Effect of hydrocolloid dressings in the management of different grades of pressure wound ulcers in critically ill adult subjects: A meta-analysis.

A meta-analysis was implemented to appraise the effect of hydrocolloid dressings (HCDs) in the management of different grades of pressure wound ulcers (PWUs) in critically ill adult subjects (CIUSs). Inclusive literature research until April 2023 was done, and 969 interconnected researches were revised. The 8 picked researches, enclosed 679 critically ill adult persons at the utilized researchers' starting point; 355 of them were utilizing HCDs, and 324 were controls. Odds ratio (OR) and 95% confidence intervals (CIs) were utilized to appraise the consequences of HCDs in treating CIUSs by the dichotomous approach and a fixed or random model. HCDs had significantly higher PWU complete healing (OR, 2.15; 95% CI, 1.54-3.02, p < 0.001), PWU stage II ulcers complete healing (OR, 2.82; 95% CI, 1.40-5.69, p = 0.004), and PWU stage III ulcers complete healing (OR, 3.73; 95% CI, 1.23-11.35, p = 0.02) compared to control in critically ill adult persons. HCDs had significantly higher PWU complete healing, PWU stage II ulcers complete healing, and PWU stage III ulcers complete healing compared with control in critically ill adult persons. However, caution needs to be taken when interacting with its values since there was a low sample size of most of the chosen research found for the comparisons in the meta-analysis.

Effect of adjunctive prophylactic macrolides used at the caesarean section on endometritis and surgical site wound infection: A meta-analysis.

A meta-analysis investigation was executed to measure the outcome of adjunctive prophylactic macrolides (APM) used at caesarean section (CS) on endometritis and surgical site wound infection (SSWI). A comprehensive literature inspection till February 2023 was applied and 1023 interrelated investigations were reviewed. The 10 chosen investigations enclosed 22 676 females with CS were in the chosen investigations' starting point, 14 034 of them were utilising APM, and 8642 were utilising control. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to compute the value of the effect of APM used at CS on endometritis and SSWI by the dichotomous approaches and a fixed or random model. Adjunctive prophylactic macrolides had significantly lower SSWI (OR, 0.43; 95% CI, 0.34-0.55, P < .001), and endometritis (OR, 0.34; 95% CI, 0.20-0.60, P = .005) compared with those with control in females with CS. Adjunctive prophylactic macrolides had significantly lower SSWI, and endometritis compared with those with control in females with CS. However, care must be exercised when dealing with its values because of the low number of nominated investigations for the meta-analysis.

Siglec15 Checkpoint Blockade for Simultaneous Immunochemotherapy and Osteolysis Inhibition in Lung Adenocarcinoma Spinal Metastasis via a Hollow Nanoplatform.

Low responsiveness to anti-programmed death-1/programmed death-ligand 1 (anti-PD-1/PD-L1) for solid tumors indicates the presence of other immunosuppressive pathways. Siglec15, a newly discovered immune checkpoint, has been reported to repress immune responses in the tumor microenvironment (TME) and regulate osteoclast differentiation. However, the role of Siglec15 in the treatment for bone metastasis remains unclear. Herein, Siglec15 shows significantly higher expression in lung adenocarcinoma spinal metastasis (LUAD-SM) than in para-cancerous spinal tissues and primary LUAD. Subsequently, a TME-responsive hollow MnO2 nanoplatform (H-M) loaded with Siglec15 siRNA and cisplatin (H-M@siS15/Cis) is developed, and the surface is modified with an aspartic acid octapeptide (Asp8 ), thus allowing H-M to target spinal metastasis. High drug-loading capacity, good biocompatibility, effective tumor accumulation, and efficient Siglec15 silencing are demonstrated. Furthermore, the nanoparticles could reverse immunosuppression caused by tumor cells and tumor-associated macrophages (TAMs) and inhibit osteoclast differentiation via Siglec15 downregulation in vitro. In a LUAD-SM mouse model, H-M@siS15/Cis-Asp8 exhibits superior therapeutic efficacy via synergetic immunochemotherapy and osteolysis inhibition. Taken together, this single nanoplatform reveals the therapeutic potential of the new immune checkpoint Siglec15 in LUAD-SM and provides a strategy to treat this disease.

Dual-Phosphorescent Iridium(III) Complexes Extending Oxygen Sensing from Hypoxia to Hyperoxia.

Hypoxia and hyperoxia, referring to states of biological tissues in which oxygen supply is in sufficient and excessive, respectively, are often pathological conditions. Many luminescent oxygen probes have been developed for imaging intracellular and in vivo hypoxia, but their sensitivity toward hyperoxia becomes very low. Here we report a series of iridium(III) complexes in which limited internal conversion between two excited states results in dual phosphorescence from two different excited states upon excitation at a single wavelength. Structural manipulation of the complexes allows rational tuning of the dual-phosphorescence properties and the spectral profile response of the complexes toward oxygen. By manipulating the efficiency of internal conversion between the two emissive states, we obtained a complex exhibiting naked-eye distinguishable green, orange, and red emission in aqueous buffer solution under an atmosphere of N2, air, and O2, respectively. This complex is used for intracellular and in vivo oxygen sensing not only in the hypoxic region but also in normoxic and hyperoxic intervals. To the best of our knowledge, this is the first example of using a molecular probe for simultaneous bioimaging of hypoxia and hyperoxia.

Reprogramming the future: Capitalizing on in vitro embryo culture by advancing stem cell technologies in the fight against rare genetic disorders.

Capitalizing on breakthroughs in reproductive genetics, the utilization of in vitro embryo culture and stem cell technologies heralds a transformative era in addressing global challenges posed by rare genetic diseases. These cutting-edge practices illuminate the intricacies of early human development, elucidate the mechanisms behind rare diseases, and guide the development of potential therapies. Balancing this remarkable innovation with necessary ethical considerations, these technologies have the potential to revolutionize the trajectory of rare genetic disorders, transforming the landscape of diagnosis, treatment, and genetic counseling while offering renewed hope for affected individuals and families worldwide.

Effects of proxy solicitation and director ownership on directors' career consequences.

This study investigates how proxy solicitation and director ownership jointly affect directors' career consequences in Taiwan. We report that assent votes partly arising from proxies without shareholder voice increase the likelihood of departure for directors with higher ownership in firms soliciting proxies, especially for busy directors. Since proxy votes do not build extra reputation, this generates no spillover effect for both non-busy and busy directors. Overall, we support the arguments based on prior studies that votes holding information on shareholder voice have implications on directors' careers. Furthermore, different board seats provide unequal incentives for busy directors.

Whether long-term use of proton pump inhibitor increases the risk of precancerous lesions in the stomach: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: To evaluate through meta-analysis whether long-term use of proton pump inhibitor (PPI) increases the risk of precancerous lesions in the stomach. METHODS: Randomized controlled trials that compared the occurrence and progression of precancerous lesions in patients receiving PPI treatment versus non-PPI treatment were retrieved from CNKI, VIP, Wanfang, CBM, Pubmed, Embase, Web of Science, and Cochrane Library databases (from database inception to May 1, 2023). The Revman 5.3 and STATA 17.0 software were used for analysis, and subgroup analysis was conducted based on follow-up time (≤12 months and > 12 months) and lesion type (atrophic gastritis, intestinal metaplasia, and epithelial dysplasia). RESULTS: Six randomized controlled trials with a total of 1623 cases were included, including 1015 cases in the experimental group and 608 cases in the control group. The meta-analysis results showed that the overall abnormal lesion rate combined with statistical relative risk (RR) = 1.31 (0.85-2.02), P = .23. Subgroup analysis showed that the follow-up time > 12 months combined result was RR = 2.21 (1.47-3.33), P = .0001, the intestinal metaplasia group combined result was RR = 1.96 (0.91-2.47), P = .04. CONCLUSION SUBSECTIONS: During long-term follow-up, patients using PPI exhibited a significantly higher incidence of overall abnormal lesions compared to the control group, particularly with a higher risk observed for intestinal metaplasia. However, there were no statistically significant differences between the 2 groups in terms of short-term follow-up and other types of lesions. It is important to exercise caution when interpreting these findings due to the limited number of nominated investigations included in the meta-analysis.

Piezoresistive MXene/Silk fibroin nanocomposite hydrogel for accelerating bone regeneration by Re-establishing electrical microenvironment.

The electrical microenvironment plays an important role in bone repair. However, the underlying mechanism by which electrical stimulation (ES) promotes bone regeneration remains unclear, limiting the design of bone microenvironment-specific electroactive materials. Herein, by simple co-incubation in aqueous suspensions at physiological temperatures, biocompatible regenerated silk fibroin (RSF) is found to assemble into nanofibrils with a ß-sheet structure on MXene nanosheets, which has been reported to inhibit the restacking and oxidation of MXene. An electroactive hydrogel based on RSF and bioencapsulated MXene is thus prepared to promote efficient bone regeneration. This MXene/RSF hydrogel also acts as a piezoresistive pressure transducer, which can potentially be utilized to monitor the electrophysiological microenvironment. RNA sequencing is performed to explore the underlying mechanisms, which can activate Ca2+/CALM signaling in favor of the direct osteogenesis process. ES is found to facilitate indirect osteogenesis by promoting the polarization of M2 macrophages, as well as stimulating the neogenesis and migration of endotheliocytes. Consistent improvements in bone regeneration and angiogenesis are observed with MXene/RSF hydrogels under ES in vivo. Collectively, the MXene/RSF hydrogel provides a distinctive and promising strategy for promoting direct osteogenesis, regulating immune microenvironment and neovascularization under ES, leading to re-establish electrical microenvironment for bone regeneration.

Precise manipulation of circadian clock using MnO2 nanocapsules to amplify photodynamic therapy for osteosarcoma.

Circadian rhythm (CR) disruption contributes to tumor initiation and progression, however the pharmacological targeting of circadian regulators reversely inhibits tumor growth. Precisely controlling CR in tumor cells is urgently required to investigate the exact role of CR interruption in tumor therapy. Herein, based on KL001, a small molecule that specifically interacts with the clock gene cryptochrome (CRY) functioning at disruption of CR, we fabricated a hollow MnO2 nanocapsule carrying KL001 and photosensitizer BODIPY with the modification of alendronate (ALD) on the surface (H-MnSiO/K&B-ALD) for osteosarcoma (OS) targeting. The H-MnSiO/K&B-ALD nanoparticles reduced the CR amplitude in OS cells without affecting cell proliferation. Furthermore, nanoparticles-controlled oxygen consumption by inhibiting mitochondrial respiration via CR disruption, thus partially overcoming the hypoxia limitation for photodynamic therapy (PDT) and significantly promoting PDT efficacy. An orthotopic OS model demonstrated that KL001 significantly enhanced the inhibitory effect of H-MnSiO/K&B-ALD nanoparticles on tumor growth after laser irradiation. CR disruption and oxygen level enhancement induced by H-MnSiO/K&B-ALD nanoparticles under laser irradiation were also confirmed in vivo. This discovery first demonstrated the potential of CR controlling for tumor PDT ablation and provided a promising strategy for overcoming tumor hypoxia.

Effect of Bushen Antai recipe on pyroptosis mechanism of subclinical hypothyroidism decidual cells in early pregnancy.

Background: Subclinical hypothyroidism (SH) is common during pregnancy. It is not clear whether decidual cells in SH undergo pyroptosis during pregnancy. This study aimed to investigate the possible mechanism of Bushen Antai recipe (BAR) in the treatment of SH in early pregnancy and the relationship between SH during pregnancy and decidual cell pyroptosis through a rat model. Methods: A total of 60 female rats were divided into control group, model group, levothyroxine (L-T4) group, low-dose BAR group (6 g/kg), medium-dose BAR group (12 g/kg), and high-dose BAR group (24 g/kg). The control group underwent pseudothyroidectomy, while the remaining groups established nonpregnant SH rat models. Except for the blank control group, rats were successfully established with SH models during pregnancy. The control group and the model group were treated with saline or BAR. The animals were sacrificed 12 hours after the last administration. The levels of serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), interleukin-1ß (IL-1ß), and interleukin-18 (IL-18) were detected by enzyme-linked immunosorbent assay (ELISA). Western blot was used to detect the expression of decidual nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, Caspase-1, and porin family proteins. Results: There was no significant difference in serum FT4 among groups (P>0.05). Compared with the control group, serum TSH, IL-1ß, IL-18, and NLRP3, Caspase-1, and gasdermin D (GSDMD) proteins in the decidua of the model group were significantly increased (P<0.05). Compared with the model group, the L-T4 group and the high-dose BAR group could significantly decrease the levels of serum TSH, IL-1ß, IL-18, and NLRP3, Caspase-1, and GSDMD in decidual tissue (P<0.05). The medium dose of BAR could significantly decrease the levels of TSH, NLRP3, Caspase-1, and GSDMD (P<0.05), and the low dose group of BAR significantly decreased the levels of TSH, NLRP3, and GSDMD (P<0.05). Among them, the high-dose group of BAR had the best reducing effect on IL-18, NLRP3, Caspase-1, and GSDMD. Conclusions: The decidual cells of SH rats in early pregnancy underwent pyroptosis with a high inflammatory response. BAR could improve TSH level in SH during pregnancy, inhibit decidual cell pyroptosis, and reduce the expression of inflammatory factors.

Ultra-early endovascular treatment improves prognosis in High grade aneurysmal subarachnoid hemorrhage: A single-center retrospective study.

Background: The long-term survival prognosis of patients with high-grade (Hunt-Hess grade IV-V or World Federation of Neurosurgical Societies grade IV-V) aneurysmal subarachnoid hemorrhage (aSAH) is generally poor, and the association between endovascular treatment timing and the prognosis of high-grade aSAH has not been explored in depth. This retrospective cohort study aimed to determine whether endovascular treatment within 24 h of high-grade aSAH is associated with a better prognosis. Methods: We retrospectively analyzed the clinical data of patients with high-grade aSAH who were admitted to our institution between January 2018 and January 2021. The Modified Rankin Scale score was used to assess the 6-month prognosis of patients. Univariate and multivariate logistic regression analyses were used to identify the factors associated with prognosis. The area under the receiver operating characteristic (ROC) curve was used to assess the model's discriminatory ability. Results: Eighty-six patients were included in the study. In the multivariate analysis, the timing of endovascular treatment (odds ratio = 7.003 [1.800-27.242], P = 0.005) was an independent risk factor for prognosis. The ROC curve showed that the predictive power of the timing of endovascular treatment was 0.744, the best cut-off value was 12.5 h, and the corresponding sensitivity and specificity were 71.4 and 70.5%, respectively. Hydrocephalus (P = 0.005) and pulmonary infection (P = 0.029) were also associated with prognosis. In addition, cerebrospinal fluid drainage immediately after endovascular treatment had a significant effect on reducing hydrocephalus formation. Conclusions: Endovascular therapy within 24 h is feasible and improves the prognosis of patients with high-grade aSAH.

Electroacupuncture improves endometrial receptivity through miRNA-223-3p-mediated regulation of leukemia inhibitory factor / signal transducer and activator of transcription 3 signaling pathway.

Ovulation-inducing drugs such as endogenous steroids could reduce endometrial receptivity during the implantation window, resulting in lower clinical pregnancy rates and higher miscarriage rates. The present study employed electroacupuncture therapy along with different frequencies on elevating impaired endometrial receptivity to elucidate the mechanism therein. The rats were split up into seven groups of normal, model, low-frequency electroacupuncture (LF-EA), high-frequency electroacupuncture (HF-EA), LF-EA+anti-miRNA, HF-EA+anti-miRNA, and anti-miRNA. PCR assays were used to detect miR-223-3p expressions. The effects of electroacupuncture and miR-223-3p on rats' endometrial membrane cell-drinking process in a manner of scanning electron microscopy were recorded. After that we observed on the electroacupuncture effects on the conditions of adhesion molecules and LIF/STAT3 signaling pathway with assays of immunofluorescence and Western Blot. This study was end up with dual luciferase assay, where combination of miR-233-3p onto the 3'-UTR sequence of LIF was determined. PCR assay demonstrated that HF-EA procured an inhibition in miR-223-3p expression, whereas scanning electron microscopy turned out that both electroacupuncture and miR-223-3p were capable of raising the amount of intrauterine pinocytosis and the number of blastocyst implantation in rats. Additionally, assays of Western Blot and immunofluorescence showed that therapy of electroacupuncture brought about decreasing expressions in adhesion molecules of E-cadherin, ß-catenin and claudin-1 (CLDN1). We found that both electroacupuncture and miR-223-3p were able to fortify LIF/STAT3 signaling pathway, then the fact of miR-223-3p combination to LIF 3'-UTR sequence was validated via our dual-luciferase assay. Electroacupuncture therapy inhibited the miR-223-3p expression upon LIF/STAT3 signaling pathway to elevate endometrial receptivity.

TJZYF Improves Endometrial Receptivity through Regulating VEGF and PI3K/AKT Signaling Pathway.

The endometrium receptivity was impaired by controlled ovarian hyperstimulation (COH), which would then lead to fertility issues and increased abortion clinically. In the present study, to explore the effectiveness of Tiaojing Zhuyun Formula (TJZYF) in improving endometrial receptivity of COH rats and the possible active ingredients and mechanisms, an approach of network pharmacology was performed and a COH animal model was established. As analyzed, stigmasterol and quercetin may be the active ingredients of TJZYF on improving endometrial receptivity and positive regulation of ion transport, the cytokine-mediated signaling pathway, and endocrine process, and vascular endothelial growth factor receptor signaling pathway may be involved. Eighty female rats were divided into four groups randomly: control, model, TJZYF, and TJZYF+si-VEGFA. COH rat models were constructed by injecting with human menopausal gonadotropin (HMG) and human chorionic gonadotropin (HCG). We found that both endometrial thickness and number of embryo implantations in model were substantially reduced vs. control. The gene and protein expressions of VEGF, PI3K, and p-Akt in the uterus were significantly reduced. TJZYF could increase the endometrial thickness and number of embryo implantations and enhance the expressions of VEGF, PI3K, and p-Akt in the uterus. In the TJZYF+si-VEGFA group, the effect of TJZYF was impaired. Generally, TJZYF could improve the endometrium receptivity and facilitate embryo implantation of COH rats by upregulating VEGF and enhancing the PI3K/Akt signaling pathway.

Dual enzyme-mimic nanozyme based on single-atom construction strategy for photothermal-augmented nanocatalytic therapy in the second near-infrared biowindow.

Nanozyme-based catalytic therapy, an emerging therapeutic pattern, has significantly incorporated in the advancement of tumor therapy by generating lethal reactive oxygen species. Nevertheless, most of the nanozymes have mono catalytic performances with H2O2 in the tumor microenvironment (TME), which lowers their therapeutic efficiency. Herein, we design a newly-developed single-atom Fe dispersed N-doped mesoporous carbon nanospheres (SAFe-NMCNs) nanozyme with high H2O2 affinity for photothermal-augmented nanocatalytic therapy. The SAFe-NMCNs nanozyme possesses dual enzyme-mimic catalytic activity which not only acts as a catalase-mimic role to achieve ultrasonic imaging in tumor site by O2 generation, but also exhibits the superior peroxidase-mimic catalytic performance to generate •OH for nanocatalytic therapy. Besides, the SAFe-NMCNs nanozyme with strong optical absorption in the second near-infrared (NIR-II) region shows excellent photothermal conversion performance. The peroxidase-mimic catalytic process of SAFe-NMCNs nanozyme is realized using density functional theory (DFT). Both in vitro and in vivo results indicate that the SAFe-NMCNs nanozyme can efficiently suppress tumor cells growth by a synergistic therapy effect with photothermal-augmented nanocatalytic therapy. The work developed a single-atom-coordinated nanozyme with dual-enzyme catalytic performance and achieve hyperthermia-augmented nanocatalytic therapy effect, can open a window for potential biological applications.

Mechanically and electrically biocompatible hydrogel ionotronic fibers for fabricating structurally stable implants and enabling noncontact physioelectrical modulation.

Narrowing the mechanical and electrical mismatch between tissue and implantable microelectronics is essential for reducing immune responses and modulating physioelectrical signals. Nevertheless, the design of such implantable microelectronics remains a challenge due to the limited availability of suitable materials. Here, the fabrication of an electrically and mechanically biocompatible alginate hydrogel ionotronic fiber (AHIF) is reported, which is constructed by combing ionic chelation-assisted wet-spinning and mechanical training. The synergistic effects of these two processes allow the alginate to form a highly-oriented nanofibril and molecular network, with a hierarchical structure highly similar to that of natural fibers. These favourable structural features endow AHIF with tissue-mimicking mechanical characteristics, such as self-stiffening and soft tissue-like mechanical properties. In addition, tissue-like chemical components, i.e., biomacromolecules, Ca2+ ions, and water, endow AHIF with properties including biocompatibility and tissue-matching conductivity. These advantages bring light to the application of AHIFs in electrically-conductive implantable devices. As a prototype, an AHIF is designed to perform physioelectrical modulation through noncontact electromagnetic induction. Through experimental and machine learning optimizations, physioelectrical-like signals generated by the AHIF are used to identify the geometry and tension state of the implanted device in the body. Such an intelligent AHIF system has promising application prospects in bioelectronics, IntelliSense, and human-machine interactions.

Precisely Targeted Nano-Controller of PD-L1 Level for Non-Small Cell Lung Cancer Spinal Metastasis Immunotherapy.

Although immune checkpoint inhibitors (ICIs) have been widely applied to treat non-small cell lung cancer (NSCLC), a significant proportion of patients, especially those with spinal metastasis (NSCLC-SM), are insensitive to anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) ICIs. A drug delivery nano-controller of PD-L1 that targets NSCLC-SM can solve this problem, however, none have been developed to date. In this study, it is shown that integrin ß3 (ß3-int) is strongly upregulated in NSCLC-SM. Its inhibitor RGDyK promotes PD-L1 ubiquitination, indicating the potential application of RGDyK as a new PD-L1 inhibitor in nano-controller and a targeting peptide for NSCLC-SM treatment. According to the synergistic effect of photodynamic therapy and ICIs on T-cell activation through the release of tumor antigens, RGDyK-modified and zinc protoporphyrin (ZnPP)-loaded mesoporous silicon nanoparticles (ZnPP@MSN-RGDyK) are fabricated. The ZnPP@MSN-RGDyK nanoparticles precisely target ß3-int to inhibit PD-L1, exhibiting high photodynamic therapy efficiency, and excellent immunotherapeutic effects in an NSCLC-SM mouse model. Collectively, the findings indicate that ZnPP@MSN-RGDyK is a promising immunotherapeutic agent for treating NSCLC-SM.

Siglec15 facilitates the progression of non-small cell lung cancer and is correlated with spinal metastasis.

Background: Non-small cell lung cancer (NSCLC) frequently metastasizes to bone, leading to poor prognosis. Siglec15 has been identified as a newly discovered immune checkpoint and exists in a variety of tumors. However, the expression and function of Siglec15 in NSCLC and bone metastasis remains largely unclear. Methods: Siglec15 expression in NSCLC and the correlation between Siglec15 expression and the clinicopathological factors of patients with NSCLC were analyzed using The Cancer Genome Atlas (TCGA) dataset. Correlation analysis between Siglec15 and bone metastasis-related genes expression was based on the Molecular Signatures Database (MSigDB). Western blotting and immunohistochemistry were applied to detect Siglec15 expression in NSCLC and spinal metastasis. Human A549 and mouse CMT167 cells were transfected with Siglec15 siRNA to investigate its biological functions in NSCLC proliferation, migration, and invasion. The immune-related signaling pathways and correlations between Siglec15 and tumor-infiltrating immune cells and different immune checkpoints in the NSCLC tumor microenvironment (TME) were analyzed using Estimating Relative Subsets of RNA Transcripts (CIBERSORT) and gene set enrichment analysis (GSEA). To demonstrate Siglec15 in NSCLC cell-mediated T cell suppression and investigate the potential mechanism of Siglec15 silencing in antitumor immunity, we used a T cell killing assay in vitro and the high­throughput sequencing approach. Results: Siglec15 expression was positively associated with the tumor stage and lymph node metastasis, and was markedly up-regulated in NSCLC bone metastasis. Functionally, Siglec15 knockdown inhibited the proliferation, migration, and invasion of NSCLC cells (A549 and CMT167 cell lines). A total of eight kinds of tumor-infiltrating immune cells were found to have a strong association with the Siglec15 expression in NSCLC cases. The expression of previously discovered immune checkpoints was higher in the high Siglec15 expression NSCLC group. Furthermore, an in vitro T cell killing assay showed that the down-regulation of Siglec15 in tumor cells could enhance the antitumor immune responses of CD8+ T cells. High­throughput sequencing revealed the potential molecular mechanisms underlying the Siglec15-mediated immunosuppression effect of tumor cells on immune cells. Conclusions: Siglec15 may be involved in the pathogenesis of spinal metastasis in NSCLC and provide a new potential therapeutic target for the treatment of NSCLC and bone metastasis.

Enhancement of anti-PD-1/PD-L1 immunotherapy for osteosarcoma using an intelligent autophagy-controlling metal organic framework.

Poor immunogenicity and compromised T cell infiltration impede the application of immune-checkpoint blockade (ICB) immunotherapy for osteosarcoma (OS). Although autophagy is involved in enhancing the immune response, the synergistic role of autophagy in ICB immunotherapy and the accurate control of autophagy levels in OS remain elusive and challenging. Here, we designed a pH-sensitive autophagy-controlling nanocarrier, CUR-BMS1166@ZIF-8@PEG-FA (CBZP), loading a natural derivative, curcumin (CUR), to boost the immunotherapeutic response of PD-1/PD-L1 blockade by activating immunogenic cell death (ICD) via autophagic cell death, and BMS1166 to inhibit the PD-1/PD-L1 interaction simultaneously, enhancing the tumor immunogenicity and sensitizing the antitumor T cell immunity. After entering tumor cells, the pH-sensitive nanoparticles induced autophagy and decreased the intracellular pH, which in turn further facilitated the release of CUR to enhance autophagic activity. Transferring CBZP to orthotopic OS tumor-bearing mice showed powerful antitumor effects and established long-term immunity against tumor recurrence, accompanied by enhanced dendritic cell maturation and tumor infiltration of CD8+ T lymphocytes. Collectively, CBZP exhibited synergistic effects in treating OS by combining ICD induction with checkpoint blockade, thereby shedding light on the use of autophagy control as a potential clinical therapy for OS.

High-frequency electroacupuncture improves endometrial receptivity via regulating cell adhesion molecules and leukemia inhibitory factor / signal transducer and activator of transcription signaling pathway.

Controlled ovarian hyperstimulation (COH) impairs the endometrium receptivity during the implantation window, resulting in a lower clinical pregnancy rate and a higher abortion rate. Our study explored the effect of electroacupuncture on the endometrial receptivity of COH rats. Female rats were randomly divided into normal treatment (Normal), model treatment (Model), low-frequency electroacupuncture treatment (LF-EA) and high-frequency electroacupuncture treatment (HF-EA). Rats in the Model, LF-EA, and HF-EA treatment groups were injected with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (HCG) to establish a model of COH rats. Compared with the Normal, the endometrial thickness, the number of pinopodes and amount of blastocyst implantation in the Model group were significantly reduced. Among them, the endometrial thickness and the amount of blastocyst implantation in the Model group were substantially decreased than those in the HF-EA group. High-frequency electroacupuncture treatment could markedly reduce the protein expression levels of E-cadherin, ß-catenin and claudin-1 (CLDN1). During HF-EA treatment, the LIF/STAT3 signaling pathway of COH rats was enhanced. In conclusion, electroacupuncture could improve the endometrium receptivity and promote the blastocyst implantation in COH rats by reducing cell adhesion molecules and enhancing the LIF/STAT3 signaling pathway.Highlights High-frequency electroacupuncture could effectively improve endometrial receptivity and blastocyst implantation amount in COH rats.Electroacupuncture, especially high-frequency electroacupuncture, could significantly increase endometrial thickness and the number of pinopodes.High-frequency electroacupuncture significantly reduced the protein expression levels of E-cadherin, ß-catenin and CLDN1 adhesion molecules in COH rats.High-frequency electroacupuncture could markedly enhance the LIF/STAT3 signaling pathway in COH rats.

Shu-Di-Huang and Gan-Cao Herb Pair Restored the Differentiation Potentials of Mesenchymal Stem Progenitors in Treating Osteoporosis via Downregulation of NF-κB Signaling Pathway.

BACKGROUND: Shu-Di-Huang (Radix Rehmanniae Praeparata, RR) and Gan-Cao (liquorice, L) are frequently used traditional Chinese herb pair in treating osteoporosis (OP). However, the exact mechanism of the RR and L herb pair (RR-L) remains unclear. To explore the efficacy and possible mechanisms of RR-L in treating OP, in silico, in vitro, and in vivo experiments were conducted in the current study. METHODS: In silico, potential therapeutic target genes and active chemical compounds of RR-L herb pair were predicted and constructed into a network. In vivo, 30 Sprague Dawley rats were divided into 3 groups, including the sham group, the OP model group, and the RR-L-treated OP group. Micro-CT and pathological sections were conducted to validate the therapeutic effects of RR-L in treating OP. MSCs of rats were isolated and cultured in vitro to validate the mesenchymal stem cells (MSCs) related phenotype changes, including Alizarin red staining, Oil red staining, and immunofluorescence. In vitro, cell proliferation analysis, Alizarin red staining, Oil red staining, immunofluorescence of NF-κB, and protein expression of PPARγ, RUNX2, OCN, and p65 were conducted on MSCs to explore the RR-L containing serum in vitro. Also, activator and inhibitor of NF-κB signaling pathway were introduced to determine the possible mechanism of RR-L in the treatment of OP via enhancing MSCs proliferation and differentiation. RESULTS: In silico, 168 chemical compounds with a property of oral bioavailability ≥30% and drug-likeness ≥0.18 were recognized as potentially active compounds in RR-L and 249 genes were found to be the targets of which. Among them, 120 genes were found to be therapeutic genes of RR-L in treating OP and KEGG and GO analysis of which demonstrated that RR-L involves in lipid metabolism and multiple inflammation-related signaling pathways. In vivo, ovariectomy- (OVX-) induced OP phenotypes in Sprague Dawley rats include bone mineral density and microarchitecture damaging, abnormal bone metabolism, upregulation of inflammation markers, and damaged differentiation potential of MSCs. Treatment of RR-L reversed the trend and restored the differentiation potential of MSCs. In vitro, RR-L containing serum promoted the osteogenic differentiation and suppressed adipogenic differentiation of MSCs via downregulation of the NF-κB signaling pathway. Also, RR-L containing serum inhibited the tumor necrosis factor-α (TNF-α) induced activation of the NF-κB signaling pathway. On the opposite, the addition of the NF-κB specific inhibitor significantly reduced the effect of RR-L on MSCs. CONCLUSIONS: In the current study, network pharmacology prediction and experimental validation elucidated that the RR-L herb pair restored damaged MSC differentiation potential via the NF-κB signaling pathway; this could be the possible mechanism of RR-L in treating OP. This finding provides an alternative option in OP therapy.