Combined Treatment Research Articles

Combination treatment with telitacicept, mycophenolate mofetil and glucocorticoids for immunoglobulin A nephropathy: A case report

BACKGROUND Telitacicept reduces B cell activation and abnormal immunoglobulin A (IgA) antibody production by inhibiting the activity of B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), thereby decreasing IgA deposition in the glomeruli and local inflammatory response. This ultimately protects the kidneys from damage. This mechanism suggests that Telitacicept has potential efficacy in the treatment of IgA nephropathy. CASE SUMMARY We present the case of a 24-year-old female who was diagnosed with IgA nephropathy due to significant proteinuria and mild renal impairment. Pathologically, she exhibited focal proliferative glomerulonephritis. Treatment with angiotensin II receptor blocker, hormones, and mycophenolate mofetil did not lead to a significant improvement in her condition. However, upon the addition of telitacicept, the patient’s renal function recovered and her proteinuria rapidly reduced. Hormones were swiftly tapered and discontinued, with no occurrence of severe infections or related complications. CONCLUSION Telitacicept combined with hormones and mycophenolate mofetil may be a safe and effective induction therapy for IgA nephropathy.

Synergistic combination of perphenazine and temozolomide suppresses patient-derived glioblastoma tumorspheres.

Glioblastoma (GBM), a primary malignant brain tumor, has a poor prognosis, even with standard treatments such as radiotherapy and chemotherapy. In this study, we explored the anticancer effects of the synergistic combination of perphenazine (PER), a dopamine receptor D2/3 (DRD2/3) antagonist, and temozolomide (TMZ), a standard treatment for GBM, in patient-derived human GBM tumorspheres (TSs). The biological effects of the combination of PER and TMZ in GBM TSs were assessed by measuring cell viability, ATP, stemness, invasiveness, and apoptosis. Changes in protein and mRNA expression were analyzed using western blotting and RNA sequencing. Co-administration of PER and TMZ was evaluated in vivo using a mouse orthotopic xenograft model. The Severance dataset showed that DRD2 and DRD3 expression was higher in tumor tissues than in the tumor-free cortex of patients with GBM. DRD2/3 knockout by CRISPR/Cas9 in patient-derived human GBM TSs inhibited cell growth and ATP production. The combined treatment with PER and TMZ resulted in superior effects on cell viability and ATP assays compared to those in single treatment groups. Flow cytometry, western blotting, and RNA sequencing confirmed elevated apoptosis in GBM TSs following combination treatment. Additionally, the combination of PER and TMZ downregulated the expression of protein and mRNA associated with stemness and invasiveness. In vivo evaluation showed that combining PER and TMZ extended the survival period of the mouse orthotopic xenograft model. The synergistic combination of PER and TMZ has potential as a novel combination treatment strategy for GBM.

Synergistic ferroptosis in triple-negative breast cancer cells: Paclitaxel in combination with Erastin induced oxidative stress and Ferroportin-1 modulation in MDA-MB-231 cells.

Ferroptosis is an important regulated cell death mechanism characterized by iron-dependent lipid peroxidation and oxidative stress. In this study, we examined the ferroptosis-inducing effect of the combined use of Paclitaxel, a microtubule-stabilizing agent, and Erastin, a ferroptosis inducer, in breast cancer cells. In this context, the combination of the compounds in question was applied to the cells and the presence of a synergistic effect was determined by calculating the combination index. Glutathione (GSH) levels and glutathione peroxidase (GPX) activity were determined by commercial assay kits, and the effect of the compounds on lipid peroxidation was determined by measurement of malondialdehyde (MDA) levels. Additionally, the effect of combination treatment on ferroptotic protein expression was determined by western blot. Our findings revealed that the combination treatment caused a significant change in mitochondrial function by causing an increase in the depolarized/viable cell population. Additionally, there was a significant increase in intracellular reactive oxygen species (ROS) levels compared to single applications of the compounds. The significant increase observed in malondialdehyde (MDA) levels revealed that the combination treatment increased lipid peroxidation. Moreover, intracellular GSH levels and glutathione peroxidase (GPX) activity significantly decreased by Paclitaxel-Erastin combination. The expression of ferroptosis-regulating proteins was significantly downregulated. The findings showed that the Paclitaxel-Erastin combination synergistically contributed to the accumulation of lipid reactive oxygen species and induced the ferroptotic cell death pathway in breast cancer cells.

Pre-Plant Soil Treatments Influence Tree Performance and Nematode Dynamics in Replanted Cherry Orchards.

In this two-year field study, the impacts of pre-plant soil management strategies, including soil fumigation, nematicide application, and organic amendments, on the growth and nematode community dynamics on cherry cultivars 'Emperor Francis' and 'Ulster' grafted to 'Mahaleb' rootstock were investigated in a replanted orchard site. In the first year, fumigation with 1,3-dichloropropene - chloropicrin mixture (Telone C-35) led to significantly increased trunk cross-sectional area and canopy height in both cultivars. Pratylenchus penetrans population densities were suppressed only short-term. Plots treated with the fungicide/nematicide fluopyram (Velum® Prime) had P. penetrans reproduction factors below one throughout both years independent of the scion. Additionally, the combined application of Seed Starter 101®, Dairy Doo® compost, and straw mulch reduced the reproduction factor of P. penetrans to below one in the first year. In the same time period, this combinatory treatment had the highest reproduction factor for bacterivore and fungivore nematodes. Based on results of this study, fumigation with Telone® C-35 resulted in improvement of tree establishment and provided effective short-term suppression of P. penetrans. Velum® Prime exhibited longer-term efficacy for the suppression of P. penetrans.

Effects of Combined Biochar and Chemical Fertilizer Application on Soil Fertility and Properties: A Two-Year Pot Experiment

A two-year pot experiment was conducted to investigate the effects of the combined application of biochar and chemical fertilizer on soil quality and vegetable growth by adding different proportions of chemical fertilizer and biochar to the soil in 2022 and no fertilizer in 2023. It was concluded that the combined treatment improved the soil’s properties. After two consecutive years of planting vegetables, the improvement of soil properties was the most significant with the 1.5 g biochar + 80% chemical fertilizer optimal fertilizer application (BCF6) treatment. In comparison to the control (CK), soil pH, electrical conductivity, and dissolved organic carbon increased by 0.59 units, 166.6%, and 282.6%, respectively. Soil fertility also improved significantly, indicating that the combined treatments resulted in the slow release of nutrients to enhance the effectiveness of the fertilizers. Co-application significantly increased the yield of the edible parts of Chinese cabbage and improved its quality. The most significant effects of vitamin C content and soluble protein were observed in Chinese cabbage under BCF6 treatment, which were 3.33 and 1.42 times more than the CK, respectively. Utilizing biochar as a partial substitute for chemical fertilizers can improve soil structure and fertility over the long term while reducing the reliance on chemical fertilizers, ultimately providing sustained economic and ecological benefits for agricultural production.

Efficacy of endovascular therapy in short-term two-stage operation for thrombosed giant cerebral aneurysm

Background: Giant cerebral aneurysms have a high rupture rate, are often difficult to treat, and have a poor prognosis. We report two cases in which good results were achieved with a short, two-stage operation using a combination of endovascular treatment (EVT) and direct surgery. Case Description: Case 1 - A 50-year-old man had become immobile due to truncal ataxia after nausea. Magnetic resonance imaging, computed tomography (CT), and angiography revealed a giant thrombosed aneurysm of the right vertebral artery 30 mm in diameter, which compressed medulla oblongata. He underwent endovascular parent artery occlusion (PAO) followed by direct surgical thrombectomy 3 days later.The patient’s outcome was modified Rankin score (mRS) 1 at 7 days after the operation and mRS 0 at 1 year. Case 2 - A 40-year-old man developed a progressive visual disturbance. CT showed a giant thrombosed aneurysm of 50 mm diameter in the C2 portion of the left internal carotid artery. A balloon test occlusion (BTO) and cerebral blood flow single-photon emission computed tomography under BTO suggested partial ischemic tolerance due to PAO. PAO followed by low flow bypass and thrombectomy of the aneurysm by direct surgery was performed on the same day.The patient’s vision was improved with the outcome of mRS 1. Conclusion: EVT in a short-term two-stage operation for a thrombosed giant cerebral aneurysm is effective for the purpose of hemostasis in the thrombectomy designed to decompress the suffered brain or nerve. Complete PAO and meticulous perioperative use of antithrombotic agents are necessary to avoid perforator failure and hemorrhagic complications in this technique.

Optimization of water and nitrogen management in wheat cultivation affected by biochar application − Insights into resource utilization and economic benefits

In the context of global climate change and natural resource scarcity, agricultural production is facing multiple challenges in improving crop yields and optimizing natural resource use. It is of great practical significance to optimize agricultural practices to achieve sustainable agricultural development. In this study, a two-year winter wheat field experiment was conducted in the Guanzhong Plain, Shaanxi, China, from 2020 to 2022 to assess the effects of biochar, irrigation, and N fertilizer rates on the yield, water-nitrogen use efficiency, and economic benefits of winter wheat. Specifically, biochar was applied to winter wheat at 30 t ha−1 in combination with two irrigation application rates, including regular irrigation (I100; actual evapotranspiration) and deficit irrigation (I80; 0.8 actual evapotranspiration), and three different N fertilizer rates at 210 (NH; conventional applied N rate by local farmers), 160 (NM; moderate N rate), and 110 kg ha−1 (NL; low N rate). The control groups in this study consisted of experimental plots under the NM and N0 (no N) without biochar application. The aboveground dry matter mass (ADM), yield, and net ecosystem economic budget (NEEB) of winter wheat showed increasing trends with increasing N application rates without significant differences between the NH and NM treatments. On the other hand, the water use efficiency (WUE), agronomic N fertilizer use efficiency (aNUE), and N fertilizer recovery efficiency (NRE) showed increasing-decreasing trends with increasing N fertilizer rates, reaching the highest values under the NM treatment scenario. The biochar addition significantly increased the winter wheat yield and WUE (P<0.05). On the other hand, the I80 treatment resulted in higher WUE and irrigation water use efficiency (IWUE) than those under I100 by 5.63 and 13.52 %, respectively. TOPSIS results indicated that the combined I80B1NM treatment was the optimal winter wheat management practice, maintaining high productivity while improving resource use efficiency and economic benefits. The results of the present study provide an important scientific basis and guidance for ensuring efficient and high-quality agricultural products in the Guanzhong Plain and other regions in China with similar climatic characteristics.

Combination of low-dose, long-term immunoglobulin and mirtazapine is effective in progressive multifocal leukoencephalopathy caused by JC virus infection

BackgroundProgressive multifocal leukoencephalopathy (PML) is an often fatal disease of the central nervous system caused by opportunistic infection of John Cunningham Polyomavirus (JCV). There’s still no antiviral therapeutic strategy which was generally recognized as effective. The prognosis may differ in patients with different pathological mechanisms and treatments. We aim to report the effectiveness of combined treatment of low-dose, long-term immunoglobulin and mirtazapine in a pathologically proved PML case.Case presentationA patient presented with progressive acalculia, right-left confusion and visual neglection was recorded. She received 10-year immunosuppressive therapy for dermatomyositis. White matter lesions located in bilateral parietal lobe and callosum area symmetrically in MR scanning. JC virus analysis and brain biopsy in left parietal lobe were performed. The number of JCV copies was 2595 in CSF and 282,809 in brain specimen. Abundant foamy macrophages and the lymphatic cells were obvious in immunohistochemistry staining. Few SV-40 positive JC infected cell and more CD4 + and CD68 + cells were predominant. Immunosuppressive drugs were terminated after being diagnosed as PML for positive JCV and pathological characteristics. In addition, immunoglobulin (5 g/day) and mirtazapine (45 mg/day) were used. JC virus in CSF decreased to 0 after treatment for 4 months and was still negative in June 2023. The clinical symptoms improved, and white matter lesions recovered significantly.ConclusionsWe demonstrated that the combination treatment of IVIG and mirtazapine was effective in PML. Low-dose, long-term immunoglobulin might regulate the immune status in our case with controlled inflammatory reaction instead of destructive virus spreading. The therapy may be a prospective option for PML.

Study of TRAIL and SAHA Co-Treatment on Leukemia K562 Cell Line.

TRAIL (Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand) is an attractive agent being considered a potential cancer treatment. It attaches to its death receptors, leading many cancer cells to apoptosis. However, some malignancies indicate substantial resistance to TRAIL, challenging anticancer scientists. Herein, combination therapy with TRAIL plus SAHA (Suberoyl Anilide Hydroxamic Acid) was conducted to evaluate the capability of SAHA to overcome TRAIL resistance in the leukemia K562 cell line. First, the IC50 for SAHA was calculated (2 µM) at 12, 24, 48, and 72 h of treatment using MTT assay. Second, the K562 cells were treated with concentrations of 50 and 100 nM of TRAIL and 2 μM of SAHA separately and together for 24, 48, and 72 h and the survival of these cells was evaluated by Flowcytometry following the annexin-V and PI staining. To demonstrate the non-toxicity of the combined treatment for normal cells, the HEK-293 cell line was treated with the TRAIL 100 nM and SAHA 2 μM combined and separated at the same periods. In the end, by performing real-time PCR, the amount of candidate genes' expression implicated in TRAIL resistance, and the levels of BCR-ABL expression was measured. The drug dosages were not toxic to normal cells. SAHA plus TRAIL strongly triggered apoptosis in K562 cells after 24, 48, and 72 h of exposure. Furthermore, it was shown that DR4, DR5, and CHOP expressions were enhanced, and PI3K, Akt, ERK, STAT3, c-FLIPL, NF-κB, and BCR-ABL expressions were decreased by SAHA in K562 cells. Our study indicated that SAHA combined with TRAIL can increase the sensitivity of K562 leukemic cells to TRAIL by suppressing intracellular anti-apoptotic molecules and augmenting the expressions of DR4/DR5 and CHOP.

High dose chemotherapy with autologous stem cell rescue in children and young adults with high-risk Ewing sarcoma: A single institute experience in Taiwan.

A combination treatment of surgery, chemotherapy, and radiotherapy can improve the survivals of pediatric patients with Ewing sarcoma (ES). However, prognosis remains poor for patients with metastatic disease at diagnosis or recurrence. Other high-risk (HR) features include large tumor burden, tumors of the axial skeleton and poor histologic response. Several studies have documented high dose chemotherapy with autologous stem cell rescue (HDC-ASCR) to be effective in such patients. In this retrospective study, we present the results of HDC-ASCR for high-risk Ewing sarcoma in children and young adults in a single institute. From March 2004 to March 2021, patients with ES, Ewing-like sarcoma, or round cell sarcoma received HDC-ASCR as part of treatment were included. The patients' characteristics, disease status, stem cell dose, engraftment status, post-transplant complications, and outcomes were analyzed. Twenty patients receiving HDC-ASCR at complete response (n = 6), partial response (n = 13), and stable disease (n = 1) were enrolled. The male to female ratio was 11:9. Median age at diagnosis and transplant was 15.6 years old (range: 3.3-28.9) and 16.2 (range: 4.2-29.9), respectively. The conditioning regimens included ifosfamide-based in two and melphalan-based in 19. All patients achieved successful engraftment without tansplant-related mortality. The 5-year progression-free and overall survival (OS) rate were 35% and 54.5%, respectively. The causes of death (n = 8) were all contributed to disease progression. Patients in the complete response group or with localized HRES exhibited a higher 5-year OS (p = 0.047 and 0.05, respectively). Compared to the historical cohort without HDC-ASCR as part of primary treatment, the current cohort had a significantly better 5-year OS (p = 0.018). HDC-ASCR seems promising as an alternative treatment for HRES in improving OS in this retrospective study with limited case number.

Application of straw-derived biochar: a sustainable approach to improve soil quality and crop yield and reduce N2O emissions in paddy soil.

The burning of agricultural straw is a pressing environmental issue, and identifying effective strategies for the rational utilization of straw resources is decisive for achieving sustainable development. Owing to its high carbon content and exceptional stability, straw biochar produced via pyrolysis has emerged as a key focus in multidisciplinary research. However, the efficacy of biochar in mitigating nitrous oxide (N2O) emissions from paddy soils is not consistent. A 2-year field experiment was conducted and investigated the impact of biochar derived from two feedstocks (rice straw and wheat straw, pyrolyzed at 450°C) on N2O emissions, global warming potential (GWP), greenhouse gas intensity (GHGI), nitrogen use efficiency (NUE), crop yield, and soil quality. The static chamber technique was used for collecting N2O gas samples, and concentrations were analyzed through gas chromatography methods. The treatment combinations included BR0 (control), BR1 (NPK at the recommended dose, 120:60:40kgha-1), BR2 (wheat straw biochar, 5 t ha-1), and BR3 (rice straw biochar, 5 t ha-1). The results exhibited that cumulative N2O emissions from BR2 and BR3 treatments decreased by 10.55% and 13.75% respectively, compared to BR1. Lower GWP and GHGI were observed under both biochar treatments compared with BR1. The highest rice grain yield (3.48Mgha-1) and NUE (76.72%) were recorded from BR3, which also exhibitedthe lowest yield-scaled N2O emission. We observed positive correlations between soil nitrate, ammonia and water-filled pore spaces, while NUE showed negative correlations with N2O emissions. Significant (p < 0.05) improvements in soil quality were also detected in both the biochar treated plots, indicated by increased soil pH, water holding capacity, porosity, and nutrient contents. Overall, the results suggest that applying biochar at a rate of 5 t ha-1 in paddy soil is a viable nutrient management strategy with the potential to reduce reliance on inorganic fertilizers, mitigate N2O emissions, and contribute to sustainable food production.

Cognitive effects, pharmacokinetics, and safety of zuranolone administered alone or with alprazolam or ethanol in healthy adults in a phase 1 trial.

Zuranolone is an oral, once-daily, 14-day treatment course approved for adults with postpartum depression in the United States. To assess cognitive effects, pharmacokinetics, and safety of zuranolone, alone or with alprazolam/ethanol. This was a phase 1, two-part, two-period, randomized, double-blind, placebo-controlled crossover trial. Participants received zuranolone 50 mg or placebo once daily for 9 days, and additionally received alprazolam (1 mg, Part A), ethanol (males: 0.7 g/kg; females: 0.6 g/kg, Part B), or corresponding placebo on days 1, 5, and 9. Within each part, participants received all treatment combinations. Cognition was assessed using a computerized test battery; pharmacokinetics and safety were also evaluated. All participants (Part A, N = 24; Part B, N = 25) received ⩾1 dose of zuranolone/placebo. Compared to placebo, zuranolone produced small-to-moderate cognitive decline (Cohen's |d| = 0.126-0.76); effects were larger with alprazolam (Cohen's |d| = 0.523-0.93) and ethanol (Cohen's |d| = 0.345-0.88). Zuranolone coadministration with alprazolam (Cohen's |d| = 0.6-1.227) or ethanol (Cohen's |d| = 0.054-0.5) generally worsened cognitive decline when compared with zuranolone alone. Maximal pharmacodynamic effects occurred at approximately 5 h and were resolved by 12 h postbaseline. No pharmacokinetic interactions were observed. Incidence of adverse events was similar between groups; most events were mild or moderate in severity. A general small-to-moderate magnitude decline in cognition occurred with zuranolone alone. Coadministration with alprazolam/ethanol increased the magnitude, but not the duration, of effects compared with single-agent administration. Zuranolone prescribers and patients should be aware of the potential for increased central nervous system-depressant effects if coadministered with GABAergic active compounds such as alprazolam and ethanol.

Comprehensive population pharmacokinetic modelling of sugemalimab, an anti-programmed death-ligand 1 (PD-L1) human monoclonal antibody, in patients with solid tumours or lymphomas across multiple Phase I-III studies.

The aim of this study was to develop a population pharmacokinetics model for sugemalimab, a monoclonal antibody that targets programmed death-ligand 1 (PD-L1), using data from Phase I-III trials and to assess clinical factors affecting sugemalimab exposure. A nonlinear mixed-effect modelling approach was employed to analyse pooled data from nine studies involving 1628 subjects to characterize the PopPK of sugemalimab. This investigation examined the influence of various covariates on sugemalimab pharmacokinetics (PK), encompassing demographics, baseline hepatic and renal function-related covariates, and others (including anti-drug antibody [ADA], combination treatment, Eastern Cooperative Oncology Group [ECOG] performance score, tumour burden and tumour type). Estimation accuracy and predictive ability of the final model were evaluated using various methods. The influence of covariates on sugemalimab exposure was assessed by simulation from the final model. A two-compartment model with first-order elimination and time-varying clearance effectively described the PK of sugemalimab. Covariate analyses revealed significant relationships between sugemalimab clearance and body weight, albumin, gender, ADA, tumour burden and tumour type. The statistically significant covariates on central volume were body weight, albumin, gender and tumour type. No significant relationships were found in the final model for age, race, alanine aminotransferase, aspartate aminotransferase, creatinine, total bilirubin, alkaline phosphatase, combination treatment, creatinine clearance, ECOG, renal function or hepatic function. All significant covariates demonstrated less than a 20% effect on sugemalimab exposure. The PopPK model adequately described the pharmacokinetic profile of sugemalimab with no clinically meaningful impact observed on its exposure across all covariates. Dose adjustment does not appear to be necessary.

Newcastle disease virus enhances the antitumor efficacy of Doxorubicin in a cervical cancer mouse model

Background and aimsCervical cancer (CC) is a common cancer among women, often treated with Doxorubicin (Doxo). Research is underway to explore the use of oncolytic virus (OV) therapy as a means to improve drug efficacy and enhance the immune system’s tumor-fighting capabilities. Hence, our study purposes to evaluate the therapeutic potential of Newcastle disease virus (NDV) in increasing the antitumor efficacy of Doxo in mouse models of CC.Methods and materialsTC1 cells were administered to C57BL/6 mice (Female) in a range of 6 to 8 weeks age (n = 40) to induce tumor growth. After tumor development, four treatment groups of mice were formed. Treatment were performed through NDV, Doxo, and a combination of both in three groups of treatment twice in a one-week intervention manner, while the control group treated with PBS. Following the last treatment, half of these mice were subjected to euthanize due to the immune-response assessment, and the other half were followed up till they died naturally in a certain period of time.ResultsMice that underwent the combined treatment showed significantly improved survival rates and slower tumor progression in comparison with the control group. This combined treatment substantially elevated nitric oxide (NO) and lactate dehydrogenase (LDH) levels in the splenocytes cultures of mice bearing cervical tumors. Furthermore, combination therapy resulted in a notable elevation in TNF-α, IL-12, and IFN-γ, secretion alongside a reduction in the release of TGF-β and IL-4 within the splenocytes in counter with the treatment of just NDV or Doxo.ConclusionAccording to the findings of this study, it seems that utilizing NDV can improve the effectiveness of Doxo in a mouse model of CC, suggesting it can serve as an adjunct therapy alongside chemotherapy.

Transcriptional repression by HDAC3 mediates T cell exclusion from Kras mutant lung tumors

Histone Deacetylase 3 (HDAC3) function in vivo is nuanced and directed in a tissue-specific fashion. The importance of HDAC3 in Kras mutant lung tumors has recently been identified, but HDAC3 function in this context remains to be fully elucidated. Here, we identified HDAC3 as a lung tumor cell-intrinsic transcriptional regulator of the tumor immune microenvironment. In Kras mutant lung cancer cells, we found that HDAC3 is a direct transcriptional repressor of a cassette of secreted chemokines, including Cxcl10. Genetic and pharmacological inhibition of HDAC3 robustly up-regulated this gene set in human and mouse Kras, LKB1 (KL) and Kras, p53 (KP) mutant lung cancer cells through an NF-κB/p65-dependent mechanism. Using genetically engineered mouse models, we found that HDAC3 inactivation in vivo induced expression of this gene set selectively in lung tumors and resulted in enhanced T cell recruitment at least in part via Cxcl10. Furthermore, we found that inhibition of HDAC3 in the presence of Kras pathway inhibitors dissociated Cxcl10 expression from that of immunosuppressive chemokines and that combination treatment of entinostat with trametinib enhanced T cell recruitment into lung tumors in vivo. Finally, we showed that T cells contribute to in vivo tumor growth control in the presence of entinostat and trametinib combination treatment. Together, our findings reveal that HDAC3 is a druggable endogenous repressor of T cell recruitment into Kras mutant lung tumors.

Effects of pomegranate exocarp extract on H. pylori-induced pancreatic EMT: Molecular mechanisms and therapeutic potential

BackgroundPrevious studies have linked Helicobacter pylori infection with pancreatic diseases, including cancer. PurposeTo explore the influence of pomegranate exocarp extract (PEE) on epithelial-mesenchymal transition (EMT) in H. pylori-induced pancreatic rat tissue and to uncover the underlying molecular mechanisms. Study designTwenty-eight rats were divided into six groups: group 1 (negative control), group 2 (H. pylori-infected), group 3 (infected + PEE pretreatment), group 4 (infected + PEE treatment), group 5 (infected + metronidazole treatment), and group 6 (infected + metronidazole/PEE co-treatment). Methods and resultsThis study aimed to assess the effectiveness of pomegranate exocarp extract (PEE) in treating Helicobacter pylori infection and its associated pancreatic tissue changes in Wistar rats. The study involved Forty-eight male rats divided into six groups: H. pylori-infected control, PEE-preventive, PEE treatment, metronidazole treatment, PEE combined with metronidazole treatment, and negative control. The results showed a significant reduction in H. pylori concentration in the antrum in the PEE-treated groups (27.08 %) compared to that in the positive control group (p < 0.05). The group receiving the combined treatment exhibited the highest reduction (55.8 %) in H. pylori concentration (p < 0.005), with no significant difference observed between the PEE-preventive and metronidazole-treated groups. The ELISA results showed that the groups treated with PEE, PEE-preventive, and PEE combined with metronidazole experienced a significant increase in pancreatic E-cadherin levels by 47.7 %, 73.8 %, and 118.06 % respectively, and a substantial decrease in vimentin levels by 16.6 %, 31.6 %, and 43.5 % respectively, compared to the positive control group (p < 0.05). The results of the RT-qPCR analysis showed that the PEE treatment group, as well as the PEE preventive and PEE combined with metronidazole treatment groups, displayed significant downregulation of vimentin, sirtuin1, and lncRNA MALAT-1, and upregulation of E-cadherin compared to the positive control group. However, there was no significant difference between the PEE-preventive and metronidazole-treated groups (p < 0.05). Histopathological analysis showed considerable improvement in pancreatic tissue morphology in the PEE-treated groups. The inflammation score was significantly lower in these groups (p < 0.05), and the combined treatment group exhibited minimal signs of metaplasia and mononuclear cell infiltration. A computational study identified 54 human target genes of bioactive compounds in PEE. These findings shed light on the crucial interactions and pathways in treating pancreatic tumors. Additionally, GO enrichment and KEGG pathway analyses revealed significant pathways, such as the MAPK signaling and RTK pathway, enriched with genes targeted by PEE. Furthermore, evaluation of drug-likeness and ADME properties indicated that ellagic acid possesses drug-like properties and has a high potential for oral absorption. In conclusion, PEE has shown significant therapeutic potential in reducing H. pylori load and improving pancreatic tissue health while influencing key molecular markers and pathways associated with pancreatic tumors.

A multi-task graph deep learning model to predict drugs combination of synergy and sensitivity scores

BackgroundDrug combination treatments have proven to be a realistic technique for treating challenging diseases such as cancer by enhancing efficacy and mitigating side effects. To achieve the therapeutic goals of these combinations, it is essential to employ multi-targeted drug combinations, which maximize effectiveness and synergistic effects.ResultsThis paper proposes ‘MultiComb’, a multi-task deep learning (MTDL) model designed to simultaneously predict the synergy and sensitivity of drug combinations. The model utilizes a graph convolution network to represent the Simplified Molecular-Input Line-Entry (SMILES) of two drugs, generating their respective features. Also, three fully connected subnetworks extract features of the cancer cell line. These drug and cell line features are then concatenated and processed through an attention mechanism, which outputs two optimized feature representations for the target tasks. The cross-stitch model learns the relationship between these tasks. At last, each learned task feature is fed into fully connected subnetworks to predict the synergy and sensitivity scores.The proposed model is validated using the O’Neil benchmark dataset, which includes 38 unique drugs combined to form 17,901 drug combination pairs and tested across 37 unique cancer cells. The model’s performance is tested using some metrics like mean square error (MSE\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$MSE$$\\end{document}), mean absolute error (MAE\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$MAE$$\\end{document}), coefficient of determination (R2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${R}^{2}$$\\end{document}), Spearman, and Pearson scores. The mean synergy scores of the proposed model are 232.37, 9.59, 0.57, 0.76, and 0.73 for the previous metrics, respectively. Also, the values for mean sensitivity scores are 15.59, 2.74, 0.90, 0.95, and 0.95, respectively.ConclusionThis paper proposes an MTDL model to predict synergy and sensitivity scores for drug combinations targeting specific cancer cell lines. The MTDL model demonstrates superior performance compared to existing approaches, providing better results.

Cell cycle inhibitors activate hypoxia-induced DDX41-STING pathway to mediate anti-tumor immune response in liver cancer.

Cell cycle inhibitors have a long history as cancer treatment. Here, we reported that these inhibitors combated cancer partially via Stimulator of IFN genes (STING) signaling pathway. We demonstrated that Paclitaxel (microtubule stabilizer), Palbociclib (cyclin dependent kinase 4/6 inhibitor), AZD1152 and GSK1070916 (aurora kinase B inhibitors) have anti-cancer functions beyond arresting cell cycle. They consistently caused cytosolic DNA accumulation and DNA damage, which inadvertently triggered the cytosolic DNA sensor DEAD-box helicase 41 (DDX41) and activated STING to secrete pro-inflammatory senescence-associated secretory phenotype factors (SASPs). Interestingly, we found that DDX41 was a transcriptional target of HIF. Hypoxia induced expression of DDX41 through HIF-1, making hypoxic HCC cells more sensitive to the anti-mitotic agents in STING activation and SASP production. The SASPs triggered immune cell infiltration in tumors for cancer clearance. The treatment of cell cycle inhibitors, especially Paclitaxel, extends survival by perturbing mouse HCC growth when used in combination with anti-PD-1. We observed a trend that Paclitaxel suppressed STINGWT HCC more effectively than STINGKO HCC, suggesting that STING might contribute to the anti-tumor effects of Paclitaxel. Our study revealed the immune-mediated tumor-suppressing properties of cell cycle inhibitors and suggested combined treatment with immunotherapy as a potential therapeutic approach.

Mitigative Effect and Mechanism of Caffeic Acid Combined with Umbilical Cord-Mesenchymal Stem Cells on LPS-Induced Mastitis.

Mastitis is an inflammation of the mammary gland tissue that can lead to decreased milk production and altered milk composition, carrying serious implications for the safety of dairy products. Although both caffeic acid (CA) and umbilical cord-mesenchymal stem cells (UC-MSCs) showed potential anti-inflammatory and immunomodulatory properties, little is known about their combined roles in treating mastitis. Here, we report the combined effects and mechanisms of CA and UC-MSCs on lipopolysaccharide (LPS)-induced mastitis. Based on the network pharmacological analysis, the potential relevant genes involved in the alleviating effects of CA on LPS-induced mastitis were inferred. In LPS-treated mammary epithelial cells, CA or/and UC-MSC conditioned medium (UC-MSC-CM) inhibited the phosphorylation of p65, p50, p38, IκB, and MKK3/6 proteins and the expression of downstream inflammatory factors TNF-α, IL-1β, IL-6, IL-8, and COX-2. Additionally, CA or/and hydrogel-loaded UC-MSCs also suppressed the activation of the above inflammatory pathway, leading to the alleviation of pathological damages in the LPS-induced mouse mastitis model. UC-MSCs exhibited more significant effects than CA, and the combined treatment of both was more effective. Our study sheds light on the synergistic and complementary effects of CA and UC-MSCs in alleviating mastitis, offering clues for understanding the regulation of the p38-MAPK/NF-κB↔TNF-α signal transduction loop in the tumor necrosis factor (TNF) pathway as a potential mechanism. This study provides a theoretical basis for developing a novel antibiotic alternative treatment of mastitis that may contribute to reducing economic losses in animal husbandry and protecting public health safety.

Active-bromide and surfactant synergy for enhanced microfouling control.

Biofilms are structured microbial communities encased in a matrix of self-produced extracellular polymeric substance (EPS) and pose significant challenges in various industrial cooling systems. A nuclear power plant uses a biocide active-bromide for control of biological growth in its condenser cooling system. This study is aimed at evaluating the anti-bacterial and anti-biofilm efficacy of active-bromide against planktonic and biofilm-forming bacteria that are commonly encountered in seawater cooling systems. The results demonstrated that active-bromide at the concentration used at the power plant (1 ppm) exhibited minimal killing activity against Pseudomonas aeruginosa planktonic cells. The bacterial cell surface hydrophobicity assay using Staphylococcus aureus and P. aeruginosa indicated that Triton-X 100 significantly decreased the hydrophobicity of planktonic cells, enhancing the susceptibility of the cells to active-bromide. Biofilm inhibition assays revealed limited efficacy of active-bromide at 1 ppm concentration, but significant inhibition at 5 ppm and 10 ppm. However, the addition of a surfactant, Triton-X 100, in combination with 1 ppm active-bromide displayed a synergistic effect, leading to significant biofilm dispersal of pre-formed P. aeruginosa biofilms. This observation was substantiated by epifluorescence microscopy using a live/dead bacterial assay that showed the combination treatment resulted in extensive cell death within the biofilm, as indicated by a marked increase in red fluorescence, compared to treatments with either agent alone. These findings suggest that active bromide alone may be insufficient for microfouling control in the seawater-based condenser cooling system of the power plant. Including a biocompatible surfactant that disrupts established biofilms (microfouling) can significantly improve the efficacy of active bromide treatment.