Efficacy of Mesenchymal Stem Cell-Derived Extracellular Vesicles in the Animal Model of Female Reproductive Diseases: A Meta-Analysis.

BACKGROUND: Female reproductive disorders, such as premature ovarian insufficiency (POI), intrauterine adhesion (IUA) or thin endometrium, and polycystic ovary syndrome (PCOS), are the main factors affecting fertility. Mesenchymal stem cells derived-extracellular vesicles (MSC-EVs) have gained traction as a new potential treatment and were widely studied in these diseases. However, their impact is still not fully clear. METHODS: A systematic search of PubMed, Web of Science, EMBASE, the Chinese National Knowledge of Infrastructure, and WanFang online databases was performed up to September 27th, 2022, and the studies of MSC-EVs-based therapy on the animal models of female reproductive diseases were included. The primary outcomes were anti-Müllerian hormone (AMH) in POI and endometrial thickness in IUA, respectively. RESULTS: 28 studies (POI, N = 15; IUA, N = 13) were included. For POI, MSC-EVs improved AMH at 2 weeks (SMD 3.40, 95% CI 2.02 to 4.77) and 4 weeks (SMD 5.39, 95% CI 3.43 to 7.36) compared with placebo, and no difference was found when compared with MSCs in AMH (SMD -2.03, 95% CI -4.25 to 0.18). For IUA, MSC-EVs treatment could increase the endometrial thickness at 2 weeks (WMD 132.36, 95% CI 118.99 to 145.74), but no improvement was found at 4 weeks (WMD 166.18, 95% CI -21.44 to 353.79). The combination of MSC-EVs with hyaluronic acid or collagen had a better effect on the endometrial thickness (WMD 105.31, 95% CI 85.49 to 125.13) and glands (WMD 8.74, 95% CI 1.34 to 16.15) than MSC-EVs alone. The medium dose of EVs may allow for great benefits in both POI and IUA. CONCLUSIONS: MSC-EVs treatment could improve the functional and structural outcomes in female reproductive disorders. The combination of MSC-EVs with HA or collagen may enhance the effect. These findings can accelerate the translation of MSC-EVs treatment to human clinical trials.

Two Ferulic Acid Derivatives Inhibit Neuroinflammatory Response in Human HMC3 Microglial Cells via NF-κB Signaling Pathway.

Various physiological and pathological changes are related to the occurrence and development of neurodegenerative diseases. Neuroinflammation is a major trigger and exacerbation of neurodegenerative diseases. One of the main symptoms of neuritis is the activation of microglia. Thus, to alleviate the occurrence of neuroinflammatory diseases, an important method is to inhibit the abnormal activation of microglia. This research evaluated the inhibitory effect of trans-ferulic acid (TJZ-1) and methyl ferulate (TJZ-2), isolated from Zanthoxylum armatum, on neuroinflammation, by establishing the human HMC3 microglial cell neuroinflammation model induced by lipopolysaccharide (LPS). The results showed both compounds significantly inhibited the production and expression of nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) contents, and increased the level of anti-inflammatory factor ß-endorphin (ß-EP). Furthermore, TJZ-1 and TJZ-2 can inhibit LPS-induced activation of nuclear factor kappa B (NF-κB). It was found that of two ferulic acid derivatives, both had anti-neuroinflammatory effects by inhibiting the NF-κB signaling pathway and regulating the release of inflammatory mediators, such as NO, TNF-α, IL-1ß, and ß-EP. This is the first report that demonstrates that TJZ-1 and TJZ-2 had inhibitory effects on LPS-induced neuroinflammation in human HMC3 microglial cells, which indicates that two ferulic acid derivates from Z. armatum could be used as potential anti-neuroinflammatory agents.

Surgical management of Marjolin ulcer with the anterolateral thigh free flap: a retrospective analysis.

INTRODUCTION: MU is an aggressive entity, and extended surgical resection is the primary treatment. The defects from an MU extended resection need repair using free flaps, of which the ALT free flap is the most common. OBJECTIVE: This study described the feasibility and application value of the ALT free flap in repairing defects after MU resection. MATERIALS AND METHODS: Fifteen patients with MU had repairs with ALT free flaps and were treated by the authors' unit from June 2015 through June 2021. All defects were repaired with 1 ALT free flap except for 1 case that required 2 flaps. RESULTS: The average age of the 11 male and 4 female patients was 52 years (range, 36-71 years). Defect sizes ranged from 8 cm × 5.5 cm to 21 cm × 13.5 cm (mean size, 10.9 cm × 6.5 cm). Flap sizes ranged from 10 cm × 7.5 cm to 23 cm × 15.5 cm (mean size, 12.9 cm × 8.5 cm). All flaps survived completely except for 1 flap in which re-exploration was needed. CONCLUSIONS: The individualized ALT free flap may be selected based on the receiving area characteristics and has certain clinical application value in defect repair after MU resection.

GAS6-mediated dialogue between decidual stromal cells and macrophages is essential for early pregnancy maintenance by inducing M2-like polarization and cell proliferation of decidual macrophages.

Maternal immunotolerance towards the semi-allogeneic foetus is critical for normal pregnancy (NP). As a secretory protein, growth arrest-specific factor 6 (GAS6) promotes cancer progression by inducing the conversion of tumour-associated macrophages to an immunosuppressive M2-like phenotype. However, little is known about whether GAS6 regulates decidual macrophages (dMφs) in the early maternal-foetal interface. In this study, first-trimester decidual tissues were obtained from normal pregnant women undergoing elective terminations and patients with miscarriages. The expression of GAS6 and its receptors (AXL, TYRO3 and MERTK) in decidua and GAS6 secretion by decidual stromal cells (DSCs) was measured. Then, we investigated the effect of recombinant human GAS6 (rhGAS6) on dMφs isolated from NP and THP-1 cells, and revealed the underlying mechanism. Both the expression of GAS6 in DSCs and MERTK in dMφs, in addition to GAS6 secretion by DSCs, was found to be significantly decreased in miscarriage patients compared to that in NPs. Additionally, we observed that rhGAS6 polarized dMφs and THP-1 cells towards an M2-like phenotype, as evidenced by the up-regulated CD163 expression. Moreover, rhGAS6 enhanced the clearance of toxic cell-free haemoglobin by dMφs by up-regulating CD163 expression, and rhGAS6 also boosted cell proliferation of dMφs and THP-1 cells. Finally, we demonstrated that rhGAS6 stimulated CD163 expression and cell proliferation by activating the PI3K/Akt signalling pathway. Collectively, these findings suggest that GAS6-mediated dialogue between DSCs and dMφs is crucial for the establishment and maintenance of maternal-foetal immunotolerance, and decreased GAS6 secretion by DSCs may lead to the occurrence of miscarriage in the first trimester.

Transplantation of Human Amnion Epithelial Cells Improves Endometrial Regeneration in Rat Model of Intrauterine Adhesions.

Intrauterine adhesions (IUAs) are characterized by the injury of endometrium due to curettage and/or endometritis. The loss of functional endometrium in uterine cavity usually results in hypomenorrhea, amenorrhea, infertility, and/or recurrent pregnancy loss. Recently, stem cell transplantation has been applied to promote the endometrial regeneration. Human amnion epithelial cells (hAECs) have been shown to have stem cell characteristics. In this study, we found that PKH26-labeled hAECs were mainly distributed in the basal layer of endometrium after transplantation, and hAEC transplantation, including uterine injection and tail vein injection, could increase pregnancy rate and the number of embryos in rat model of IUAs. Moreover, hAEC transplantation was demonstrated to increase the endometrial thickness, promote the proliferation of glands and blood vessels, and decrease fibrotic areas in the endometrium. The immunohistochemical and quantitative polymerase chain reaction analysis showed the upregulated expression of growth factors, such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1) after hAEC transplantation; and the downregulated expression of collagen type I alpha 1 (COL1A1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and transforming growth factor-ß (TGF-ß), all of which are associated with the extracellular matrix (ECM) deposition after hAEC transplantation. The mRNA sequencing indicated that platelet-derived growth factor-C (PDGF-C), thrombospondin-1 (THBS1), connective tissue growth factor (CTGF), Wnt5a, and Snai2 were significantly modulated in treatment groups. These results indicate that hAEC transplantation promotes endometrial regeneration and the restoration of fertility in rat model of IUAs.

miR-27b-3p/MARCH7 regulates invasion and metastasis of endometrial cancer cells through Snail-mediated pathway.

Ubiquitin E3 ligase membrane-associated RING-CH-type finger 7 (MARCH7), also known as axotrophin, was originally identified in mouse embryonic stem cells. MARCH7 is involved in T-cell proliferation, neuronal development, and the immune system. However, its role in endometrial cancer (EC) remains unclear. This study aimed to investigate the role of MARCH7 in EC. Quantitative polymerase chain reaction, immunohistochemistry, and western blot analysis were used to examine the expression of MARCH7, E-cadherin, Snail, and Vimentin in EC cell lines or clinical specimens. The role of MARCH7 in maintaining EC cell malignant phenotype was determined by transwell assay and using xenograft tumor model. Dual-luciferase reporter gene assay was performed to determine whether MARCH7 is an authentic target of miR-27b-3p. Our data showed that the expression level of MARCH7 in EC tissues was higher than that in normal endometrium tissues. The level of MARCH7 was positively associated with that of Snail and Vimentin, clinical stage, and histological grade, while negatively associated with that of E-cadherin. Knockdown of MARCH7 inhibited the invasion and metastasis of EC cells in vitro and in vivo. The opposite effect was observed after overexpressing MARCH7. MARCH7 promoted invasion and metastasis of EC cells via the Snail-mediated pathway. Furthermore, MARCH7 was demonstrated to be an authentic target of miR-27b-3p, and miR-27b-3p decreased the stimulus effect induced by MARCH7. These data indicate that MARCH7 may be an oncogenic factor and a therapeutic target for EC. miR-27b-3p/MARCH7 may also regulate EC cell invasion and metastasis via the Snail-mediated pathway.

Cisplatin and photodynamic therapy exert synergistic inhibitory effects on small-cell lung cancer cell viability and xenograft tumor growth.

Lung cancer is the leading cause of cancer death worldwide. Small-cell lung cancer (SCLC) is an aggressive type of lung cancer that shows an overall 5-year survival rate below 10%. Although chemotherapy using cisplatin has been proven effective in SCLC treatment, conventional dose of cisplatin causes adverse side effects. Photodynamic therapy, a form of non-ionizing radiation therapy, is increasingly used alone or in combination with other therapeutics in cancer treatment. Herein, we aimed to address whether low dose cisplatin combination with PDT can effectively induce SCLC cell death by using in vitro cultured human SCLC NCI-H446 cells and in vivo tumor xenograft model. We found that both cisplatin and PDT showed dose-dependent cytotoxic effects in NCI-H446 cells. Importantly, co-treatment with low dose cisplatin (1 µM) and PDT (1.25 J/cm2) synergistically inhibited cell viability and cell migration. We further showed that the combined therapy induced a higher level of intracellular ROS in cultured NCI-H446 cells. Moreover, the synergistic effect by cisplatin and PDT was recapitulated in tumor xenograft as revealed by a more robust increase in the staining of TUNEL (a marker of cell death) and decrease in tumor volume. Taken together, our findings suggest that low dose cisplatin combination with PDT can be an effective therapeutic modality in the treatment of SCLC patients.

Enzyme activated photodynamic therapy for methicillin-resistant Staphylococcus aureus infection both inv itro and in vivo.

In recent years, methicillin-resistant Staphylococcus aureus (MRSA) has become one of the most common multi-drug resistant bacteria in both hospital and community. The aim of this study is to investigate the selective inhibition of MRSA by a modified photosensitizer (LAEtNBS) in vitro and the efficacy of MRSA infection treatment by photodynamic therapy (PDT) with LAEtNBS in vivo. LAEtNBS was synthesized by adding a cationic photosensitizer molecule (EtNBS-COOH) and a quencher molecule to two side chains of cephalosporin, which was then shown to have similar absorption and emission wavelengths with EtNBS-COOH, but suppressed yields of fluorescence quantum and singlet oxygen. The selective inactivation and less phototoxicity of LAEtNBS, compared to that of EtNBS-COOH, were assessed and confirmed by conducting PDT to two Staphylococcus aureus strains and human skin cells at a fluence of 15 J/cm(2) with 640±10 nm LED light. Furthermore, using mouse skin wound model infected with 10(8) CFU of MRSA, we found that both LAEtNBS and EtNBS-COOH were able to treat MRSA infection and enhance wound repair. However, there was no significant difference in the two photosensitizers that might be due to the environment in vivo. Modification of the photosensitizer will be very beneficial for developing new strategies to treat drug resistant bacterial infection with less harm to host tissue.