Combined Treatment Research Articles

Inoculation with Funneliformis mosseae promotes selenium accumulation and transformation in pepper (Capsicum annuum L.)

Selenium (Se) is one of the fifteen essential nutrients required by the human body. Mycorrhizal microorganisms play a crucial role in enhancing selenium availability in plants. However, limited research exists on the impact of arbuscular mycorrhizal fungi (AMF) on selenium accumulation and transport in pepper plants. This study employed a pot experiment to investigate the changes in pepper plant growth, selenium accumulation, and transformation following inoculation with AMF and varying concentrations of exogenous selenium. The results indicate that exogenous selenium application in pepper has dual effects. At low concentrations (≤8 mg L⁻1), it promotes growth and nutrient accumulation, whereas high concentrations (>16 mg L⁻1) inhibit these processes. AMF inoculation positively influences selenium accumulation and transport in peppers, significantly increasing yield per plant by 17.89%, vitamin C content by 67.36%, flavonoid content by 43.26%, capsaicin content by 14.82%, DPPH radical scavenging rate by 18.18%, and ABTS radical scavenging rate by 27.81%. Additionally, it significantly reduces selenocysteine methyltransferase (SMT) enzyme activity, while minimally affecting ATP sulfurylase (ATPS) and adenosyl sulfate reductase (APR) enzyme activities. The combined treatment of AMF and 8 mg L⁻1 exogenous selenium has been proven to be the most effective for selenium enrichment in peppers, offering new insights into utilizing exogenous selenium and AMF inoculation to enhance selenium content in peppers.

Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia.

In chronic myeloid leukemia (CML), the persistence of leukemic stem cells (LSCs) after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, can lead to disease relapse. It is known that therapy-resistant LSCs rely on oxidative phosphorylation (OXPHOS) for their survival and that targeting mitochondrial respiration sensitizes CML LSCs to imatinib treatment. However, current OXPHOS inhibitors have demonstrated limited efficacy or have shown adverse effects in clinical trials, highlighting that identification of clinically safe oxidative pathway inhibitors is warranted. We performed a high-throughput drug repurposing screen designed to identify mitochondrial metabolism inhibitors in myeloid leukemia cells. This identified lomerizine, a US Food and Drug Administration (FDA)-approved voltage-gated Ca2+ channel blocker now used for the treatment of migraines, as one of the top hits. Transcriptome analysis revealed increased expression of voltage-gated CACNA1D and receptor-activated TRPC6 Ca2+ channels in CML LSCs (CD34+CD38-) compared with normal counterparts. This correlated with increased endoplasmic reticulum (ER) mass and increased ER and mitochondrial Ca2+ content in CML stem/progenitor cells. We demonstrate that lomerizine-mediated inhibition of Ca2+ uptake leads to ER and mitochondrial Ca2+ depletion, with similar effects seen after CACNA1D and TRPC6 knockdown. Through stable isotope-assisted metabolomics and functional assays, we observe that lomerizine treatment inhibits mitochondrial isocitrate dehydrogenase activity and mitochondrial oxidative metabolism and selectively sensitizes CML LSCs to imatinib treatment. In addition, combination treatment with imatinib and lomerizine reduced CML tumor burden, targeted CML LSCs, and extended survival in xenotransplantation model of human CML, suggesting this as a potential therapeutic strategy to prevent disease relapse in patients.

Chemo-immunotherapy by nanoliposomal epacadostat and docetaxel combination to IDO1 inhibition and tumor microenvironment suppression

The over-activation of tryptophan (Trp) metabolism to kynurenine (Kyn) catalyzed by Indoleamine 2,3-dioxygenase-1 (IDO1) enzyme, is one of the main metabolic pathways involved in tumor microenvironment (TME) immune escape and cancer treatment failure. The most efficient of IDO1 inhibitors is Epacadostat (EPA). Since monotherapy with single-agent IDO1 inhibitor regimen has led to an insufficient anti-tumor activity, we examined the efficacy of simultaneous treatment by Liposomal epacadostat (Lip-EPA) as a potent IDO inhibitor, in combination with docetaxel (DTX) as a complement immunogenic cell death (ICD) agent against B16F10 model. First, the in vitro combination index (CI) of epacadostat (EPA) and DTX was investigated by using the unified theory. Then, the in vivo efficacy of the combination therapy was assessed. Results indicated the synergestic cytotoxic effect of the combination on B16F10 compared to normal fibroblast cells (NIH). The immune profiling demonstrated a significant increase in the percentage of infiltrated T lymphocytes and IFN-γ release, a significant decrease in the percentage of regulatory T cells (Treg) population and the subsequent low levels of IL-10 generation in mice treated with Lip-EPA + DTX. Further, a significant tumor growth delay (TGD = 69.15 %) and an increased life span (ILS > 47.83 %) was observed with the combination strategy. Histopathology analysis revealed a remarkable increase in the Trp concentration following combination treatment, while Kyn levels significantly decreased. Results showed that the nano-liposomal form of IDO1 inhibitor in combination with chemotherapy could significantly improve the imunity response and dominate the tumor immuno-suppressive micro-environment, which merits further investigations.

Phase II study to determine the anti-tumor activity and safety of simlukafusp alfa (FAP-IL2v) combined with atezolizumab in esophageal cancer.

Reported here are results from the esophageal squamous cell carcinoma (SCC) cohort of a Phase II, non-comparative, basket study, evaluating the anti-tumor activity and safety of FAP-IL2v plus atezolizumab in patients with advanced/metastatic solid tumors (NCT03386721). Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1; measurable metastatic, persistent, or recurrent esophageal SCC; progression on ≥1 prior therapy; and were checkpoint inhibitor naive. Patients received FAP-IL2v 10 mg plus atezolizumab 1200 mg intravenously every 3 weeks, or FAP-IL2v weekly for 4 weeks, then every 2 weeks, plus atezolizumab 840 mg intravenously every 2 weeks. Primary endpoint was investigator-assessed objective response rate (ORR). In the response-evaluable population (N=34), best confirmed ORR was 20.6% (95% confidence interval [CI]: 10.4-36.8) with a complete response (CR) seen in one patient and partial responses (PR) in six patients. Disease control rate was 44.1% (CR=2.9%; PR=17.6%; stable disease [SD]=23.5%) and median duration of response was 10.1 months (95% CI: 5.6-26.7). Median progression-free survival was 1.9 months (95% CI: 1.8-3.7). Analysis of response by PD-L1 expression (Ventana SP263) resulted in an ORR of 26.7 % for patients with PD-L1-positive tumors (tumor area positivity [TAP] cut-off ≥1%; n=15) and 7.1% for patients with PD-L1-negative tumors (TAP cut-off <1%; n=14). Overall, the treatment combination was tolerable and adverse events were consistent with the known safety profiles of each drug. FAP-IL2v plus atezolizumab demonstrated clinical activity and was tolerable in patients with previously treated esophageal SCC.

Varietal Evaluation of Bottle Gourd on Growth and Yield under Prayagraj Conditions or Respective Agro Climatic Zone

The experiment was carried out in the SHUATS horticulture department field, which is located in the Prayagraj agroclimatic zone in Uttar Pradesh. The study, "Varietal Evaluation in Bottle Gourd," used a combination of treatments on 12 different varieties of bottle gourd, including 2021/BOGVAR -1 TO BOGVAR-12, MAHASHAKTI, and Faizabadhi long. The primary conclusions were vine length, where MAHASHAKTI showed the highest growth and 2021/BOGVAR-03 showed the lowest. The 2021/BOGVAR-06 shows the most node growth, while the 2021/BOGVAR-10 shows the lowest. In terms of fruit weight the maximum weight was seen in 2021/BOGVAR-07(1200g) and the minimum weight was observed in 2021/BOGVAR-02(492.5g), in terms of fruit yield per ha the maximum yield was seen in 2021/BOGVAR-07, 2021/BOGVAR-08 and the minimum weight was observed in 2021/BOGVAR-02, 2021/BOGVAR-03.

Еffect of Radiation Therapy on Breast Reconstruction in Breast Cancer Patients

Background. The surgical stage remains the main one in the combined and complex treatment of breast cancer. Radical mastectomy and reconstructive plastic surgery are the main option for surgical treatment of vast majority patients. Radiation therapy can lead to the development of complications after breast reconstruction, and vice versa, the reconstructed mammary gland can cause technical difficulties for the radiologist to properly adjust the required dose of irradiation. Aim — to choose the optimal method of breast reconstruction using various implants, as well as endoprostheses to minimize post-radiation complications and maintain a high level of quality of life for patients after breast cancer treatment. Methods. The retrospective study was conducted in the department of oncology and reconstructive plastic surgery of the breast and skin in the P.A. Herzen Moscow Research Oncology Institute from June 2013 to November 2017. There were performed 132 operations: 111 subcutaneous mastectomy with one-stage reconstruction with an endoprothesis and 21 mastectomy with a one-stage reconstruction with an endoprothesis. The distribution by stages: I — 57, IIA — 39, IIB — 17, IIIA — 13, IIIC 4; 2 cases of breast sarcoma. Prophylactic mastectomy of the contralateral gland was performed in 22 patients, mastopexy in 8, augmentation in 20. Polyurethane implants were applied in 82 cases (62%). Radiation therapy was performed in 47 patients with total dose 45 Gy. Bilateral reconstruction was performed in 22 patients. Results. The mean follow-up period was 28.44 ± 14.66 months (from 6 to 48 months). The most frequent complication in the postoperative period was the development of capsular contracture: seroma — 20 patients, hematoma — 2, edge necrosis — 6, protrusion — 6, infection — 2 patients. The most common capsular contracture by Baker was III degree, n = 18. The average period of development of capsular contracture was 7.6 ± 11.65 months. Conclusion. Despite the greater number of complications during the one-stage reconstruction, the implants remain in advantage in choosing a method of treating breast cancer by both the patient and the surgeon.

Autophagy‐Inducing MoO3‐x Nanowires Boost Photothermal‐Triggered Cancer Immunotherapy

AbstractAutophagy could play suppressing role in cancer therapy by facilitating release of tumor antigens from dying cells and inducing immunogenic cell death (ICD). Therefore, discovery and rational design of more effective inducers of cytotoxic autophagy is expected to develop new strategies for finding innovative drugs for precise and successful cancer treatment. Herein, we develop MoO3‐x nanowires (MoO3‐x NWs) with high oxygen vacancy and strong photothermal responsivity to ablate tumors through hyperthermia, thus promote the induction of cytotoxic autophagy and severe ICD. As expected, the combination of MoO3‐x NWs and photothermal therapy (PTT) effectively induces autophagy to promote the release of tumor antigens from the ablated cells, and induces the maturation and antigen presentation of dendritic cells (DCs), subsequently activates cytotoxic T lymphocytes (CTLs)‐mediated adaptive immunity. Furthermore, the combination treatment of MoO3‐x NWs with immune checkpoint blockade of PD‐1 could promote the tumor‐associated macrophages (TAMs) polarization into tumor‐killing M1 macrophages, inhibit infiltration of Treg cells at tumor sites, and alleviate immunosuppression in the tumor microenvironment, finally intensify the anti‐tumor activity in vivo. This study provides a strategy and preliminary elucidation of the mechanism of using MoO3‐x nanowires with high oxygen vacancy to induce autophagy and thus enhance photothermal immunotherapy.

Autophagy-Inducing MoO3-x Nanowires Boost Photothermal-Triggered Cancer Immunotherapy.

Autophagy could play suppressing role in cancer therapy by facilitating release of tumor antigens from dying cells and inducing immunogenic cell death (ICD). Therefore, discovery and rational design of more effective inducers of cytotoxic autophagy is expected to develop new strategies for finding innovative drugs for precise and successful cancer treatment. Herein, we develop MoO3-x nanowires (MoO3-x NWs) with high oxygen vacancy and strong photothermal responsivity to ablate tumors through hyperthermia, thus promote the induction of cytotoxic autophagy and severe ICD. As expected, the combination of MoO3-x NWs and photothermal therapy (PTT) effectively induces autophagy to promote the release of tumor antigens from the ablated cells, and induces the maturation and antigen presentation of dendritic cells (DCs), subsequently activates cytotoxic T lymphocytes (CTLs)-mediated adaptive immunity. Furthermore, the combination treatment of MoO3-x NWs with immune checkpoint blockade of PD-1 could promote the tumor-associated macrophages (TAMs) polarization into tumor-killing M1 macrophages, inhibit infiltration of Treg cells at tumor sites, and alleviate immunosuppression in the tumor microenvironment, finally intensify the anti-tumor activity in vivo. This study provides a strategy and preliminary elucidation of the mechanism of using MoO3-x nanowires with high oxygen vacancy to induce autophagy and thus enhance photothermal immunotherapy.

CHK1 inhibitor induced PARylation by targeting PARG causes excessive replication and metabolic stress and overcomes chemoresistance in ovarian cancer

Chemoresistance contributes to the majority of deaths in women with ovarian cancer (OC). Altered DNA repair and metabolic signaling is implicated in mediating therapeutic resistance. DNA damage checkpoint kinase 1 (CHK1) integrates cell cycle and DNA repair in replicating cells, and its inhibition causes replication stress, repair deficiency and cell cycle dysregulation. We observed elevated Poly-ADP-ribosylation (PAR) of proteins (PARylation) and subsequent decrease in cellular NAD+ levels in OC cells treated with the CHK1 inhibitor prexasertib, indicating activation of NAD+ dependent DNA repair enzymes poly-ADP-ribose polymerases (PARP1/2). While multiple PARP inhibitors are in clinical use in treating OC, tumor resistance to these drugs is highly imminent. We reasoned that inhibition of dePARylation by targeting Poly (ADP-ribose) glycohydrolase (PARG) would disrupt metabolic and DNA repair crosstalk to overcome chemoresistance. Although PARG inhibition (PARGi) trapped PARylation of the proteins and activated CHK1, it did not cause any significant OC cell death. However, OC cells deficient in CHK1 were hypersensitive to PARGi, suggesting a role for metabolic and DNA repair crosstalk in protection of OC cells. Correspondingly, OC cells treated with a combination of CHK1 and PARG inhibitors exhibited excessive replication stress-mediated DNA lesions, cell cycle dysregulation, and mitotic catastrophe compared to individual drugs. Interestingly, increased PARylation observed in combination treatment resulted in depletion of NAD+ levels. These decreased NAD+ levels were also paralleled with reduced aldehyde dehydrogenase (ALDH) activity, which requires NAD+ to maintain cancer stem cells. Furthermore, prexasertib and PARGi combinations exhibited synergistic cell death in OC cells, including an isogenic chemoresistant cell line and 3D organoid models of primary patient-derived OC cell lines. Collectively, our data highlight a novel crosstalk between metabolism and DNA repair involving replication stress and NAD+-dependent PARylation, and suggest a novel combination therapy of CHK1 and PARG inhibitors to overcome chemoresistance in OC.

Retrospective Large Database Study of Central Serous Chorioretinopathy Treatments and Visual Outcomes Analysis in the United States

Purpose: To evaluate a large database detailing the changes in visual acuity (VA) and central subfield thickness after various treatments for central serous chorioretinopathy (CSCR). Methods: A retrospective analysis was performed of patients with CSCR from January 2015 to September 2022 using the Vestrum Health Retina Database of aggregated de-identified electronic medical records from retina specialists in the United States. The cases of CSCR were categorized by age, sex, and treatment provided. Results: The annual incidence of CSCR was 1.72% (61 755 of 3 598 672 patient eyes), with a mean patient age of 53 years. Male eyes comprised 71.8% of the patient population. Eighty-five percent of patients received no treatment within 1 year of diagnosis. Of the patients needing treatment, 21% received thermal laser therapy, 23% photodynamic therapy, and 49% antivascular endothelial growth factor (anti-VEGF) intraocular injection. Patients not receiving treatment had the best baseline and 1-year VA. All treatment groups had an increased percentage of patients gaining letters compared with patients not receiving treatment. Conclusions: Although most patients did not require treatment, those who received treatment generally did well, with a large proportion having visual gain. Statistical analysis suggests treatment has a positive impact on VA outcomes. Patients receiving combination treatment were older and had the least visual gain of the treated cohorts. Younger patients with CSCR treated with anti-VEGF (and without a secondary diagnosis of macular degeneration) had the greatest increase in VA at 1 year.

Upcycled Graphene Oxide Nanosheets for Reversible Room Temperature NO2 Gas Sensor

Graphene oxide (GO) nanosheets, as one of the most studied graphene derivatives, have demonstrated an intrinsically strong physisorption-based gas–matter behavior, owing to its enhanced volume–surface ratio and abundant surface functional groups. The exploration of efficient and cost-effective synthesis methods for GO is an ongoing task. In this work, we explored a novel approach to upcycle inexpensive polyethylene terephthalate (PET) plastic waste into high-quality GO using a combination of chemical and thermal treatments based on a montmorillonite template. The obtained material had a nanosheet morphology with a lateral dimension of around ~2 µm and a thickness of ~3 nm. In addition, the GO nanosheets were found to be a p-type semiconductor with a bandgap of 2.41 eV and was subsequently realized as a gas sensor. As a result, the GO sensor exhibited a fully reversible sensing response towards ultra-low-concentration NO2 gas with a limit of detection of ~1.43 ppb, without the implementation of an external excitation stimulus including elevating the operating temperature or bias voltages. When given a thorough test, the sensor maintained an impressive long-term stability and repeatability with little performance degradation after 5 days of experiments. The response factor was estimated to be ~11% when exposed to 1026 ppb NO2, which is at least one order of magnitude higher than that of other commonly seen gas species including CH4, H2, and CO2.

Induction versus Adjuvant Chemotherapy Combined with Concurrent Chemoradiation: What Is Beneficial in Locally Advanced Nasopharyngeal Carcinoma—A 5-Year Comparative Study at a Tertiary Care Center in North India

Background In locally advanced nasopharyngeal cancer (LANPC), concurrent chemoradiotherapy (CCRT) has been established as the current standard of care, but recently, the addition of induction chemotherapy to CCRT has presented an attractive multidisciplinary approach. Objectives The aim of the study was to explore the clinical outcome of induction chemotherapy (IC) followed by CCRT and CCRT followed by adjuvant chemotherapy (AC) in LANPC. Material and Methods In this propensity score–matched retrospective cohort study, we enrolled LANPC patients from October 2016 to June 2022. Study variables were evenly distributed by propensity score matching. Independent prognostic factors were identified using Cox regression analysis, and the outcome between the two chemotherapy treatment combinations was compared for patients in different subgroups. Result A total of 80 patients were included in the study. Survival outcomes indicated that the IC followed by CCRT group (IC + CCRT) achieved a higher 5-year overall survival (OS; 90 vs. 81%, p = 0.253), failure-free survival (FFS; 80 vs. 77.50%, p = 0.17), and distant metastasis-free survival (DMFS; 88 vs. 82.50%, p = 0.314) compared with the CCRT followed by AC group (CCRT + AC), although it was not statistically significant. The stratified analysis revealed that IC followed by CCRT (IC + CCRT) was associated with significantly improved OS (hazard ratio [HR] = 0.212; 95% confidence interval [CI] = 0.014–3.16; p = 0.0026) in N2 disease. However, the superiority of CCRT followed by AC (CCRT + AC) was only observed in LRRFS (HR = 0.45; 95% CI = 0.05–0.89; p = 0.036) for the T4 subgroup. Conclusion In patients with LANPC, especially with T3 or N2 disease, IC should be strongly considered followed by CCRT.

The root-lesion nematode, Pratylenchus penetrans, affects early growth and physiology of grafted M.9, G.41 and G.935 apple rootstocks similarly under field microplot conditions.

The root-lesion nematode, Pratylenchus penetrans, is a ubiquitous parasite of roots of temperate fruit trees. It affects early growth of trees replanted into former orchard sites where populations have built up, and may contribute to decline complexes of older trees. Most British Columbia, Canada apple acreage is planted with M.9 rootstock, but growers are increasingly considering Geneva-series rootstocks such as G.41 and G.935. Among these rootstocks, responses to P. penetrans, specifically, are poorly known. To compare the resistance and tolerance to P. penetrans of G.41, G.935 and M.9 rootstocks ('Ambrosia' scion), a field microplot experiment was established in spring of 2020 at the Summerland Research and Development Centre. The experimental design was a 2 x 3 factorial combination of: P. penetrans inoculation (+/-) and rootstock (G.41, G.935, M.9), with 20 replicate microplots of each of the six treatment combinations arranged in a randomized complete block design. The P. penetrans inoculum was 5400 nematodes per microplot (54 P. penetrans L-1 soil), which is below commonly accepted damage thresholds. Though P. penetrans population densities were lower for the G.41 rootstock by the end of the 2021 growing season, the effects of P. penetrans were similar among rootstocks. In the establishment year (2020), P. penetrans caused significant reductions in aboveground growth. In 2021, shoot growth and root weight were reduced by P. penetrans. The nematode also reduced rates of leaf gas exchange and stem water potential. These data suggest that while G.41 and G.935 may have other horticultural benefits over M.9, they are equally susceptible to P. penetrans at the early stages of tree growth.

Preliminary result of combined treatment with scanning carbon-ion radiotherapy and image-guided brachytherapy for locally advanced cervical adenocarcinoma.

Although there is growing evidence of the efficacy of carbon-ion radiotherapy (CIRT) for locally advanced cervical adenocarcinoma, reports on combined treatment with CIRT and image-guided brachytherapy (IGBT) are scarce. We retrospectively analyzed patients with International Federation of Gynecology and Obstetrics (2008) stage II-IVA locally advanced cervical adenocarcinoma who received combined scanning CIRT (sCIRT) and IGBT between April 2019 and March 2022. sCIRT consisted of whole-pelvic irradiation with 36Gy (relative biological effectiveness [RBE]) in 12 fractions and subsequent local boost irradiation with 19.2Gy (RBE) in 4 fractions. Three sessions of IGBT were administered after completion of sCIRT. Concurrent chemotherapy using weekly cisplatin (40mg/m2/week) was also administered. Efficacy, toxicity and dose-volume parameters were analyzed. Fifteen patients were included in the analysis. The median follow-up period was 25months. The 2-year overall survival, progression-free survival and local control rates were 92.3% (95% confidence interval [CI] = 77.8-100%), 52.5% (95% CI = 26.9-78.1%) and 84.8% (95% CI = 65.2-100%), respectively. Neither severe acute toxicity necessitating treatment cessation nor grade 3 or higher late toxicity were observed. The sigmoid D2cm3 of the patient who developed grade 2 late sigmoid hemorrhage was 65.6Gy, which exceeded the standard deviation and target dose. The combination of sCIRT and IGBT for locally advanced cervical adenocarcinoma showed acceptable efficacy and safety. Further large-scale and long-term studies are warranted to confirm the efficacy and safety of this treatment.

Microbial metabolite sodium butyrate enhances the anti-tumor efficacy of 5-fluorouracil against colorectal cancer by modulating PINK1/Parkin signaling and intestinal flora

Colorectal cancer (CRC) is a prevalent global health issue, with 5-fluorouracil (5-FU) being a commonly used chemotherapeutic agent for its treatment. However, the efficacy of 5-FU is often hindered by drug tolerance. Sodium butyrate (NaB), a derivative of intestinal flora, has demonstrated anti-cancer properties both in vitro and in vivo through pro-apoptotic effects and has shown promise in improving outcomes when used in conjunction with traditional chemotherapy agents. This study seeks to evaluate the impact and potential mechanisms of NaB in combination with 5-FU on CRC. We employed a comprehensive set of assays, including CCK-8, EdU staining, Hoechst 33258 staining, flow cytometry, ROS assay, MMP assay, immunofluorescence, and mitophagy assay, to detect the effect of NaB on the biological function of CRC cells in vitro. Western blotting and immunohistochemistry were used to verify the above experimental results. The xenograft tumor model was established to evaluate the in vivo anti-CRC activity of NaB. Subsequently, 16S rRNA gene sequencing was used to analyze the intestinal flora. The findings of our study demonstrate that sodium butyrate (NaB) exerts inhibitory effects on tumor cell proliferation and promotes tumor cell apoptosis in vitro, while also impeding tumor progression in vivo through the enhancement of the mitophagy pathway. Furthermore, the combined treatment of NaB and 5-fluorouracil (5-FU) yielded superior therapeutic outcomes compared to monotherapy with either agent. Moreover, this combination therapy resulted in the specific enrichment of Bacteroides, LigiLactobacillus, butyric acid-producing bacteria, and acetic acid-producing bacteria in the intestinal microbiota. The improvement in the intestinal microbiota contributed to enhanced therapeutic outcomes and reduced the adverse effects of 5-FU. Taken together, these findings indicate that NaB, a histone acetylation inhibitor synthesized through intestinal flora fermentation, has the potential to significantly enhance the therapeutic efficacy of 5-FU in CRC treatment and improve the prognosis of CRC patients.

Efficacy of astragalus combined with renin-angiotensin-aldosterone system blockers in the treatment of stage III diabetic nephropathy: a systematic review and meta-analysis

Objective To determine the efficacy and safety of Astragalus combined with renin-angiotensin-aldosterone system (RAAS) blockers in treating stage III diabetic nephropathy (DN) by meta-analysis. Methods PubMed, Embase, Cochrane Library, Wiley, and Web of Science databases were searched for articles published between August 2007 and August 2022. Clinical studies on Astragalus combined with RAAS blockers for the treatment of stage III DN were included. Meta-analysis was performed by RevMan 5.1 and Stata 14.3 software. Results A total of 32 papers were included in this meta-analysis, containing 2462 patients from randomized controlled trials, with 1244 receiving the combination treatment and 1218 solely receiving RAAS blockers. Astragalus combined with RAAS blockers yielded a significantly higher total effective rate (TER) (mean difference [MD] 3.63, 95% confidence interval [CI] 2.59–5.09) and significantly reduced urinary protein excretion rate (UPER), serum creatinine (Scr), blood urine nitrogen (BUN) and glycosylated hemoglobin (HbAlc) levels. In subgroup analysis, combining astragalus and angiotensin receptor blocker significantly lowered fasting plasma glucose (FPG) and 24 h urinary protein (24hUTP) levels, compared with the combined astragalus and angiotensin-converting enzyme inhibitor treatment. Meanwhile, the latter significantly decreased the urinary microprotein (β2-MG). Importantly, the sensitivity analysis confirmed the study’s stability, and publication bias was not detected for UPER, BUN, HbAlc, FPG, or β2-MG. However, the TER, SCr, and 24hUTP results suggested possible publication bias. Conclusions The astragalus-RAAS blocker combination treatment is safe and improves outcomes; however, rigorous randomized, large-scale, multi-center, double-blind trials are needed to evaluate its efficacy and safety in stage III DN.

Extracellular vesicles promote autophagy in human microglia through lipid raft-dependent mechanisms.

Autophagy dysfunction has been closely related with pathogenesis of many neurodegenerative diseases and therefore represents a potential therapeutic target. Extracellular vesicles (EVs) may act as potent anti-inflammatory agents and also modulators of autophagy in target cells. However, the molecular mechanisms by which EVs modulate autophagy flux in human microglia remain largely unexplored. In the present study, we investigated the effects of EVs derived from human oral mucosa stem cells on the autophagy in human microglia. We demonstrate that EVs promoted autophagy and autophagic flux in human microglia and that this process was dependent on the integrity of lipid rafts. Lipopolysaccharide (LPS) also activated autophagy, but combined treatment with EVs and LPS suppressed autophagy response, indicating interference between these signaling pathways. Blockage of Toll-like receptor 4 (TLR4) with anti-TLR4 antibody suppressed EV-induced autophagy. Furthermore, inhibition of the EV-associated heat shock protein (HSP70) chaperone which is one of the endogenous ligands of the TLR4 also suppressed EV-induced lipid raft formation and autophagy. Pre-treatment of microglia with a selective inhibitor of αvβ3/αvβ5 integrins cilengitide inhibited EV-induced autophagy. Finally, blockage of purinergic P2X4 receptor (P2X4R) with selective inhibitor 5-BDBD also suppressed EV-induced autophagy. In conclusion, we demonstrate that EVs activate autophagy in human microglia through interaction with HSP70/TLR4, αVβ3/αVβ5, and P2X4R signaling pathways and that these effects depend on the integrity of lipid rafts. Our findings could be used to develop new therapeutic strategies targeting disease-associated microglia.

Andrographolide targets EGFR to impede epithelial–mesenchymal transition in human breast cancer cells

Despite the primary surgical treatment for breast cancer patients, malignant invasiveness and metastasis remain threatening factors for women with breast cancer. As chemotherapy yields unsatisfactory results, it prompted us to search for effective natural agents with few side-effects. Although andrographolide (ADGL), a natural diterpenoid lactone isolated from Andrographis paniculata, presents anticancer effects, the molecular mechanism remains unknown. Initially, on comparing the expression of proteins related to epithelial–mesenchymal transition (EMT) between nonmetastatic cancer MCF7 cells and highly metastatic cancer MDA-MB-231 cells, we found that MDA-MB-231 cells exhibit higher protein levels of N-cadherin and vimentin and lower protein levels of E-cadherin when compared to MCF7 cells. Moreover, MDA-MB-231 cells also exhibited higher EGFR expression and activity, higher STAT1 activity and abundant HDAC4 expression. To elucidate whether these proteins are closely associated with EMT, EGFR, STAT1 or HDAC4, the proteins were silenced in MDA-MB-231 breast cancer cells by their specific siRNAs. We found that silencing these proteins reduced EMT, indicating an important role of EGFR, STAT1 and HDAC4 in EMT progression. When we treated MDA-MB-231 cells with ADGL as a potential therapeutic drug, we found that ADGL treatment inhibited cell migration and invasion. Furthermore, it also recovered E-cadherin expression and decreased N-cadherin and vimentin protein levels. ADGL treatment reduced EGFR expression at a lower concentration (1 μg/mL); however, STAT1 activity and HDAC4 expression was reduced by a higher concentration (5 μg/mL) of ADGL. Moreover, we observed that the combined treatment with ADGL and siRNAs against these proteins highly sensitized the MDA-MB-231 cells to apoptosis compared to that with ADGL and control siRNA. Collectively, our results suggest that ADGL targets EGFR, thereby inhibiting EMT in human breast cancer cells.

Novel Compound MMV1804559 from the Global Health Priority Box Exhibits In Vitro and In Vivo Activity against Madurella mycetomatis.

Eumycetoma is a neglected tropical disease (NTD) characterized by subcutaneous lesions and the formation of grains. Attempts to treat eumycetoma involve a combination of antifungal treatment and surgery, although the outcome is frequently disappointing. Therefore, there is a need to identify novel antifungal drugs to treat eumycetoma. In this respect, Medicines for Malaria Venture (MMV) has assembled libraries of compounds for researchers to use in drug discovery research against NTD. Therefore, we screened two MMVOpen compound libraries to identify novel leads for eumycetoma. A total of 400 compounds from the COVID Box and the Global Health Priority Box were screened in vitro at 100 µM and 25 µM against the most common causative agents of eumycetoma, namely Madurella mycetomatis and Falciformispora senegalensis, and the resulting IC50 and MIC50 values were obtained. Compounds with an IC50 < 8 µM were identified for possible in vivo efficacy studies using an M. mycetomatis grain model in Galleria mellonella larvae. Out of the 400 compounds, 22 were able to inhibit both M. mycetomatis and F. senegalensis growth at 100 µM and 25 µM, with compounds MMV1593278, MMV020335, and MMV1804559 being selected for in vivo testing. Of these three, only the pyrazolopyrimidine derivative MMV1804559 was able to prolong the survival of M. mycetomatis-infected G. mellonella larvae. Furthermore, the grains in MMV1804559-treated larvae were significantly smaller compared to the PBS-treated group. MMV1804559 shows promising in vitro and in vivo activity against M. mycetomatis.

Long-term efficacy and safety of levonorgestrel releasing intrauterine system in the treatment of adenomyosis: evidence mapping.

To summarize evidence on levonorgestrel releasing intrauterine system (LNG-IUS) in the treatment of adenomyosis (AM) and to identify potential research gaps. Search was conducted in MEDLINE, The Cochrane Library, EMBASE, CBM, CNKI, and Wanfang. We included studies investigating patients with AM treated with LNG-IUS combined with conservative therapy. Thirty-nine studies compared LNG-IUS with other conservative therapeutic drugs. The most common comparison was GnRH-a+LNG-IUS vs. LNG-IUS alone, followed by LNG-IUS vs. mifepristone, expected treatment, and GnRH-a. GnRH-a+LNG-IUS was more beneficial in reducing the intensity of dysmenorrhea than LNG-IUS alone at the 6-month follow-up in patients with an enlarged uterus and moderate to severe dysmenorrhea. Large and well-designed studies are needed to confirm the efficacy of LNG-IUS and GnRH-a on reducing uterine volume at 6-month follow-up. Thirty-two studies investigated LNG-IUS as the postoperative management. The most common comparison was surgical excision+LNG-IUS vs. surgical excision. Results showed VAS scores were lower in the surgical excision+LNG-IUS group than in the surgical excision group at the 1-year follow-up. Evidence on endometrial thickness, quality of life, adverse events and beneficial effect at 3 and 5years are needed. Combined GnRH-a and LNG-IUS treatment was more efficacious than LNG-IUS alone for patients with an enlarged uterus and moderate to severe dysmenorrhea. Moreover, LNG-IUS seemed to show potential long-term benefits in postoperative therapy, warranting further meta-analysis for confirmation.