [SMD = 0.83, 95% CI (-0.12, 1.78), p = 0.09] and thyroid stimulating hormone (TSH) [SMD = -0.80, 95% CI (-1.71, 0.11), p = 0.08]. In terms of safety, three studies reported adverse reactions in 10 patients in each of the experimental and control groups. Conclusion: OS preparations in combination with other treatments (low-iodine diet or levothyroxine) may decrease thyroid autoantibodies and inflammatory responses in patients with HT. In HT patients with hypothyroidism, the combination of the OS preparations with levothyroxine also improved FT4. However, the quality of the included studies was generally low. Moreover, the safety of OS preparations remains unclear. Therefore, more high-quality, multicenter, large-sample RCTs are needed in the future to validate the efficacy and safety of OS preparations. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023432663.

Mechanism of Chinese botanical drug Dizhi pill for myopia: An integrated study based on bioinformatics and network analysis.

To identify the active constituents, core targets, immunomodulatory functions and potential mechanisms of Dizhi pill (DZP) in the treatment of myopia. The active constituents and drug targets of DZP were searched in the TCMSP, Herb databases and correlational studies. The targets of myopia were searched in the TTD, Genecards, OMIM and Drugbank databases. Gene expression profile data of GSE136701 were downloaded from the GEO database and subjected to WGCNA and DEG analysis to screen for significant modules and targets of myopia. Intersectional targets of myopia and DZP and core targets of myopia were analyzed through the String database. The GO and KEGG enrichment analyses of the interested targets were conducted. Cibersort algorithm was used for immune infiltration analysis to investigate the immunomodulatory functions of DZP on myopia. Autodock was used to dock the important targets and active constituents. Eight targets (STAT3, PIK3CA, PIK3R1, MAPK1, MAPK3, HSP90AA1, MIP, and LGSN) and 5 active constituents (Quercetin, Beta-sitosterol, Diincarvilone A, Ferulic acid methyl ester, and Naringenin) were identified from DZP. In pathways identified by the GO and KEGG enrichment analyses, "ATP metabolic process" and "AGE-RAGE diabetes complication signaling" pathways were closely related to the mechanisms of DZP in the treatment of myopia. Molecular docking showed that both the intersectional targets and core targets of myopia could bind stably and spontaneously with the active constituents of DZP. This study suggested that the mechanisms of DZP in the treatment of myopia were related to active constituents: Quercetin, Beta-sitosterol, Diincarvilone A, Ferulic acid methyl ester and Naringenin, intersectional targets: STAT3, PIK3CA, PIK3R1, MAPK1, MAPK3, and HSP90AA1, core targets of myopia: MIP and LGSN, AGE-RAGE signaling pathway, positive regulation of ATP metabolic process pathway and immunomodulatory functions.

F-box and leucine-rich repeat protein 16 controls tamoxifen sensitivity via regulation of mitochondrial respiration in estrogen receptor-positive breast cancer cells.

Tamoxifen is one of the most effective therapeutic tools for estrogen receptor-positive (ER +) breast cancer. However, the intrinsic insensitivity and resistance to tamoxifen remains a significant hurdle for achieving optimal responses and curative therapy. In this study, we report that F-box and leucine-rich repeat protein 16 (FBXL16) is located in the mitochondria of ER + breast cancer cells. The mitochondrial FBXL16 plays an essential role in sustaining mitochondrial respiration and thereby regulates the sensitivity of ER + breast cancer cells to tamoxifen treatment. Importantly, high FBXL16 expression is significantly correlated with poor overall survival of ER + breast cancer patients. Moreover, mitochondrial inhibition phenocopies FBXL16 depletion in terms of sensitizing the ER + breast cancer cells to tamoxifen treatment. Together, our study demonstrates that FBXL16 acts as a novel regulator of tamoxifen sensitivity. Thus, targeting FBXL16 may serve as a promising approach for improving the therapeutic efficacy of tamoxifen in ER + breast cancer cells.

Using landscape genomics to assess local adaptation and genomic vulnerability of a perennial herb Tetrastigma hemsleyanum (Vitaceae) in subtropical China.

Understanding adaptive genetic variation of plant populations and their vulnerabilities to climate change are critical to preserve biodiversity and subsequent management interventions. To this end, landscape genomics may represent a cost-efficient approach for investigating molecular signatures underlying local adaptation. Tetrastigma hemsleyanum is, in its native habitat, a widespread perennial herb of warm-temperate evergreen forest in subtropical China. Its ecological and medicinal values constitute a significant revenue for local human populations and ecosystem. Using 30,252 single nucleotide polymorphisms (SNPs) derived from reduced-representation genome sequencing in 156 samples from 24 sites, we conducted a landscape genomics study of the T. hemsleyanum to elucidate its genomic variation across multiple climate gradients and genomic vulnerability to future climate change. Multivariate methods identified that climatic variation explained more genomic variation than that of geographical distance, which implied that local adaptation to heterogeneous environment might represent an important source of genomic variation. Among these climate variables, winter precipitation was the strongest predictor of the contemporary genetic structure. F ST outlier tests and environment association analysis totally identified 275 candidate adaptive SNPs along the genetic and environmental gradients. SNP annotations of these putatively adaptive loci uncovered gene functions associated with modulating flowering time and regulating plant response to abiotic stresses, which have implications for breeding and other special agricultural aims on the basis of these selection signatures. Critically, modelling revealed that the high genomic vulnerability of our focal species via a mismatch between current and future genotype-environment relationships located in central-northern region of the T. hemsleyanum's range, where populations require proactive management efforts such as assistant adaptation to cope with ongoing climate change. Taken together, our results provide robust evidence of local climate adaption for T. hemsleyanum and further deepen our understanding of adaptation basis of herbs in subtropical China.

Graves' disease as a driver of depression: a mechanistic insight.

Graves' disease (GD) is characterized by diffuse enlargement and overactivity of the thyroid gland, which may be accompanied by other physical symptoms. Among them, depression can dramatically damage patients' quality of life, yet its prevalence in GD has not received adequate attention. Some studies have established a strong correlation between GD and increased risk of depression, though the data from current study remains limited. The summary of mechanistic insights regarding GD and depression has underpinned possible pathways by which GD contributes to depression. In this review, we first summarized the clinical evidence that supported the increased prevalence of depression by GD. We then concentrated on the mechanistic findings related to the acceleration of depression in the context of GD, as mounting evidence has indicated that GD promotes the development of depression through various mechanisms, including triggering autoimmune responses, inducing hormonal disorders, and influencing the thyroid-gut-microbiome-brain axis. Finally, we briefly presented potential therapeutic approaches to decreasing the risk of depression among patients with GD.

Therapeutic role of curcumin in adult neurogenesis for management of psychiatric and neurological disorders: a scientometric study to an in-depth review.

Aberrant neurogenesis is a major factor in psychiatric and neurological disorders that have significantly attracted the attention of neuroscientists. Curcumin is a primary constituent of curcuminoid that exerts several positive pharmacological effects on aberrant neurogenesis. First, it is important to understand the different processes of neurogenesis, and whether their dysfunction promotes etiology as well as the development of many psychiatric and neurological disorders; then investigate mechanisms by which curcumin affects neurogenesis as an active participant in pathophysiological events. Based on scientometric studies and additional extensive research, we explore the mechanisms by which curcumin regulates adult neurogenesis and in turn affects psychiatric diseases, i.e., depression and neurological disorders among them traumatic brain injury (TBI), stroke, Alzheimer's disease (AD), Gulf War Illness (GWI) and Fragile X syndrome (FXS). This review aims to elucidate the therapeutic effects and mechanisms of curcumin on adult neurogenesis in various psychiatric and neurological disorders. Specifically, we discuss the regulatory role of curcumin in different activities of neural stem cells (NSCs), including proliferation, differentiation, and migration of NSCs. This is geared toward providing novel application prospects of curcumin in treating psychiatric and neurological disorders by regulating adult neurogenesis.

The role of primary cilia in thyroid diseases.

Primary cilia (PC) are non-motile and microtube-based organelles protruding from the surface of almost all thyroid follicle cells. They maintain homeostasis in thyrocytes and loss of PC can result in diverse thyroid diseases. The dysfunction of structure and function of PC are found in many patients with common thyroid diseases. The alterations are associated with the cause, development, and recovery of the diseases and are regulated by PC-mediated signals. Restoring normal PC structure and function in thyrocytes is a promising therapeutic strategy to treat thyroid diseases. This review explores the function of PC in normal thyroid glands. It summarizes the pathology caused by PC alterations in thyroid cancer (TC), autoimmune thyroid diseases (AITD), hypothyroidism, and thyroid nodules (TN) to provide comprehensive references for further study.

Probiotics for the improvement of metabolic profiles in patients with metabolic-associated fatty liver disease: A systematic review and meta-analysis of randomized controlled trials.

Objective: This meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy of probiotics in the treatment of metabolic-associated fatty liver disease (MAFLD) mainly in terms of liver function, glucose and lipid metabolism, and inflammation. Methods: RCTs were searched on PubMed, Web of Science, Embase, and the Cochrane Library until June 2022. A meta-analysis was performed on the therapeutic efficacy of probiotics on liver function, glucose and lipid metabolism, and inflammatory biomarkers by using RevMan 5.4 software. Results: A total of 772 patients from 15 studies were included in the analysis. The methodological quality varied across studies. We found that adding probiotic therapies could reduce the levels of alanine aminotransferase [mean difference (MD): -11.76 (-16.06, -7.46), p < 0.00001], aspartate aminotransferase (MD: -9.08 (-13.60, -4.56), p < 0.0001], γ-glutamyltransferase [MD: -5.67 (-6.80, -4.54), p < 0.00001] and homeostasis model assessment-insulin resistance [MD: -0.62 (-1.08, -0.15), p = 0.01], in patients with MAFLD compared with those in control individuals. However, there was no statistically significant improvement in the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, C-reactive protein and tumor necrosis factor α among patients with MAFLD. Subgroup analyses showed that other key factors, such as age, participants' baseline body mass index, and the duration of intervention, may influence probiotic therapy outcomes. Conclusion: There is promising evidence that probiotic supplementation can reduce liver enzyme levels and regulate glycometabolism in patients with MAFLD. Further rigorous and long-term trials exploring these novel therapeutic perspectives are warranted to confirm these results.

Electrospun PCL/collagen hybrid nanofibrous tubular graft based on post-network bond processing for vascular substitute.

Inhibiting thrombus formation and intimal hyperplasia is essential for orthotopic tissue-engineered vascular grafts. The matching mechanical properties of autologous blood vessels and inhibition of platelet aggregation are considered as two points to improve the success rate of transplantation. The poly(ε-caprolactone)/collagen/heparin composite vascular graft (PCLHC) with three-dimensional network structure were constructed by electrospinning, which can mimic natural vascular biomechanics and enhance the viability of cells viability in vitro. The hybrid collagen matrix network nanofibers formed by electrospinning exhibited uniform and smooth morphology. The results of mechanical experiments showed that PCLHC had similar mechanical properties to natural blood vessels. And the addition of heparin enhanced the anticoagulation of PCLHC. Simultaneous three-component hybrid nanofibers showed a potentially reliable ability to promote the proliferation of human umbilical vein endothelial cells (HUVECs). In summary, all the results showed that the three-dimensional network structure of PCLHC presented the potential to heal injured vessels.

Mycobacterium tuberculosis Induced Osteoblast Dysregulation Involved in Bone Destruction in Spinal Tuberculosis.

Disturbance of bone homeostasis caused by Mycobacterium tuberculosis (Mtb) is a key clinical manifestation in spinal tuberculosis (TB). However, the complete mechanism of this process has not been established, and an effective treatment target does not exist. Increasing evidence shows that abnormal osteoclastogenesis triggered by an imbalance of the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) axis may play a key role in the disturbance of bone homeostasis. Previous studies reported that RANKL is strongly activated in patients with spinal TB; however, the OPG levels in these patients were not investigated in previous studies. In this study, we investigated the OPG levels in patients with spinal TB and the dysregulation of osteoblasts caused by Mtb infection. Inhibition of the Mce4a gene of Mtb by an antisense locked nucleic acid (LNA) gapmer (Mce4a-ASO) was also investigated. Analysis of the serum OPG levels in clinical samples showed that the OPG levels were significantly decreased in patients with spinal TB compared to those in the group of non-TB patients. The internalization of Mtb in osteoblasts, the known major source of OPG, was investigated using the green fluorescent protein (GFP)-labeled Mycobacterium strain H37Ra (H37RaGFP). The cell-associated fluorescence measurements showed that Mtb can efficiently enter osteoblast cells. In addition, Mtb infection caused a dose-dependent increase of the CD40 mRNA expression and cytokine (interleukin 6, IL-6) secretion in osteoblast cells. Ligation of CD40 by soluble CD154 reversed the increased secretion of IL-6. This means that the induced CD40 is functional. Considering that the interaction between CD154-expressing T lymphocytes and bone-forming osteoblast cells plays a pivotal role in bone homeostasis, the CD40 molecule might be a strong candidate for mediating the target for treatment of bone destruction in spinal TB. Additionally, we also found that Mce4a-ASO could dose-dependently inhibit the Mce4a gene of Mtb and reverse the decreased secretion of IL-6 and the impaired secretion of OPG caused by Mtb infection of osteoblast cells. Taken together, the current finding provides breakthrough ideas for the development of therapeutic agents for spinal TB.

Multi-omic machine learning predictor of breast cancer therapy response.

Breast cancers are complex ecosystems of malignant cells and the tumour microenvironment1. The composition of these tumour ecosystems and interactions within them contribute to responses to cytotoxic therapy2. Efforts to build response predictors have not incorporated this knowledge. We collected clinical, digital pathology, genomic and transcriptomic profiles of pre-treatment biopsies of breast tumours from 168 patients treated with chemotherapy with or without HER2 (encoded by ERBB2)-targeted therapy before surgery. Pathology end points (complete response or residual disease) at surgery3 were then correlated with multi-omic features in these diagnostic biopsies. Here we show that response to treatment is modulated by the pre-treated tumour ecosystem, and its multi-omics landscape can be integrated in predictive models using machine learning. The degree of residual disease following therapy is monotonically associated with pre-therapy features, including tumour mutational and copy number landscapes, tumour proliferation, immune infiltration and T cell dysfunction and exclusion. Combining these features into a multi-omic machine learning model predicted a pathological complete response in an external validation cohort (75 patients) with an area under the curve of 0.87. In conclusion, response to therapy is determined by the baseline characteristics of the totality of the tumour ecosystem captured through data integration and machine learning. This approach could be used to develop predictors for other cancers.

Clinical efficacy and safety of ultra-short-course chemotherapy in treatment of spinal tuberculosis after complete debridement: an observational study.

OBJECTIVE: To evaluate the clinical efficacy and safety of ultra-short-course chemotherapy (<4 months) in treating spinal tuberculosis following complete debridement. METHODS: Clinical data of patients diagnosed with spinal tuberculosis, who underwent surgery with postoperative chemotherapy for < 4 months at the General Hospital of Ningxia Medical University between January 2005 and March 2015, were retrospectively analysed. Clinical manifestations, American Spinal Injury Association grades, states of bone fusion and lesion healing, deformity correction, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels and adverse drug reactions, observed before and after surgery and at the final follow-up, were assessed. RESULTS: Sixty patients were included, comprising 26 male and 34 female patients aged 16-78 years (mean, 40.85 years). Patients received postoperative chemotherapy for 3-4 months (mean, 3.61 months) and were followed for 25-129 months (mean, 70.61 months). Spinal tuberculosis recurred after surgery in one patient, who was cured by subsequent surgery. At the final follow-up, no symptoms of tuberculosis, local pain, abscess or sinus were observed. Daily life and working abilities were almost recovered in all patients. ESR and CRP levels were restored to normal, bone grafts fused, lesions healed and neurological functions were recovered. Postoperative chemotherapy-induced complications occurred in 10 patients (16.67%). CONCLUSIONS: Complete debridement plus ultra-short-course chemotherapy for 3-4 months may be safe and efficacious in treating spinal tuberculosis, and requires further investigation.

Mechanism of tauroursodeoxycholic acid-mediated neuronal protection after acute spinal cord injury through AKT signaling pathway in rats.

OBJECTIVE: To explore themechanism of tauroursodeoxycholic acid- (TUDCA) mediated neuronal protection after acute spinal cord injury (ASCI) in rats. Methods: ASCI rat model was established following modified Allen's weight-drop method and these rats were assigned to sham group (received sham operation), model group (ASCI rats), TUDCA group (ASCI rats received TUDCA treatment), MK2206 group (ASCI rats received AKT inhibitor MK2206 orally) and TUDCA + MK2206 group. Motor function of rats was evaluated using Basso Beattie Bresnahan (BBB) method. Hematoxylin-eosin (H&E) staining was used to detect histopathologic changes in the spinal cord and TUNEL fluorescence staining was used to check apoptosis. Real time fluorescence quantitative polymerase chain reaction (qRT-PCR) and western blot were employed to detect the production of AKT pathway related factors, apoptosis related factors (Bax, Bcl-2, caspase-3), autophagy related factor Beclin-1 and endoplasmic reticulum (ER) stress related factors (IRE1, Chop, ATF6) in spinal cord of rats. RESULTS: Compared to the rats in the sham group, rats in ASCI group had decreased BBB scores (P<0.05), more significant tissue edema, structural cavity and apoptosis. Compared to rats in sham group, AKT pathway was inactivated in ASCI rats and was activated by TUDCA treatment (P<0.05). Compared to sham group, expressions of ER stress-related factors were increased, apoptosis was largely induced in other four groups, and expression of Beclin-1 was increased in the model group (P<0.05). TUDCA increased the expression of Beclin-1 and Bcl-2, and inhibited the expression of Bax, Caspase-3, and ER stress-related factors, thus suppressing apoptosis (P<0.05). Treatment by MK2206 had contrary effects and protective effects of TUDCA on ASCI rats could be counteracted by MK2206. CONCLUSION: TUDCA can significantly improve the neural damage, enhance neuron autophagy, alleviate ER stress, and inhibit apoptosis in ASCI rats, by activating the AKT signaling pathway.

Using Yoda-1 to mimic laminar flow in vitro: A tool to simplify drug testing.

The endothelium is an attractive drug target and an important site of adverse drug reactions. Endothelial dysfunction is strongly associated with inflammation and contributes to drug-induced cardiovascular toxicity. Endothelial cells in the circulation are exposed to haemodynamic forces including shear stress. Including shear stress may improve future endothelial cell drug discovery or toxicity screening. Piezo-1 is required for endothelial cells to respond to shear stress. In this study, we investigated whether a small molecule activator of Piezo-1, Yoda-1, can mimic the effect of laminar flow-induced shear stress on endothelial cell inflammation, and endothelial cytotoxicity in response to the chemotherapy agent, doxorubicin. First, we tested whether Yoda-1 could mimic the effects of shear stress of expression of the endothelial adhesion molecules, ICAM-1 and VCAM-1. Human umbilical vein endothelial cells (HUVEC) were cultured in static conditions (with or without Yoda-1) or under laminar flow-induced shear stress (5 dyn/cm2). Yoda-1 and laminar flow had similar anti-inflammatory effects, reducing the ability of TNF-α to induce ICAM-1 and VCAM-1 expression. We then tested whether Yoda-1 could mimic the effect of shear stress on doxorubicin-induced cytotoxicity. Both laminar flow and Yoda-1 treatment of static cultures increased the cytotoxicity of doxorubicin. These findings show that Piezo-1 activation with Yoda-1 in static culture leads to an endothelial cell phenotype that mimics endothelial cells under laminar flow. Pharmacological activation of Piezo-1 may be a useful approach to mimic constant shear stress in static cultures, which may improve endothelial drug discovery and toxicity testing.

C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa.

Complement activation has been implicated as contributing to neurodegeneration in retinal and brain pathologies, but its role in retinitis pigmentosa (RP), an inherited and largely incurable photoreceptor degenerative disease, is unclear. We found that multiple complement components were markedly up-regulated in retinas with human RP and the rd10 mouse model, coinciding spatiotemporally with photoreceptor degeneration, with increased C3 expression and activation localizing to activated retinal microglia. Genetic ablation of C3 accelerated structural and functional photoreceptor degeneration and altered retinal inflammatory gene expression. These phenotypes were recapitulated by genetic deletion of CR3, a microglia-expressed receptor for the C3 activation product iC3b, implicating C3-CR3 signaling as a regulator of microglia-photoreceptor interactions. Deficiency of C3 or CR3 decreased microglial phagocytosis of apoptotic photoreceptors and increased microglial neurotoxicity to photoreceptors, demonstrating a novel adaptive role for complement-mediated microglial clearance of apoptotic photoreceptors in RP. These homeostatic neuroinflammatory mechanisms are relevant to the design and interpretation of immunomodulatory therapeutic approaches to retinal degenerative disease.

Absence of TGFß signaling in retinal microglia induces retinal degeneration and exacerbates choroidal neovascularization.

Constitutive TGFß signaling is important in maintaining retinal neurons and blood vessels and is a factor contributing to the risk for age-related macular degeneration (AMD), a retinal disease involving neurodegeneration and microglial activation. How TGFß signaling to microglia influences pathological retinal neuroinflammation is unclear. We discovered that ablation of the TGFß receptor, TGFBR2, in retinal microglia of adult mice induced abnormal microglial numbers, distribution, morphology, and activation status, and promoted a pathological microglial gene expression profile. TGFBR2-deficient retinal microglia induced secondary gliotic changes in Müller cells, neuronal apoptosis, and decreased light-evoked retinal function reflecting abnormal synaptic transmission. While retinal vasculature was unaffected, TGFBR2-deficient microglia demonstrated exaggerated responses to laser-induced injury that was associated with increased choroidal neovascularization, a hallmark of advanced exudative AMD. These findings demonstrate that deficiencies in TGFß-mediated microglial regulation can drive neuroinflammatory contributions to AMD-related neurodegeneration and neovascularization, highlighting TGFß signaling as a potential therapeutic target.