A diminutive perivascular epithelioid cell tumor in the colon.

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor. Some papers have reported that colonoscopy could be used to treat PEComa with a predominantly pedunculated polyp, whereas surgical intervention is often required for cases with submucosal-type tumors. These findings suggest that the morphology of PEComa changes dramatically with disease progression. Because of the rapid progression of PEComa, endoscopic treatment remains challenging, and early-stage PEComa morphology is not well understood. A 64-year-old man presented to our hospital for a follow-up colonoscopy after undergoing multiple polypectomies. He had a medical history of colorectal adenoma and prostate cancer. A 4-mm pale blue elevated but not pedunculated lesion was observed in the transverse colon, an area where he had not had polyps previously. Since no epithelial change was observed, the presence of a submucosal tumor, such as a gastrointestinal stromal tumor, was suspected. Cold snare polypectomy was performed, and the lesion was completely resected. Histological evaluation using hematoxylin and eosin staining identified that the submucosal tumor included thickened vascular walls and adipose tissue. Although fragmented due to significant degeneration, spindle-shaped cells staining positive for smooth muscle actin were observed within and surrounding the unstructured hyalinized tissue with calcifications. Based on these findings, the lesion was diagnosed as angiomyolipoma, a subtype of PEComa. Complete resection was confirmed by histopathology. To our knowledge, this PEComa is the smallest of any PEComa reported in the literature. Our finding provides valuable insights into the very early stage of colorectal PEComas.

The Effect of Exercise on Mesenchymal Stem Cells and their Application in Obesity Treatment.

Mesenchymal stem cells (MSCs) have demonstrated considerable potential in tissue repair and the treatment of immune-related diseases, but there are problems with homing efficiency during MSCs transplantation. Exercise, as an intervention, has been shown to have an important impact on the properties of MSCs. This review summarizes the effects of exercise on the properties (including proliferation, apoptosis, differentiation, and homing) of bone marrow-derived MSCs and adipose-derived MSCs. Studies indicated that exercise enhances bone marrow-derived MSCs proliferation, osteogenic differentiation, and homing while reducing adipogenic differentiation. For adipose-derived MSCs, exercise enhances proliferation and reduces adipogenic differentiation. In addition, studies have investigated the therapeutic effects of combined therapy of MSCs transplantation with exercise on diseases of the bone, cardiac, and nervous systems. The combined therapy improves tissue repair by increasing the homing of transplanted MSCs and cytokine secretion (such as neurotrophin 4). Furthermore, MSCs transplantation also has potential for the treatment of obesity. Although the effect is not significant in weight loss, MSCs transplantation shows effects in controlling blood glucose, improving dyslipidemia, reducing inflammation, and improving liver disease. Finally, the potential role of combined MSCs transplantation and exercise therapy in addressing obesity is discussed.

Accumulation of DNA G-quadruplex in mitochondrial genome hallmarks mesenchymal senescence.

Searching for biomarkers of senescence remains necessary and challenging. Reliable and detectable biomarkers can indicate the senescence condition of individuals, the need for intervention in a population, and the effectiveness of that intervention in controlling or delaying senescence progression and senescence-associated diseases. Therefore, it is of great importance to fulfill the unmet requisites of senescence biomarkers especially when faced with the growing global senescence nowadays. Here, we established that DNA G-quadruplex (G4) in mitochondrial genome was a reliable hallmark for mesenchymal senescence. Via developing a versatile and efficient mitochondrial G4 (mtG4) probe we revealed that in multiple types of senescence, including chronologically healthy senescence, progeria, and replicative senescence, mtG4 hallmarked aged mesenchymal stem cells. Furthermore, we revealed the underlying mechanisms by which accumulated mtG4, specifically within respiratory chain complex (RCC) I and IV loci, repressed mitochondrial genome transcription, finally impairing mitochondrial respiration and causing mitochondrial dysfunction. Our findings endowed researchers with the visible senescence biomarker based on mitochondrial genome and furthermore revealed the role of mtG4 in inhibiting RCC genes transcription to induce senescence-associated mitochondrial dysfunction. These findings depicted the crucial roles of mtG4 in predicting and controlling mesenchymal senescence.

The differences between pure and mixed invasive micropapillary breast cancer: the epithelial-mesenchymal transition molecules and prognosis.

PURPOSE: Invasive micropapillary carcinoma (IMPC) of the breast is known for its high metastatic potential, but the definition of pure and mixed IMPC remains unclear. This retrospective cohort study aims to investigate the prognostic significance of the micropapillary component ratio and the expression of critical molecules of epithelial-mesenchymal transition (EMT), including E-cadherin (E-cad), N-cadherin (N-cad), CD44s, and ß-catenin (ß-cat), in distinguishing between pure and mixed IMPCs. METHODS: We analyzed 100 cases of locally advanced IMPC between 2000 and 2018 and excluded patients who received neoadjuvant chemotherapy. Pure IMPC was defined as having a micropapillary component of over 90%. A comprehensive recording of prognostic parameters was conducted. The IMPC areas were analyzed using the immunohistochemical (IHC) staining method on the microarray set for pure and mixed IMPC patients. Pearson's chi-square, Fisher's exact tests, Kaplan-Meier analysis, and Cox proportional hazards analysis were employed. RESULTS: The comparative survival analysis of the entire group, based on overall survival (OS) and disease-free survival (DFS), revealed no significant difference between the pure and mixed groups (P = 0.480, HR = 1.474 [0.502-4.325] and P = 0.390, HR = 1.587 [0.550-4.640], respectively). However, in the pure IMPC group, certain factors were found to be associated with a higher risk of short survival. These factors included skin involvement (P = 0.050), pT3&4 category (P = 0.006), a ratio of intraductal component (> 5%) (P = 0.032), and high-level expression of N-cad (P = 0.020). Notably, none of the risk factors identified for short OS in pure IMPC cases were observed as significant risks in mixed cases and vice versa. Furthermore, N-cad was identified as a poor prognostic marker for OS in pure IMPCs (P = 0.002). CONCLUSION: The selection of a 90% ratio for classifying pure IMPCs revealed significant differences in certain molecular and prognostic parameters between pure and mixed groups. Notably, the involvement of N-cadherin in the epithelial-mesenchymal transition (EMT) process provided crucial insights for predicting OS and DFS while also distinguishing between the two groups. These findings strongly support the notion that the pure IMPC subgroup represents a distinct entity characterized by unique molecular characteristics and behavioral patterns.

TGF-ß/SMAD Pathway Mediates Cadmium Poisoning-Induced Chicken Liver Fibrosis and Epithelial-Mesenchymal Transition.

Cadmium(Cd) is a toxic heavy metal widely present in the environment, capable of accumulating in the liver and causing liver damage. In this study, the mechanism of cadmium-induced liver fibrosis in chickens was investigated from the perspective of hepatocyte epithelial-mesenchymal transition (EMT) based on the establishment of a model of chicken cadmium toxicity and a model of cadmium-stained cells in a chicken hepatocellular carcinoma cell line (LMH). The 7-day-old chickens were randomly divided into the regular group (C group) and cadmium poisoning group (Cd group), and the entire test cycle was 60 days. Three sampling time points of 20 days, 40 days, and 60 days were established. By testing the liver coefficient, histopathological and ultrastructural changes in chicken livers were observed. The enzyme activities of liver function and the expression changes of fibrosis markers (COL1A1, Fibronectin), epithelial-mesenchymal transition markers (E-cadherin, Vimentin, and α-SMA), and the critical factors of the TGF-ß/SMAD signaling pathway (TGF-ß1, SMAD 2, and SMAD 3) were detected in the liver expression changes. The results showed that at the same sampling time point, the chicken liver coefficient in group Cd was significantly higher than that in control group (P < 0.01); the activities of the liver function enzymes ALT and AST in chickens in the Cd group were significantly higher than those in the C group (P < 0.01); liver hepatocytes degenerated and necrotic, the number of erythrocytes in the blood vessels was increased, and inflammatory cells infiltrated in the sinusoidal gap; the perisinusoidal gap of the liver was enlarged, and there was an apparent aggregation of collagen fibers in the intervening period as seen by transmission electron microscopy. The results of Masson staining showed that the percentage of fiber area was significantly higher in the chickens' livers of the Cd group. The fiber area percentage was significantly higher. The results of real-time fluorescence quantitative PCR and Western Blot showed that the expression of E-cadherin in the livers of chickens in the Cd group was significantly lower than that in the C group (P < 0.01). The expression of α-SMA, Vimentin, COL1A1, Fibronectin, TGF-ß1, SMAD 2, and SMAD 3 was significantly higher than that in the C group (P < 0.01). The results of in vitro assays showed that in the LMH cell model established by adding trimethylamine N-oxide, an activator of the TGF-ß/SMAD signaling pathway, and oxidized picric acid, an inhibitor of the TGF-ß/SMAD signaling pathway, the expression of E-cadherin was significantly reduced in cadmium-stained LMH cells (P < 0.01). The expression of α-SMA, Vimentin, COL1A1, Fibronectin, TGF-ß, SMAD 2, and SMAD 3 was significantly elevated (P < 0.01). Cadmium and Trimethylamine N-oxide, an activator of the TGF-ß/SMAD signaling pathway, promoted the expression of these factors. In contrast, the inhibitor of the TGF-ß/SMAD signaling pathway, Oxymatrine, a TGF-ß/SMAD signaling pathway inhibitor, significantly slowed down these changes. These results suggest that cadmium induces hepatic epithelial-mesenchymal transition by activating the TGF-ß/SMAD signaling pathway in chicken hepatocytes, promoting hepatic fibrosis.

A Gelatin-Based Biomimetic Scaffold Promoting Osteogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells.

Background: In bone tissue engineering segment, numerous approaches have been investigated to address critically sized bone defects via 3D scaffolds, as the amount of autologous bone grafts are limited, accompanied with complications on harvesting. Moreover, the use of bone-marrow-derived stem cells is also a limiting factor owing to the invasive procedures involved and the low yield of stem cells. Hence, research is ongoing on the search for an ideal bone graft system promoting bone growth and regeneration. Purpose of the Study: This study aims to develop a unique platform for tissue development via stem cell differentiation towards an osteogenic phenotype providing optimum biological cues for cell adhesion, differentiation and proliferation using biomimetic gelatin-based scaffolds. The use of adipose-derived mesenchymal stem cells in this study also offers an ideal approach for the development of an autologous bone graft. Methods: A gelatin-vinyl acetate-based 3D scaffold system incorporating Bioglass was developed and the osteogenic differentiation of adipose-derived mesenchymal stem cells (ADMSCs) on the highly porous freeze-dried gelatin-vinyl acetate/ Bioglass scaffold (GB) system was analyzed. The physicochemical properties, cell proliferation and viability were investigated by seeding rat adipose tissue-derived mesenchymal stem cells (ADSCs) onto the scaffolds. The osteogenic differentiation potential of the ADMSC seeded GeVAc/bioglass system was assessed using calcium deposition assay and bone-related protein and genes and comparing with the 3D Gelatin vinyl acetate coppolymer (GeVAc) constructs. Results and Conclusion: According to the findings, the 3D porous GeVAc/bioglass scaffold can be considered as a promising matrix for bone tissue regeneration and the 3D architecture supports the differentiation of the ADMSCs into osteoblast cells and enhances the production of mineralized bone matrix.

Ovarian function in patients with systemic lupus erythematosus: Pathogenesis, drug application and prospective therapies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which multiple organs are damaged that prevails in fertile women. Currently, glucocorticoids and immunosuppressants are widely used to treat SLE patients. However, ovarian dysfunction occurs following the use of these drugs in women with SLE. Here, we summarize recent progress in terms of understanding ovarian injury, the effects of drug application and strategies to improve ovarian function in women with SLE. This review could be helpful to precisely cure SLE in women desiring to have offspring.

Blocking TGFßR synergistically enhances anti-tumor effects of anti-PD-1 antibody in a mouse model of incomplete thermal ablation.

The mechanism of early tumor recurrence after incomplete microwave ablation (iMWA) is poorly understood. The anti-programmed cell death protein 1 (anti-PD-1) monotherapy is reported to be ineffective to prevent the progression of residual tumor resulted from iMWA. Transforming growth factor-ß (TGFß) signaling pathway plays an important role in tumorigenesis and development. We assume blocking transforming growth factor-ß receptor (TGFßR) after incomplete iMWA may synergistically enhance the effect of anti-PD-1 antibody to prevent the progression of residual tumor. We construct an iMWA model with mice harboring Hepa1-6 derived xenograft. The Tgfb1 expression and phosphorylated-Smad3 protein expression is upregulated in the residual tumor after iMWA. With the application of TGFßR inhibitor SB431542, the cell proliferation potential, the tumor growth, the mRNA expression of epithelial mesenchymal transition (EMT) markers including Cdh2, and Vim, and cancer stem cell marker Epcam, and the infiltrating Treg cells are reduced in the residual tumor tissue. In addition, iMWA combined with TGFßR blocker and anti-PD-1 antibody further decreases the cell proliferation, tumor growth, expression of EMT markers and cancer stem cell marker, and the infiltrating Treg cells in the residual tumor tissue. Blocking TGFßR may alleviate the pro-tumoral effect of tumor microenvironment thereby significantly prevents the progression of residual tumor tissue. Our study indicates that blocking TGFßR may be a novel therapeutic strategy to enhance the effect of anti-PD-1 antibody to prevent residual hepatocellular carcinoma (HCC) progression after iMWA.

Effects of the combination of various pharmacological treatments and exercise on knee osteoarthritis: a systematic review and network meta-analysis.

Purpose: The combination of pharmacological and non-pharmacological interventions is strongly recommended by current guidelines for knee osteoarthritis. However, few systematic reviews have validated their combined efficacy. In this study, we investigated the effects of the combination of pharmacological agents and exercise on knee osteoarthritis. Methods: Randomized controlled trials that investigated the efficacy of pharmacological agents combined with exercise for knee osteoarthritis were searched in PubMed, Embase, and Cochrane Library up to February 2024. The network meta-analysis was performed within the frequentist framework. Standardized mean difference (SMD) with 95% CI was estimated for pain and function. Grading of recommendations, assessment, development, and evaluations were used to evaluate the certainty of evidence. Results: In total, 71 studies were included. The combination therapy outperformed pharmacological or exercise therapy alone. Among the various pharmacological agents combined with exercise, mesenchymal stem cell injection was ranked the best for short-term pain reduction (SMD: -1.53, 95% CI: -1.92 to -1.13, high certainty), followed by botulinum toxin A, dextrose, and platelet-rich plasma. For long-term pain relief, dextrose prolotherapy was the optimal (SMD: -1.76, 95% CI: -2.65 to -0.88, moderate certainty), followed by mesenchymal stem cells, platelet rich in growth factor, and platelet-rich plasma. Conclusion: Exercise programs should be incorporated into clinical practice and trial design. For patients undergoing exercise therapies, mesenchymal stem cell, dextrose, platelet-rich plasma, platelet rich in growth factor, and botulinum toxin A may be the optimal agents.

Functional variation among mesenchymal stem cells derived from different tissue sources.

Background: Mesenchymal stem cells (MSCs) are increasingly recognized for their regenerative potential. However, their clinical application is hindered by their inherent variability, which is influenced by various factors, such as the tissue source, culture conditions, and passage number. Methods: MSCs were sourced from clinically relevant tissues, including adipose tissue-derived MSCs (ADMSCs, n = 2), chorionic villi-derived MSCs (CMMSCs, n = 2), amniotic membrane-derived MSCs (AMMSCs, n = 3), and umbilical cord-derived MSCs (UCMSCs, n = 3). Passages included the umbilical cord at P0 (UCMSCP0, n = 2), P3 (UCMSCP3, n = 2), and P5 (UCMSCP5, n = 2) as well as the umbilical cord at P5 cultured under low-oxygen conditions (UCMSCP5L, n = 2). Results: We observed that MSCs from different tissue origins clustered into six distinct functional subpopulations, each with varying proportions. Notably, ADMSCs exhibited a higher proportion of subpopulations associated with vascular regeneration, suggesting that they are beneficial for applications in vascular regeneration. Additionally, CMMSCs had a high proportion of subpopulations associated with reproductive processes. UCMSCP5 and UCMSCP5L had higher proportions of subpopulations related to female reproductive function than those for earlier passages. Furthermore, UCMSCP5L, cultured under low-oxygen (hypoxic) conditions, had a high proportion of subpopulations associated with pro-angiogenic characteristics, with implications for optimizing vascular regeneration. Conclusions: This study revealed variation in the distribution of MSC subpopulations among different tissue sources, passages, and culture conditions, including differences in functions related to vascular and reproductive system regeneration. These findings hold promise for personalized regenerative medicine and may lead to more effective clinical treatments across a spectrum of medical conditions.

Desmoid Tumor of the Rectus Abdominis Muscle: A Case Report.

Desmoid tumors, also referred to as aggressive fibromatosis, represent an uncommon form of fibroblastic proliferation. These neoplasms may arise within any musculoaponeurotic structure throughout the body. They are classified as benign due to several distinctive features: histologically, they exhibit regular mitotic activity and are devoid of metastatic potential. Computed tomography (CT) remains the definitive modality for precise diagnosis, and surgical excision is strongly advised. This account details the manifestation of a desmoid tumor located in the anterior abdominal wall of a 31-year-old female patient who notably lacks any prior surgical interventions. The surgical intervention entailed the excision of the neoplasm and subsequent reconstruction of the abdominal wall utilizing a polypropylene mesh. Postoperatively, the patient was released from the medical facility after a period of three days, having experienced no post-surgical complications. This was followed by a six-month interval free of any adverse events.

A Giant Malignant Solitary Fibrous Tumor of the Pancreas: A Case Report and Review of the Literature.

We present a case report of a giant solitary fibrous tumor (SFT) with a review of the literature and discuss its biological features and diagnosis. A 43-year-old man presented to our emergency department with abdominal pain and distension with an evolution of two days. Contrast-enhanced computed tomography (CT) showed a large, well-circumscribed semisolid mass (12 cm x 10 cm x 12 cm) localized in the pancreatic head. The histological diagnosis obtained by endoscopic ultrasound-guided trans-duodenal tumor biopsy with fine-needle aspiration showed proliferating short spindle-shaped cells, suggesting a mesenchymal neoplasia of low grade. We proceeded to a Whipple surgical technique. The histopathological study of the resected tumor confirmed proliferating spindle-shaped cells in the tissue, and one mitotic figure was observed in 10 high-power fields (HPFs). Immunostaining was positive for CD34 and STAT-6. The histological diagnosis was a malignant pancreatic SFT. In the six months posterior to the surgical procedure, the patient has been free of recurrent disease. Preoperative diagnosis is difficult and requires comprehensive evidence including clinical, immunohistochemistry, and histological features. Since there are currently no recognized best practices, we advise total surgical excision and careful clinical monitoring.

Characterization of disease-specific alterations in metabolites and effects of mesenchymal stromal cells on dystrophic muscles.

Introduction: Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding gene that leads to muscle necrosis and degeneration with chronic inflammation during growth, resulting in progressive generalized weakness of the skeletal and cardiac muscles. We previously demonstrated the therapeutic effects of systemic administration of dental pulp mesenchymal stromal cells (DPSCs) in a DMD animal model. We showed preservation of long-term muscle function and slowing of disease progression. However, little is known regarding the effects of cell therapy on the metabolic abnormalities in DMD. Therefore, here, we aimed to investigate the mechanisms underlying the immunosuppressive effects of DPSCs and their influence on DMD metabolism. Methods: A comprehensive metabolomics-based approach was employed, and an ingenuity pathway analysis was performed to identify dystrophy-specific metabolomic impairments in the mdx mice to assess the therapeutic response to our established systemic DPSC-mediated cell therapy approach. Results and Discussion: We identified DMD-specific impairments in metabolites and their responses to systemic DPSC treatment. Our results demonstrate the feasibility of the metabolomics-based approach and provide insights into the therapeutic effects of DPSCs in DMD. Our findings could help to identify molecular marker targets for therapeutic intervention and predict long-term therapeutic efficacy.

Mechanisms and therapeutic research progress in intestinal fibrosis.

Intestinal fibrosis is a common complication of chronic intestinal diseases with the characteristics of fibroblast proliferation and extracellular matrix deposition after chronic inflammation, leading to lumen narrowing, structural and functional damage to the intestines, and life inconvenience for the patients. However, anti-inflammatory drugs are currently generally not effective in overcoming intestinal fibrosis making surgery the main treatment method. The development of intestinal fibrosis is a slow process and its onset may be the result of the combined action of inflammatory cells, local cytokines, and intestinal stromal cells. The aim of this study is to elucidate the pathogenesis [e.g., extracellular matrix (ECM), cytokines and chemokines, epithelial-mesenchymal transition (EMT), differentiation of fibroblast to myofibroblast and intestinal microbiota] underlying the development of intestinal fibrosis and to explore therapeutic advances (such as regulating ECM, cytokines, chemokines, EMT, differentiation of fibroblast to myofibroblast and targeting TGF-ß) based on the pathogenesis in order to gain new insights into the prevention and treatment of intestinal fibrosis.

Comments and illustrations of the European Federation of Societies for Ultrasound in Medicine guidelines: Rare pancreatic tumors, ultrasound and contrast-enhanced ultrasound features-Malignant mesenchymal tumors.

Rare malignant mesenchymal pancreatic tumors are systematized and reported in this review. The focus is on the appearance on imaging. The present overview summarizes the data and shows that not every pancreatic tumor corresponds to the most common entities of ductal adenocarcinoma or neuroendocrine tumor.

Controversies regarding transplantation of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) have tantalized regenerative medicine with their therapeutic potential, yet a cloud of controversies looms over their clinical transplantation. This comprehensive review navigates the intricate landscape of MSC controversies, drawing upon 15 years of clinical experience and research. We delve into the fundamental properties of MSCs, exploring their unique immunomodulatory capabilities and surface markers. The heart of our inquiry lies in the controversial applications of MSC transplantation, including the perennial debate between autologous and allogeneic sources, concerns about efficacy, and lingering safety apprehensions. Moreover, we unravel the enigmatic mechanisms surrounding MSC transplantation, such as homing, integration, and the delicate balance between differentiation and paracrine effects. We also assess the current status of clinical trials and the ever-evolving regulatory landscape. As we peer into the future, we examine emerging trends, envisioning personalized medicine and innovative delivery methods. Our review provides a balanced and informed perspective on the controversies, offering readers a clear understanding of the complexities, challenges, and potential solutions in MSC transplantation.

CCL2 promotes EGFR-TKIs resistance in non-small cell lung cancer via the AKT-EMT pathway.

Acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) represents a primary cause of treatment failure in non-small cell lung cancer (NSCLC) patients. Chemokine (C-C motif) ligand 2 (CCL2) is recently found to play a pivotal role in determining anti-cancer treatment response. However, the role and mechanism of CCL2 in the development of EGFR-TKIs resistance have not been fully elucidated. In the present study, we focus on the function of CCL2 in the development of acquired resistance to EGFR-TKIs in NSCLC cells. Our results show that CCL2 is aberrantly upregulated in EGFR-TKIs-resistant NSCLC cells and that CCL2 overexpression significantly diminishes sensitivity to EGFR-TKIs. Conversely, CCL2 suppression by CCL2 synthesis inhibitor, bindarit, or CCL2 knockdown can reverse this resistance. CCL2 upregulation can also lead to enhanced migration and increased expressions of epithelial-mesenchymal transition (EMT) markers in EGFR-TKI-resistant NSCLC cells, which could also be rescued by CCL2 knockdown or inhibition. Furthermore, our findings suggest that CCL2-dependent EGFR-TKIs resistance involves the AKT-EMT signaling pathway; inhibition of this pathway effectively attenuates CCL2-induced cell migration and EMT marker expression. In summary, CCL2 promotes the development of acquired EGFR-TKIs resistance and EMT while activating AKT signaling in NSCLC. These insights suggest a promising avenue for the development of CCL2-targeted therapies that prevent EGFR-TKIs resistance in NSCLC.

Biomimetic Metal-Organic Framework Gated Nanoplatform for Sonodynamic Therapy against Extensively Drug Resistant Bacterial Lung Infection.

Novel antimicrobial strategies are urgently needed to treat extensively drug-resistant (XDR) bacterial infections due to the high mortality rate and lack of effective therapeutic agents. Herein, nanoengineered human umbilical cord mesenchymal stem cells (hUC-MSCs), named PMZMU, are designed as a sonosensitizer for synergistic sonodynamic-nano-antimicrobial therapy against gram-negative XDR bacteria. PMZMU is composed of a bacterial targeting peptide (UBI29-41) modified hUC-MSCs membrane (MSCm), a sonosensitizer meso-tetra(4-car-boxyphenyl) porphine doped mesoporous organo-silica nanoparticle and an acidity-responsive metal-organic framework ZIF-8. This innovative formulation enables efficient loading of polymyxin B, reduces off-target drug release, increases circulation and targeting efficacy, and generates reactive oxygen species upon ultrasound irradiation. PMZMU exhibits remarkable in vitro inhibitory activity against four XDR bacteria: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa (PA), and Escherichia coli. Taking advantage of the bacterial targeting ability of UBI29-41 and the inflammatory chemotaxis of hUC-MSC, PMZMU can be precisely delivered to lung infection sites thereby augmenting polymyxin B concentration. PMZMU-mediated sonodynamic therapy significantly reduces bacterial burden, relieves inflammatory damage by promoting the polarization of macrophages toward M2 phenotype, and improves survival rates without introducing adverse events. Overall, this study offers promising strategies for treating deep-tissue XDR bacterial infections, and guides the design and optimization of biomimetic nanomedicine.

Adhesin Component Member STAG2 Enhances Cisplatin Tolerance in Colorectal Cancer Cells through the Epithelial-Mesenchymal Transition Pathway.

BACKGROUND: Platinum-based compounds are commonly used as an initial treatment for colorectal cancer (CRC). However, the development of drug resistance in patients with CRC necessitates the administration of high drug concentrations during clinical treatment, thereby augmenting the toxicity of platinum-based compounds and increasing the mortality rate. STAG2 is a significantly associated drug-resistance gene in many cancers, but it has not been studied in colorectal cancer. Therefore, the present study aimed to investigate the role and drug sensitivity of the cisplatin-resistant gene STAG2. METHODS: The effects of STAG2 on drug resistance and survival rates of patients with CRC were examined using the Genomics of Drug Sensitivity in Cancer (GDSC) and Kaplan-Meier (KM) plotter databases. Subsequently, a sh-STAG2-HT-29 cell line was generated using a knockdown test of STAG2, and the half-maximal inhibitory concentration (IC50) of the two cell lines was determined using a cell viability test. We then used various techniques, including the Cell Counting Kit-8 (CCK-8), plate cloning, 5-ethynyl-2'-deoxyuridine (EdU) fluorescence staining, flow cytometry for cell cycle detection, the scar assay, the Transwell invasion assay, and Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) fluorescence staining for apoptosis detection, to investigate the functionality of the four subgroups of cancer cell lines. Additionally, Western blotting (WB) was used to identify the potential pathways associated with the observed functional alterations. Finally, the phenotype, tumor weight, mouse weight, tumor volume, and tumor tissue structure of the developed tumors were assessed using the subcutaneous tumor formation method. RESULTS: Database analysis indicated that STAG2 plays a role in facilitating drug resistance among individuals with CRC. Furthermore, mutations in this gene lead to increased sensitivity to cisplatin, and its overexpression was associated with an unfavorable prognosis. Following the successful development of STAG2 knockdown cells, differences in IC50 concentrations were observed between HT-29 and sh-STAG2-HT-29 cells. A treatment concentration of 10 µM cisplatin was selected, and the proliferation, migration, and invasion capabilities of cancer cells decreased after STAG2 knockdown. Additionally, the sensitivity of the cells to cisplatin therapy was increased, which was potentially mediated by the epithelial-mesenchymal transition (EMT) pathway. In mice, the tumorigenic potential of HT-29 cells was reduced by STAG2 knockdown, accompanied by a decrease in resistance to cisplatin therapy. CONCLUSION: STAG2 acts as a proto-oncogene in CRC, and its resistance to cisplatin therapy is more prominent. This study confirmed the role of STAG2 in CRC and provided a theoretical basis for the further development of STAG2 as an auxiliary criterion for determining dosage when patients are treated with platinum drugs.

Lovastatin Combination Therapy Increases the Survival and Proliferation of Rat Bone Marrow-Derived Mesenchymal Stem Cells Against the Inflammatory Activity of Lipopolysaccharide.

Oxidative stress hurts the survival of transplanted mesenchymal stem cells (MSCs). Lipopolysaccharide (LPS) preconditioning inhibits apoptotic death in MSCs. Also, Lovastatin's protective effect was reported on MSCs. Here, we investigated the potential of LPS and Lovastatin combination therapy on the survival and proliferation of MSCs. MSCs harvested from adult rats (240-260 g) femur and tibia bone marrow. Third passage MSCs were divided into 6 groups control group, LPS, LPS + Lovastatin (10 and 15 µM), and Lovastatin (10 and 15 µM). Cell survival and proliferation were assessed using an MTT assay 24 h after LPS, Lovastatin, or LPS + Lovastatin treatment. Also, Malondialdehyde (MDA) as a lipid peroxidation marker and antioxidant enzymes such as Glutathione peroxidase (GPX) and Superoxide dismutase (SOD) activity levels evaluated. Finally, the expression level of tumor protein P53 (P53) and octamer-binding transcription factor 4 (OCT4) genes were measured by qRT-PCR test. Lovastatin 10 µM potentiated proliferation and survival of MSCs. It can increase the activity of GPX and SOD. 10 µM Lovastatin could not affect MDA amounts but decreased the expression levels of P53 and Oct4 significantly. Nevertheless, treatment with LPS reduced the survival and proliferation of MSCs, along with a significant reduction in GPX activity. LPS + Lovastatin could increase SOD activity, however, GPX enzyme activity and MSCs proliferation did not change so, and it was not effective. We propose Lovastatin at the dose of 10 µM as a suitable combination agent to increase the survival and proliferation of MSCs in oxidative stress conditions.