Predictive factors that influence the clinical efficacy of umbilical cord-derived mesenchymal stromal cells in the treatment of type 2 diabetes mellitus.

BACKGROUND: Our previous single-center, randomized, double-blinded, placebo-controlled phase 2 study evaluated the safety and effectiveness of human umbilical cord mesenchymal stromal cell (UC-MSC) transfusion for treating patients with type 2 diabetes mellitus (T2DM). Indeed, this potential treatment strategy was able to reduce insulin use by half in a considerable number of patients. However, many other patients' responses to UC-MSC transfusion were insignificant. The selection of patients who might benefit from UC-MSC treatment is crucial from a clinical standpoint. METHODS: In this post hoc analysis, 37 patients who received UC-MSC transfusions were divided into two groups based on whether their glycated hemoglobin (hemoglobin A1c, or HbA1c) level was less than 7% after receiving UC-MSC treatment. The baseline differences between the two groups were summarized, and potential factors influencing efficacy of UC-MSCs for T2DM were analyzed by univariate and multivariate logistic regression. The correlations between the relevant hormone levels and the treatment effect were further analyzed. RESULTS: At the 9-week follow-up, 59.5% of patients achieved their targeted HbA1c level. Male patients with lower baseline HbA1c and greater C-peptide area under the curve (AUCC-pep) values responded favorably to UC-MSC transfusion, according to multivariate analysis. The effectiveness of UC-MSCs transfusion was predicted by AUCC-pep (cutoff value: 14.22 ng/h/mL). Further investigation revealed that AUCC-pep was increased in male patients with greater baseline testosterone levels. CONCLUSIONS: Male patients with T2DM with greater AUCC-pep may be more likely to respond clinically to UC-MSC therapy, and further large-scale multi-ethnic clinical studies should be performed to confirm the conclusion.

Impact of combined propranolol and oxytocin on the process and outcomes of labor: a meta-analysis of randomized controlled trials.

PURPOSE: To systematically review the impact of propranolol combined with oxytocin on the process and outcomes of labor. METHODS: A comprehensive literature search was performed across multiple databases, including China National Knowledge Infrastructure (CNKI), VIP, Wanfang, China Biomedical Literature Database, PubMed, Embase, and the Cochrane Library. All publicly published randomized controlled trials (RCTs) of propranolol combined with oxytocin compared to the use of oxytocin alone in labor were collected. After screening the literature and extracting data, the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 recommended bias risk assessment tool was used to assess the quality of the included studies. A meta-analysis was conducted using RevMan 5.3 software, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to rate the quality of evidence for outcome measures. RESULTS: Meta-analysis results showed that the group receiving propranolol combined with oxytocin was more capable of reducing the cesarean section rate (eight studies, 815 women, RR = 0.67, 95% CI (0.53, 0.86), P = 0.001) and shortening the duration of the latent phase (two studies, 206 women, MD = - 1.20, 95% CI (- 1.97, - 0.43), P = 0.002) and the duration of the active phase on day 1 (two studies, 296 women, MD = - 0.69, 95% CI (- 0.83, - 0.54), P < 0.00001), compared to the oxytocin monotherapy group. No significant difference was found between the two groups in terms of the 5-min Apgar score (five studies, 609 women, MD = - 0.05, 95% CI (- 0.14, 0.04), P = 0.32) and the rate of admissions to the Neonatal Intensive Care Unit (NICU) (three studies, 359 women, RR = 0.82, 95% CI (0.38, 1.79), P = 0.62). CONCLUSION: The combined use of propranolol and oxytocin can significantly reduce the cesarean section rate, shorten the duration of the latent phase and the duration of the active phase on day 1, and is safe. However, due to the limitations, the conclusions of this article still need to be verified by large-sample, multicenter, rigorously designed high-quality clinical RCTs. TRIAL REGISTRATION: Registration number is INPLASY202390107.

BRAD V3.0: an upgraded Brassicaceae database.

The Brassicaceae Database (BRAD version 3.0, BRAD V3.0; http://brassicadb.cn) has evolved from the former Brassica Database (BRAD V2.0), and represents an important community portal hosting genome information for multiple Brassica and related Brassicaceae plant species. Since the last update in 2015, the complex genomes of numerous Brassicaceae species have been decoded, accompanied by many omics datasets. To provide an up-to-date service, we report here a major upgrade of the portal. The Model-View-ViewModel (MVVM) framework of BRAD has been re-engineered to enable easy and sustainable maintenance of the database. The collection of genomes has been increased to 26 species, along with optimization of the user interface. Features of the previous version have been retained, with additional new tools for exploring syntenic genes, gene expression and variation data. In the 'Syntenic Gene @ Subgenome' module, we added features to view the sequence alignment and phylogenetic relationships of syntenic genes. New modules include 'MicroSynteny' for viewing synteny of selected fragment pairs, and 'Polymorph' for retrieval of variation data. The updated BRAD provides a substantial expansion of genomic data and a comprehensive improvement of the service available to the Brassicaceae research community.

A near-complete genome assembly of Brassica rapa provides new insights into the evolution of centromeres.

Brassica rapa comprises many important cultivated vegetables and oil crops. However, Chiifu v3.0, the current B. rapa reference genome, still contains hundreds of gaps. Here, we presented a near-complete genome assembly of B. rapa Chiifu v4.0, which was 424.59 Mb with only two gaps, using Oxford Nanopore Technology (ONT) ultralong-read sequencing and Hi-C technologies. The new assembly contains 12 contigs, with a contig N50 of 38.26 Mb. Eight of the ten chromosomes were entirely reconstructed in a single contig from telomere to telomere. We found that the centromeres were mainly invaded by ALE and CRM long terminal repeats (LTRs). Moreover, there is a high divergence of centromere length and sequence among B. rapa genomes. We further found that centromeres are enriched for Copia invaded at 0.14 MYA on average, while pericentromeres are enriched for Gypsy LTRs invaded at 0.51 MYA on average. These results indicated the different invasion mechanisms of LTRs between the two structures. In addition, a novel repetitive sequence PCR630 was identified in the pericentromeres of B. rapa. Overall, the near-complete genome assembly, B. rapa Chiifu v4.0, offers valuable tools for genomic and genetic studies of Brassica species and provides new insights into the evolution of centromeres.

Cholesterol-Mediated Anchoring of Phospholipids onto Proteinosomes for Switching Membrane Permeability.

Modulated membrane functionalization is a necessary and overarching step for hollow microcompartments toward their application as nanoreactors or artificial cells. In this study, we show a way to generate phospholipid hybrid proteinosomes that could show superposed virtues of liposomes and proteinosomes. In comparison to pure proteinosomes, both the membrane fluidity and permeability are improved obviously after forming the phospholipid hybrid proteinosomes. Specifically, the integration of phospholipids also endows the hybrid proteinosomes demonstrating a stepwise release of the encapsulants of FITC-dextran (70 and 150 kDa) triggered sequentially by phospholipase and protease, and then a modulated cascaded enzymatic reaction between two different populations of proteinosomes are achieved. Therefore, it is anticipated that such constructed phospholipid hybrid proteinosomes could be employed as an improved microcompartmental model for further advanced artificial cell design toward achieving logic signal communication within the various artificial cellular populations as well as potential applications in the field of microreactors.

Construction of Hybrid Bi-microcompartments with Exocytosis-Inspired Behavior toward Fast Temperature-Modulated Transportation of Living Organisms.

Inspired by the unique characteristics of living cells, the creation of life-inspired functional ensembles is a rapidly expanding research topic, enabling transformative applications in various disciplines. Herein, we report a facile method for the fabrication of phospholipid and block copolymer hybrid bi-microcompartments via spontaneous asymmetric assembly at the water/tributyrin interface, whereby the temperature-mediated dewetting of the inner microcompartments allowed for exocytosis to occur in the constructed system. The exocytosis location and commencement time could be controlled by the buoyancy of the inner microcompartment and temperature, respectively. Furthermore, the constructed bi-microcompartments showed excellent biocompatibility and a universal loading capacity toward cargoes of widely ranging sizes; thus, the proliferation and temperature-programmed transportation of living organisms was achieved. Our results highlight opportunities for the development of complex mesoscale dynamic ensembles with life-inspired behaviors and provide a novel platform for on-demand transport of various living organisms.

Degeneration of the intestinal microbial community in PI3Kγ-knockout mice.

BACKGROUND AND AIM: PI3Kγ is closely related to inflammation and cardiovascular diseases and thus, PI3Kγ inhibitors are candidate drugs for the treatment of these disorders. Considering the potential effect of the intestinal microbiome on inflammation and cardiovascular diseases, this study aimed to identify characteristics of the intestinal microbial community under PI3Kγ deficiency, to help reveal the potential influence of PI3Kγ inhibitors mediated by the microbial community. METHODS: Exon 2 of the PI3Kγ gene was knocked out in a Balb/c mouse by using single-guide RNAs. Homozygous PI3Kγ-knockout (PI3Kγ-/-) mice were obtained by embryo transfer and hybridization. PI3Kγ-/- and wild-type (WT) mice were raised in the same specific pathogen-free conditions until 8 weeks of age. Then, colonic tissues and feces from the middle segment of the colon were collected and analyzed by Illumina MiSeq sequencing. Differences in intestinal microbial community between the PI3Kγ-/- and WT mice were detected by bioinformatics analysis. RESULTS: The richness and alpha diversity of the colonic microbial community were decreased in PI3Kγ-/- mice. The alpha diversity of the microbial community in feces did not differ between PI3Kγ-/- and WT mice. The beta diversity of the microbial community in feces of PI3Kγ-/- mice was obviously different from that in WT mice, whereas the within-group variation in Bray-Curtis distances of the mucosal microbial community was significantly decreased in PI3Kγ-/- mice. The topological structure of the species-related network of the colonic microbial community in PI3Kγ-/- mice was more polarized. Finally, we predicted that PI3Kγ deficiency might affect the synthesis of some antibiotics, bile acid, and thiamine through effects on the microbial community. CONCLUSIONS: PI3Kγ dysfunction led to degeneration of the intestinal microbial community and might alter the synthesis of some antibiotics, bile acids, and thiamine. The usage of PI3Kγ inhibitors for inflammation and cardiovascular diseases might lead to knock-on effect on our organism through intestinal microbiota.

Ursolic Acid Improves Monocrotaline-Induced Right Ventricular Remodeling by Regulating Metabolism.

Pulmonary arterial hypertension (PAH) is a progressive and malignant disease characterized by pulmonary small arteries and right ventricle (RV) remodeling that can lead to severe RV dysfunction and death. The current therapeutic targets for RV dysfunction, which is strongly linked to mortality, are far from adequate. Therefore, we investigated the effect of ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, on PAH-induced RV remodeling and its underlying mechanism. We established a PAH model by injecting Sprague Dawley rats with monocrotaline (MCT, 60 mg/kg, ip), as verified by echocardiography and hemodynamic examination. Proteomic analysis was performed on RV samples using a Q Exactive high-field mass spectrometer, followed by KEGG enrichment analysis. The effect of 4 weeks of UA (50 mg/kg) treatment on RV remodeling was explored based on ultrasound, hemodynamic parameters, and histological changes, with the mechanism verified in vivo and in vitro by qRT-PCR and western blotting. RV hypertrophy, fibrosis, increased apoptosis, and abnormal metabolism were induced by MCT and suppressed by UA via a mechanism that changed the expression of key markers. UA also attenuated the Phenylephrine-induced hypertrophy of neonatal rat ventricular myocytes and upregulated peroxisome proliferator-activated receptor-alpha (PPARα), a key fatty acid metabolism regulator, and its downstream factor carnitine palmitoyl transferase 1b. In conclusion, UA exerts beneficial effects on PAH-induced RV dysfunction and remodeling by regulating PPARα-dependent fatty acid metabolism.

Fusion-Induced Structural and Functional Evolution in Binary Emulsion Communities.

The biomimetic dynamic behaviours of emulsions are receiving increasing attention from the broad scientific community; however, the spatiotemporal control and functionalization of emulsions based on simple fusion-induced method is rarely mentioned. A design for protein-stabilized oil-in-water droplets and phospholipid-stabilized oil-in-water droplets is described and a substance-diffusion-mediated fusion mechanism proposed within these two different emulsion communities. Significantly, a range of fusion-induced high-order behaviours were successfully demonstrated including competitive fusion, fusion-induced evolution in membrane complexity, and diversified structures with the formation of Janus or various patchy morphologies, fusion-induced membrane maturation, as well as fusion-induced multifunctionalization with a directional motility behaviour. These results highlight the fusion-induced diverse dynamic behaviours in complex emulsions communities and provide a platform for advancing versatile applications of emulsions.

Small molecule Me6TREN mobilizes hematopoietic stem/progenitor cells by activating MMP-9 expression and disrupting SDF-1/CXCR4 axis.

Mobilization of hematopoietic stem and progenitor cells (HSPCs) from bone marrow into the blood circulation has been widely used for hematopoietic transplantation. However, the current methods of cytokine- or small-molecule-stimulated HSPC mobilization are far from satisfactory. New mobilizing agents are needed to increase the number of stem cells in peripheral blood for effective reconstitution of hematopoiesis. Here, we report that the molecule Me6TREN (Me6) can induce rapid mobilization of hematopoietic progenitor cells and that Me6 exhibits more significant effects than granulocyte colony-stimulating factor (G-CSF) or AMD3100. Me6 also mobilizes long-term repopulating cells, which successfully engraft and expand in a multilineage fashion in primary and secondary transplant recipients. Mechanistically, Me6 inhibits both the SDF-1α-induced migration and VLA-4-mediated adhesion of mouse and human hematopoietic cells. Me6 appears to mobilize HSPCs by activating MMP-9 expression and disrupting the SDF-1α/CXCR4 axis. Therefore, Me6 may become a new potent and efficacious mobilizing agent of HSPCs.

Predictive factors for prolonged remission after autologous hematopoietic stem cell transplantation in young patients with type 1 diabetes mellitus.

BACKGROUND AIMS: Autologous hematopoietic stem cell transplantation (auto-HSCT) followed by immunoablation is a promising therapy for type 1 diabetes mellitus (T1DM) treatment due to the immunosuppression and immunomodulation mechanisms. Indeed, a considerable number of patients have been able to discontinue insulin use with this treatment. However, nonresponse and relapse occur after auto-HSCT. It is important to select the patients who can potentially benefit from this treatment, but the factors that might influence the therapeutic outcome are unclear. The objective of this study was to explore the predictors for prolonged remission after auto-HSCT therapy. METHODS: The data for this study were extracted from an open-label prospective study, which was performed to treat new-onset T1DM patients with auto-HSCT. The 128 patients were categorized into insulin-free (IF) or insulin-dependent (ID) groups according to their response to treatment during the follow-up. We compared the baseline data of the two groups and explored possible prognostic factors and their odd ratios (ORs) with univariate analysis and multivariate logistic regression. Receiver operating characteristic curves (ROC) were performed to test the model discrimination function. RESULTS: During a follow-up of 28.5 ± 8.3 months, 71 of 128 patients in the IF group discontinued insulin use, whereas 57 of 128 patients in the ID group did not decrease their insulin dose or resumed insulin treatment after a transient remission. Multivariate logistic regression analysis demonstrated that prolonged remission was positively correlated with fasting C-peptide level (OR = 2.60, 95% confidence interval [CI]: 1.16-5.85) but negatively correlated with onset age (OR = 0.36, 95% CI: 0.14-0.88) and tumor necrosis factor-α levels (OR = 0.32, 95% CI: 0.14-0.73). ROC analysis confirmed the combined predictive function of these three variables (AUC = 0.739, 95% CI: 0.655-0.824). CONCLUSIONS: Age and fasting C-peptide and tumor necrosis factor-α levels were identified as possible predictors for prolonged remission following auto-HSCT therapy.

Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: role of the S100A4-miR155-SOCS1-MMP9 axis.

UNLABELLED: Cancer-associated mesenchymal stem cells (MSCs) play a pivotal role in modulating tumor progression. However, the interactions between liver cancer-associated MSCs (LC-MSCs) and hepatocellular carcinoma (HCC) remain unreported. Here, we identified the presence of MSCs in HCC tissues. We also showed that LC-MSCs significantly enhanced tumor growth in vivo and promoted tumor sphere formation in vitro. LC-MSCs also promoted HCC metastasis in an orthotopic liver transplantation model. Complementary DNA (cDNA) microarray analysis showed that S100A4 expression was significantly higher in LC-MSCs compared with liver normal MSCs (LN-MSCs) from adjacent cancer-free tissues. Importantly, the inhibition of S100A4 led to a reduction of proliferation and invasion of HCC cells, while exogenous S100A4 expression in HCC cells resulted in heavier tumors and more metastasis sites. Our results indicate that S100A4 secreted from LC-MSCs can promote HCC cell proliferation and invasion. We then found the expression of oncogenic microRNA (miR)-155 in HCC cells was significantly up-regulated by coculture with LC-MSCs and by S100A4 ectopic overexpression. The invasion-promoting effects of S100A4 were significantly attenuated by a miR-155 inhibitor. These results suggest that S100A4 exerts its effects through the regulation of miR-155 expression in HCC cells. We demonstrate that S100A4 secreted from LC-MSCs promotes the expression of miR-155, which mediates the down-regulation of suppressor of cytokine signaling 1, leading to the subsequent activation of STAT3 signaling. This promotes the expression of matrix metalloproteinases 9, which results in increased tumor invasiveness. CONCLUSION: S100A4 secreted from LC-MSCs is involved in the modulation of HCC progression, and may be a potential therapeutic target. (HEPATOLOGY 2013).

Breaking Barriers: Nanomedicine-Based Drug Delivery for Cataract Treatment.

Cataract is a leading cause of blindness globally, and its surgical treatment poses a significant burden on global healthcare. Pharmacologic therapies, including antioxidants and protein aggregation reversal agents, have attracted great attention in the treatment of cataracts in recent years. Due to the anatomical and physiological barriers of the eye, the effectiveness of traditional eye drops for delivering drugs topically to the lens is hindered. The advancements in nanomedicine present novel and promising strategies for addressing challenges in drug delivery to the lens, including the development of nanoparticle formulations that can improve drug penetration into the anterior segment and enable sustained release of medications. This review introduces various cutting-edge drug delivery systems for cataract treatment, highlighting their physicochemical properties and surface engineering for optimal design, thus providing impetus for further innovative research and potential clinical applications of anti-cataract drugs.

Histopathological and Immunohistochemical Mechanisms of Bone Marrow-Derived Mesenchymal Stem Cells in Reversion of Gastric Precancerous Lesions.

BACKGROUND: Gastric cancer (GC) stands as one of the most prevalent cancer types worldwide, holding the position of the second leading cause of cancer-related deaths. Gastric lesions represent pathological alterations to the gastric mucosa, with an elevated propensity to advance to gastric cancer. Limited research has explored the potential of stem cells in the treatment of gastric lesions. METHODS: This study aimed to explore the potential of intravenous transplantation of labeled bone marrow-derived mesenchymal stem cells (BMMSCs) to inhibit the progression of precancerous gastric lesions. RESULTS: In the gastric lesion disease model group, the rat tissue exhibited noteworthy mucosal atrophy, intestinal metaplasia, dysplasia, and inflammatory cell infiltration. Following the infusion of BMMSCs, a notable decrease in gastric lesions was found, with atrophic gastritis being the sole remaining lesion, which was confirmed by morphological and histological examinations. BMMSCs that were colonized at gastric lesions could differentiate into epithelial and stromal cells, as determined by the expression of pan-keratin or vimentin. The expression of vascular endothelial growth factor was significantly elevated following BMMSC transplantation. BMMSCs could also upregulate the production of humoral immune response cytokines, including interleukin (IL)-4 and IL-10, and downregulate the production of IL-17 and interferon-gamma, which could be highly associated with the cellular immune response and inflammation severity of the lesions. CONCLUSIONS: BMMSC transplantation significantly reduced inflammation and reversed gastric lesion progression.

Synthetic-Cell-Based Multi-Compartmentalized Hierarchical Systems.

In the extant lifeforms, the self-sustaining behaviors refer to various well-organized biochemical reactions in spatial confinement, which rely on compartmentalization to integrate and coordinate the molecularly crowded intracellular environment and complicated reaction networks in living/synthetic cells. Therefore, the biological phenomenon of compartmentalization has become an essential theme in the field of synthetic cell engineering. Recent progress in the state-of-the-art of synthetic cells has indicated that multi-compartmentalized synthetic cells should be developed to obtain more advanced structures and functions. Herein, two ways of developing multi-compartmentalized hierarchical systems, namely interior compartmentalization of synthetic cells (organelles) and integration of synthetic cell communities (synthetic tissues), are summarized. Examples are provided for different construction strategies employed in the above-mentioned engineering ways, including spontaneous compartmentalization in vesicles, host-guest nesting, phase separation mediated multiphase, adhesion-mediated assembly, programmed arrays, and 3D printing. Apart from exhibiting advanced structures and functions, synthetic cells are also applied as biomimetic materials. Finally, key challenges and future directions regarding the development of multi-compartmentalized hierarchical systems are summarized; these are expected to lay the foundation for the creation of a "living" synthetic cell as well as provide a larger platform for developing new biomimetic materials in the future.

Exploration of Simiao-Yongan Decoction on knee osteoarthritis based on network pharmacology and molecular docking.

Use network pharmacology combined with molecular docking to study the effects of Simiao-Yongan Decoction (SMYAD) intervenes in Knee Osteoarthritis (KOA) related targets and signaling pathways, and explores the molecular mechanism of SMYAD in treating KOA. The active ingredients and targets of SMYAD, which concluded 4 traditional Chinese medicines, were screened in TCMSP, and the related gene targets of KOA were screened in the disease databases GeneCards, MalaCards, DisGeNET, and Comparative Toxicogenomics Database, and their intersection data were obtained after integration. And used Cytoscape 3.9.1, the software topologies the network diagram of "compound-drug-active ingredient-target protein-disease." Obtains the protein-protein interaction network diagram through STRING, and enriches and analyzes the obtained core targets. Carry out molecular docking matching verification on the main active ingredients and key targets of the drug. 106 active ingredients and 175 targets were screened from SMYAD to intervene in KOA, 36 core targets were obtained through protein-protein interaction screening, and 10 key targets played an important role. The enrichment results showed that the biological process of gene ontology mainly involved positive regulation of gene expression, negative regulation of apoptosis process, and positive regulation of apoptosis process. KEGG signaling pathway mainly involves AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, hypoxia-inducible factor-1 signaling pathway, IL-17 signaling pathway. The pathway of Reactome mainly involves interleukin-4 and interleukin-13 signaling, cytokine signaling in immune system, immune system, apoptosis. Molecular docking showed that the mainly effective components of SMYAD can fully combine with TNF, IL1B, IL6, and CASP3. The results show that the main active ingredients and potential mechanism of action of SMYAD in the treatment of KOA have the characteristics of multiple targets and multiple pathways, which provides ideas and basis for further in-depth exploration of its specific mechanism.

Biotic communities inspired proteinosome-based aggregation for enhancing utilization rate of enzyme.

Compared with the individuals, the collective behavior of biotic communities could show certain superior characteristics. Inspired by this idea and based on the conjugation between phenylboronic acid-grafted mesoporous silica nanoparticles and the polysaccharide functionalized membrane of proteinosomes, a type of proteinosomes-based aggregations was constructed. We demonstrated the emergent characteristics of proteinosomes aggregations including accelerated settling velocity and population surviving by sacrificing outside members for the inside. Moreover, this kind of "hand in hand" architecture provided the proteinosomes aggregations with the characteristic of resistance to the negative pressure phagocytosis of micropipette, as well as enhancing utilization rate of the encapsulated enzymes. Overall, it is anticipated that the construction and application of proteinosomes aggregations could contribute to advance the functionality of life-like assembled biomaterial in another way.

Mechanical stress abnormalities promote chondrocyte senescence - The pathogenesis of knee osteoarthritis.

Knee osteoarthritis (KOA) is a common chronic disease in orthopedics, which brings great pain to patients' life and spirit. Therefore, it is necessary to elucidate the pathogenesis of KOA. The pathophysiology of KOA has been linked to numerous factors, including oxidative stress, apoptosis, cellular senescence, mitochondrial dysfunction, and inflammatory factors. Cellular senescence has grown in importance as a topic of study for age-related illnesses recently. KOA has also been discovered to be closely related to human aging, a process in which chondrocyte senescence may be crucial. Numerous researches have looked at the pathogenesis of KOA from the perspectives of mechanical stress abnormalities, oxidative stress, inflammatory overexpression, and mitochondrial dysfunction. Many studies have discovered that the primary pathogenesis of KOA is inflammatory overexpression and chondrocyte death brought on by an imbalance in the joint microenvironment. And abnormal mechanical stress is the initiating cause of oxidative stress, inflammation, and mitochondrial disorders. However, few findings have been reported in the literature on the relationship between these factors, especially for mechanical stress abnormalities, and chondrocyte senescence. This time, in order to better understand the pathogenesis of KOA and identify potential connections between chondrocyte senescence and these microenvironments in KOA, as well as oxidative stress, inflammatory overexpression, and mitochondrial dysfunction microenvironmental dysfunctions, we will use chondrocyte senescence as a starting point. This will allow us to develop new therapeutic approaches for KOA.

Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway.

Mesenchymal stem cells (MSCs) play a critical role in promoting cancer progression. However, it is not clear whether MSCs are located in breast cancer tissues and correlated with tumor proliferation. The aim of this study was to investigate the presence of MSCs in breast cancer tissues and evaluate their interactions with cancer cells. We successfully isolated and identified MSCs from primary breast cancer tissues. Breast cancer-associated MSCs (BC-MSCs) showed homogenous immunophenotype, and possessed tri-lineage differentiation potential (osteoblast, adipocyte, and chondrocyte). When co-transplanted with cancer cells in a xenograft model in vivo, BC-MSCs significantly increased the volume and weight of tumors. We observed that BC-MSCs stimulated mammosphere formation in the transwell co-culture system in vitro. This effect was significantly suppressed by the EGF receptor inhibitor. We verified that BC-MSCs could secrete EGF and activate cancer cell's EGF receptors. Furthermore, our data showed that EGF derived from BC-MSCs could promote mammosphere formation via the PI3K/Akt signaling pathway. Our results confirmed the presence of MSC in primary breast cancer tissues, and they could provide a favorable microenvironment for tumor cell growth in vivo, partially enhance mammosphere formation via the EGF/EGFR/Akt pathway.

Elucidating the mechanism of Hongjinshen decoction in the treatment of pulmonary fibrosis based on network pharmacology and molecular docking.

BACKGROUND: To explore the mechanism of compound Hongginshen decoction in improving pulmonary fibrosis based on network pharmacology. METHODS: The active components and targets of ginseng and Salvia miltiorrhiza were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. The chemical components of Rhodiola, Ophiopogon japonicus, and Dendrobium were screened using the Traditional Chinese Medicine Integrated Database (TCMID), and the target compounds were predicted by the Swisstargets method. The related target genes of pulmonary fiber (PF) were screened by the Genecards database and the National Center of Biotechnology Information (NCBI) database. The protein-protein interaction network was drawn using the string database and Cytoscape software, and the network topology was analyzed. Then, using R3.6.3 software, biological processes, molecular function, cell component enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were carried out on the common targets of drugs and diseases. The network diagram of the "traditional Chinese medicine composition disease target" of Compound Hongginshen Decoction was constructed and analyzed with the software of Cytoscape 3.6.1. RESULTS: We identified 159 active components and 2820 targets in Compound Hongginshen Decoction, and 2680 targets in pulmonary fibrosis. A total of 343 common targets were obtained by the intersection of drug targets and disease targets. protein-protein interaction protein interaction network analysis showed that PIK3CA, PIK3R1, MAPK1, SRC, AKT1, and so on may be the core targets of the compound Hongjingshen recipe in the treatment of pulmonary fibrosis. Gene Ontology (GO) enrichment analysis identified 3463 items, and KEGG pathway enrichment analysis identified 181 related signaling pathways, including the PI3K-Akt signaling pathway, HCMV pathway, Hb pathway, PGs pathway, and KSHV signaling pathway. CONCLUSION: Compound Hongginshen Decoction has the characteristics of a multichannel and multitargeted effect in the treatment of pulmonary fibrosis. Radix Ophiopogonis and Dendrobium officinale play a key role in the treatment of pulmonary fibrosis. The whole compound prescription may play a therapeutic role by affecting cell metabolism, being anti-inflammatory, regulating the immune system, promoting angiogenesis, and improving anaerobic metabolism.