Synergistic Effect Of Combination Research Articles

Exploring the Synergistic Effects of Biostimulant and Hydrogel Combinations on Brinjal Growth: An Assessment of Growth Parameters

Background: This study at Lovely Professional University, Phagwara, Punjab, evaluates the combined effects of hydrogel and Arka Vegetable biostimulants on brinjal (Solanum melongena L.) production. Brinjal’s high water and nutrient needs make it sensitive to water scarcity and seasonal variations. Hydrogel enhances soil moisture retention, reducing irrigation needs, while Arka Vegetable biostimulants improve plant growth and stress tolerance. Using both together aims to optimize water management and plant health, addressing key challenges in brinjal cultivation. Methods: In the study, the hydrogel was applied during the sowing stage, while Arka Vegetable Special was sprayed twice, with a 15-day interval after transplanting. The treatment designated as V2H2 (5 g/L + 1.5 kg/acre) was utilized, where ‘V’ represents concentration in grams per liter and ‘H’ denotes application rate in kilograms per acre. This treatment is aimed at optimizing vegetative growth. Various levels of Arka Vegetable Special and hydrogel application were tested to observe their effects on growth characteristics. Result: The study’s findings revealed the effectiveness of the V2H2 treatment in enhancing vegetative growth. Application of Arka Vegetable Special and hydrogel at different levels significantly improved all the studied growth characteristics. This suggests the potential of integrating biostimulants and Hydrogel practices to optimize Brinjal production, offering a sustainable solution to meet year-round vegetable demand and mitigate water scarcity challenges in agricultural systems.

Fenbendazole and Diisopropylamine Dichloroacetate Exert Synergistic Anti-cancer Effects by Inducing Apoptosis and Arresting the Cell Cycle in A549 Lung Cancer Cells.

Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for approximately 2 million new cases and 1.8 million deaths annually. Standard treatment options include surgery, radiation therapy, chemotherapy, and targeted therapies. Despite advancements over the past 25 years, the prognosis of patients with lung cancer remains poor. This study evaluated the synergistic anticancer effects of fenbendazole (FZ) and diisopropylamine dichloroacetate (DADA) on A549 lung cancer cells. Fenbendazole (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl) carbamate) is a broad-spectrum benzimidazole anthelmintic commonly used in veterinary medicine. Diisopropylamine Dichloroacetate (DADA), an over-the-counter treatment for chronic liver disease, has demonstrated anti-tumor properties as an inhibitor of pyruvate dehydrogenase kinase. The combination of FZ and DADA exhibited a synergistic effect on inhibiting the proliferation of A549 lung cancer cells. After 48 h of treatment, the FZ-DADA combination produced reactive oxygen species (ROS) and promoted apoptosis by down-regulating Bcl2 and up-regulating BAX protein expression. The combination activated caspase-3, caspase-7, and PARP, further driving apoptosis in A549 cells. The FZ-DADA treatment also induced cell cycle arrest, as evidenced by the inhibition of Cyclin A and Cyclin E proteins. The synergistic anticancer effects of the FZ-DADA combination were confirmed at both cellular and protein levels in A549 lung cancer cells. The combination modulates key apoptotic proteins, induces cell cycle arrest, and increases mitochondrial ROS production, suggesting a promising approach for lung cancer treatment that warrants further investigation and development.

Synergistic effects of bacteriophage cocktail and antibiotics combinations against extensively drug-resistant Acinetobacter baumannii

BackgroundThe extensively drug-resistant (XDR) strains of Acinetobacter baumannii have become a major cause of nosocomial infections, increasing morbidity and mortality worldwide. Many different treatments, including phage therapy, are attractive ways to overcome the challenges of antibiotic resistance.MethodsThis study investigates the biofilm formation ability of 30 XDR A. baumannii isolates and the efficacy of a cocktail of four tempetate bacteriophages (SA1, Eve, Ftm, and Gln) and different antibiotics (ampicillin/sulbactam, meropenem, and colistin) in inhibiting and degrading the biofilms of these strains.ResultsThe majority (83.3%) of the strains exhibited strong biofilm formation. The bacteriophage cocktail showed varying degrees of effectiveness against A. baumannii biofilms, with higher concentrations generally leading to more significant inhibition and degradation rates. The antibiotics-bacteriophage cocktail combinations also enhanced the inhibition and degradation of biofilms.ConclusionThe findings suggested that the bacteriophage cocktail is an effective tool in combating A. baumannii biofilms, with its efficacy depending on the concentration. Combining antibiotics with the bacteriophage cocktail improved the inhibition and removal of biofilms, indicating a promising strategy for managing A. baumannii infections. These results contribute to our understanding of biofilm dynamics and the potential of bacteriophage cocktails as a novel therapeutic approach to combat antibiotic-resistant bacteria.

Lactobacillus gasseri BNR17 and Limosilactobacillus fermentum ABF21069 Ameliorate High Sucrose-Induced Obesity and Fatty Liver via Exopolysaccharide Production and β-oxidation.

Obesity and metabolic dysfunction-associated fatty liver disease (MAFLD) are prevalent metabolic disorders with substantial global health implications that are often inadequately addressed by current treatments and may have side effects. Probiotics have emerged as promising therapeutic agents owing to their beneficial effects on gut health and metabolism. This study investigated the synergistic effects of a probiotic combination of BNR17 and ABF21069 on obesity and MAFLD in C57BL/6 mice fed a high-sucrose diet. The probiotic combination significantly reduced body weight and fat accumulation compared with the high-sucrose diet. It also alleviated elevated serum leptin levels induced by a high-sucrose diet. Histological analysis revealed a significant reduction in white adipose tissue and fatty liver in the mice treated with the probiotic combination. Furthermore, increased expression of genes related to β-oxidation, thermogenesis, and lipolysis suggested enhanced metabolic activity. The probiotic groups, particularly the BNR17 group, showed an increase in fecal exopolysaccharides, along with a tendency toward a lower expression of intestinal sugar transport genes, indicating reduced sugar absorption. Additionally, inflammatory markers in the liver tissue exhibited lower expression in the ABF21069 group than in the HSD group. Despite each strain in the combination group having distinct characteristics and functions, their combined effect demonstrated synergy in mitigating obesity and MAFLD, likely through the modulation of fecal exopolysaccharides content and improvement in lipid metabolism. These findings underscore the potential of probiotic supplementation as a promising assistant therapy for managing obesity and MAFLD and provide valuable insights into its therapeutic mechanisms in metabolic disorders.

Synergistic effects of antimicrobial components of the human-derived composite amnion-chorion membrane on bacterial growth.

The human-derived amnion-chorion membrane (ACM) has endogenous antimicrobial properties, which are important for preventing the colonization and survival of oral bacteria on exposed membranes. This project aimed to decipher the underlying mechanism by identifying the components of ACM that confer antibacterial properties. In addition, the antimicrobial efficacy of these identified components on oral bacteria was assessed. Four antimicrobial proteins, histone H2A/H2B, cathelicidin LL-37, lactoferrin, and lysozyme, were identified via mass spectrometry in ACM. These proteins were then assessed for their efficacy in killing Streptococcus gordonii Challis. Log-phased bacterial cells were cultured with the commercially available proteins that were identified in ACM, either individually or in combination, at different concentrations. After incubation for 8 or 24 hours, the bacteria were stained with a live/dead viability kit and analyzed via confocal microscopy. The combination of these proteins effectively killed S. gordonii in a dose-dependent fashion after 8 or 24 hours of incubation. When each protein was tested individually, it killed S. gordonii at a much lower efficacy relative to the combinations. The synergistic effects of the antimicrobial protein combinations were also observed in both the viable cell count recovery and minimum inhibitory concentration assays. By shedding light on the mechanisms in the ACM's antimicrobial property, this study may raise more awareness of the potential benefit of utilization of a membrane with endogenous antimicrobial properties in regeneration surgeries.

Antibacterial synergistic effect of sea cucumber extract and kelulut honey combination

Natural products remain one of the major sources of new drug molecules today. The combination of sea cucumber extract with stingless bee honey holds great potential for health supplement. However, the specific results of the combination have yet to be determined. In this study, the antibacterial activity of kelulut honey and Phyllophorus spiculata sea cucumber extract samples individually and in combination were assessed with disk-diffusion assays and broth dilution method. Most of the samples exhibit small or absence of inhibitory activity using disk-diffusion assay method. Only kelulut honey sample with 100% concentration has a positive antagonism effect against Escherichia coli and Staphylococcus epidermidis. For the broth dilution method, Gram-positive bacteria were found to be more susceptible as compared to Gram-negative bacteria species, with lower minimum inhibitory concentration (MIC) value of kelulut honey, sea cucumber or combination sample. The growth of gram-positive S. epidermidis is inhibited by sea cucumber extract at MIC value of 0.031 mg/mL, kelulut honey at MIC value of 0.063 mg/ mL and combination sample at MIC value of 0.063 mg/mL, all of which are of lower MIC value as compared to E. coli inhibition. The absorbance at optical density (OD) 600nm wavelength was also measured to monitor the growth of bacteria in solution. From the results, broth dilution proves to be a more effective method to assess the antibacterial activity in the combination samples. Two combinations showed the best antibacterial synergy (OD600 value of 0.000) against both Gram-positive and Gram-negative bacteria, which were (1) ½ sea cucumber: ½ kelulut honey combination and (2) ¾ sea cucumber: ¼ kelulut honey combination. This preliminary evidence on their antibacterial synergistic activities is promising and shows possible commercialization potential.

Synergistic anticancer effects and reduced genotoxicity of silver nanoparticles and tamoxifen in breast cancer cells

AbstractNanotechnology is emerging as a promising tool to enhance traditional cancer treatments due to rising chemotherapy resistance and the severe side effects of toxic drugs. Silver nanoparticles (AgNPs) are widely acknowledged for their antimicrobial and antiproliferative properties. Given these AgNP characteristics, this research conducts a comprehensive nanotoxicological assessment of strategic combinations involving AgNPs (68 nm) commercial formulation and tamoxifen on MCF‐7 and MDA‐MB‐231 breast tumor cells. Utilizing CompuSyn software, the combination index was determined, revealing a synergistic cytotoxic and antiproliferative effect in AgNPs and tamoxifen combinations (CI < 0.97). Furthermore, this combination impaired cell migration (the scratch zone expanded by over 270%) and significantly increased reactive oxygen species production (up to 96% for MDA‐MB‐231 and 52% for MCF‐7 cells). Surprisingly, the genotoxic effect of these mixtures was minimal (below the allowable genotoxicity index of 1.5). Additionally, both breast tumor cell lines exhibited increased proapoptotic and oxidative stress gene expression following the combined treatment. The internalization of AgNPs into breast cancer cells was observed, enhancing their synergistic antiproliferative effect when combined with tamoxifen. These findings suggest the potential of combining AgNPs with chemotherapeutic agents for innovative studies in oncology therapy.

Abstract C046: Targeting wild-type IDH1 sensitizes homologous recombination proficient pancreatic cancer to PARP inhibition

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the United States. While Poly (ADP-ribose) polymerase (PARP) inhibitors show promise for PDAC with Homologous Recombination Deficiency (HRD), this mutation is present in less than 10% of cases. Our research focuses on exploiting a vulnerability in the remaining 90% of HR proficient (HRP) tumors. We identified that wild-type isocitrate dehydrogenase 1 (IDH1) plays a critical role in HR repair. By inhibiting IDH1, we discovered suppression of the homologous recombination (HR) pathway, leading to compromised genomic integrity. This renders cancer cells more susceptible to PARP inhibitor therapy, offering a novel therapeutic approach for HRP PDAC. Methods:We assessed the impact of IDH1 inhibition on HR pathway activity using Western blotting to measure HR repair protein levels and HR reporter assays. The effect of IDH1 inhibition (Ivosidenib) combined with PARP inhibition (Olaparib) on in vitro growth inhibition was assessed through drug combination assays. Additionally, we investigated the molecular mechanisms underlying the synergistic effects of the drug combination. To further evaluate the therapeutic potential of IDH1 inhibition in combination with PARP inhibitors, we examined tumor growth in xenograft models of PDAC in athymic nude mice and survival studies were performed in C57BL/6J mice transplanted with orthotopic murine pancreatic cancer. Results:Wild-type IDH1 blockade induces a BRCA-like phenotype by decreasing α-ketoglutarate (αKG) levels and causing histone hypermethylation. This leads to decreased HR repair efficiency in HRP pancreatic cancer cells (MiaPaCa-2 and Panc-1), resulting in a strong synergistic effect when combined with the DNA-damaging agent Olaparib. The combination treatment significantly reduced cell survival in both short and long-term assays. Furthermore, we discovered that these compounds complemented each other in the DNA damage response, leading to increased γ-H2AX (DNA damage marker) and apoptosis. In vivo studies using murine PDAC models demonstrated that the combination of ivosidenib and olaparib synergistically enhanced anti-tumor activity compared to either single agent alone. Conclusion:These data provide novel insight into the mechanisms underlying in the context of HRP cancer susceptibility to a dual treatment approach involving an IDH1 inhibitor and a PARP inhibitor. This approach holds promise for precision medicine in pancreatic cancer treatment, although further pre- clinical studies are needed for validation and refinement. Citation Format: Mehrdad Zarei, Omid Hajihassani, Hallie J. Graor, Soubhi Tahhan, Alexander W. Loftus, Faith Nakazzi, Semmer A. Ali, Parnian Naji, Luke D. Rothermel, Jonothan R. Brody, Jordan M. Winter. Targeting wild-type IDH1 sensitizes homologous recombination proficient pancreatic cancer to PARP inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C046.

The SoCAP (Social Communication, Affiliation, and Presence) Taxonomy of Social Features: Scoping Review of Commercially Available eHealth Apps.

eHealth interventions have proven to be valuable resources for users with diverse mental and behavioral health concerns. As these technologies continue to proliferate, both academic researchers and commercial app creators are leveraging the use of features that foster a sense of social connection on these digital platforms. Yet, the literature often insufficiently represents the functionality of these key social features, resulting in a lack of understanding of how they are being implemented. This study aimed to conduct a methodical review of commercially available eHealth apps to establish the SoCAP (social communication, affiliation, and presence) taxonomy of social features in eHealth apps. Our goal was to examine what types of social features are being used in eHealth apps and how they are implemented. A scoping review of commercially available eHealth apps was conducted to develop a taxonomy of social features. First, a shortlist of the 20 highest-rated eHealth apps was derived from One Mind PsyberGuide, a nonprofit organization with trained researchers who rate apps based on their (1) credibility, (2) user experience, and (3) transparency. Next, both mobile- and web-based versions of each app were double-coded by 2 trained raters to derive a list of social features. Subsequently, the social features were organized by category and tested on other apps to ensure their completeness. Four main categories of social features emerged: (1) communication features (videoconferencing, discussion boards, etc), (2) social presence features (chatbots, reminders, etc), (3) affiliation and identity features (avatars, profiles, etc), and (4) other social integrations (social network and other app integrations). Our review shows that eHealth apps frequently use resource-intensive interactions (eg, videoconferencing with a clinician and phone calls from a facilitator), which may be helpful for participants with high support needs. Furthermore, among commercially available eHealth apps, there is a strong reliance on automated features (eg, avatars, personalized multimedia, and tailored content) that enhance a sense of social presence without requiring a high level of input from a clinician or staff member. The SoCAP taxonomy includes a comprehensive list of social features and brief descriptions of how these features work. This classification system will provide academic and commercial eHealth app creators with an understanding of the various social features that are commonly implemented, which will allow them to apply these features to enhance their own apps. Future research may include comparing the synergistic effects of various combinations of these social features.

The passive optimization mechanism of winter thermal performance in commercial complex based on coupled multi-spatial parameters

In cold regions, public buildings often suffer from suboptimal thermal performance due to cold air intrusion. This study explores the synergistic impact of multiple spatial parameters on winter thermal environments to discover the passive optimization potential in commercial complexes. Airflow analysis covers the entire connected space from the entrance to the large atrium, integrating the collective effects of all critical spatial parameters. Based on 4500 Computational Fluid Dynamics (CFD) simulation, the study establishes how these parameters influence wind resistance and thermal comfort. Key findings reveal that the “Atrium-plan Ratio,” “Transitional Space-width,” and “Atrium-height,” are most impactful on wind resistance, contributing over 53 % collectively. For thermal comfort, “Atrium-volume,” “Atrium-section Form,” and “Atrium-height,” are most significant, with a combined weight exceeding 57 %. As wind speed increases, the effect of single parameters gradually diminishes, highlighting the synergistic effect of spatial combinations. A case study demonstrates an 80.5 % improvement in thermal performance score following optimization, underscoring the potential for low-carbon, high-efficiency design in commercial complexes.

Synergistic combination effect of the PCA-1/ALKBH3 inhibitor HUHS015 on prostate cancer drugs in vitro and in vivo.

Prostate cancer antigen-1/ALKBH3, a DNA/RNA demethylase of 3-methylcytosine, 1-methyladenine (1-meA), and 6-meA, was found in prostate cancer as an important prognostic factor. Additionally, 1-meA has been associated with other cancers. The ALKBH3 inhibitor HUHS015 was found to be effective against prostate cancer both in vitro and in vivo. Herein, we investigated the effect of HUHS015 in combination with drugs for prostate cancer approved in Japan (including bicalutamide, cisplatin, mitoxantrone, prednisolone, ifosfamide, tegafur/uracil, docetaxel, dacarbazine, and estramustine) by treating DU145 cells with around IC50 value concentrations of these drugs for 3 days. Additionally, the cells were observed for additional 9 days after drug removal. Combination treatment with dacarbazine, estramustine, tegafur/uracil, and HUHS015 showed a slight additive effect after 3 days. After drug washout of them and mitoxantrone, the combined effects and levels were enhanced and sustained, although the effects of each treatment alone declined. HUHS015 combined with cisplatin or docetaxel elicited synergistic and sustained effects. In vivo, combining HUHS015 and docetaxel, the first chemotherapeutic agent for castration-resistant prostate cancer, showed notable effects in the DU145 xenograft model. In conclusion, HUHS015 exhibited a synergistic effect with docetaxel and drugs acting on DNA in vitro, even after drug removal. Since cancer chemotherapy is typically administered during rest periods due to its high toxicity, combining it with an ALKBH3 inhibitor could be a promising strategy for enhancing cancer treatment, as it can elicit an additive effect during treatment, allowing dosage reduction, and synergistically sustain the effect after drug washout during rest periods.

MMFSyn: A Multimodal Deep Learning Model for Predicting Anticancer Synergistic Drug Combination Effect.

Combination therapy aims to synergistically enhance efficacy or reduce toxic side effects and has widely been used in clinical practice. However, with the rapid increase in the types of drug combinations, identifying the synergistic relationships between drugs remains a highly challenging task. This paper proposes a novel deep learning model MMFSyn based on multimodal drug data combined with cell line features. Firstly, to ensure the full expression of drug molecular features, multiple modalities of drugs, including Morgan fingerprints, atom sequences, molecular diagrams, and atomic point cloud data, are extracted using SMILES. Secondly, for different modal data, a Bi-LSTM, gMLP, multi-head attention mechanism, and multi-scale GCNs are comprehensively applied to extract the drug feature. Then, it selects appropriate omics features from gene expression and mutation omics data of cancer cell lines to construct cancer cell line features. Finally, these features are combined to predict the synergistic anti-cancer drug combination effect. The experimental results verify that MMFSyn has significant advantages in performance compared to other popular methods, with a root mean square error of 13.33 and a Pearson correlation coefficient of 0.81, which indicates that MMFSyn can better capture the complex relationship between multimodal drug combinations and omics data, thereby improving the synergistic drug combination prediction.

Diclofenac Sodium Restores the Sensitivity of Colistin-Resistant Gram-Negative Bacteria to Colistin.

The continuous rise of multidrug-resistant (MDR) Gram-negative bacteria poses a severe threat to public health worldwide. Colistin(COL), employed as the last-line antibiotic against MDR pathogens, is now at risk due to the emergence of colistin-resistant (COL-R) bacteria, potentially leading to adverse patient outcomes. In this study, synergistic activity was observed when colistin and diclofenac sodium (DS) were combined and used against clinical COL-R strains of Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Acinetobacter baumannii (A. baumannii), and Pseudomonas aeruginosa (P. aeruginosa) both in vitro and in vivo. The checkerboard method and time-killing assay showed that DS, when combined with COL, exhibited enhanced antibacterial activity compared to DS and COL monotherapies. Crystal violet staining and scanning electron microscopy showed that COL-DS inhibited biofilm formation compared with monotherapy. The in vivo experiment showed that the combination of DS and COL reduced bacterial loads in infected mouse thighs. Synergistic activity was observed when COL and DS were use in combination against clinical COL-R strains of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa both in vitro and in vivo. The synergistic antibacterial effect of the COL-DS combination has been confirmed by performing various in vitro and in vivo experiments, which provides a new treatment strategy for infections caused by MDR bacteria.

Dual targeting of histone deacetylases and MYC as potential treatment strategy for H3-K27M pediatric gliomas.

Diffuse midline gliomas (DMGs) are aggressive and fatal pediatric tumors of the central nervous system that are highly resistant to treatments. Lysine to methionine substitution of residue 27 on histone H3 (H3-K27M) is a driver mutation in DMGs, reshaping the epigenetic landscape of these cells to promote tumorigenesis. H3-K27M gliomas are characterized by deregulation of histone acetylation and methylation pathways, as well as the oncogenic MYC pathway. In search of effective treatment, we examined the therapeutic potential of dual targeting of histone deacetylases (HDACs) and MYC in these tumors. Treatment of H3-K27M patient-derived cells with Sulfopin, an inhibitor shown to block MYC-driven tumors in vivo, in combination with the HDAC inhibitor Vorinostat, resulted in substantial decrease in cell viability. Moreover, transcriptome and epigenome profiling revealed synergistic effect of this drug combination in downregulation of prominent oncogenic pathways such as mTOR. Finally, in vivo studies of patient-derived orthotopic xenograft models showed significant tumor growth reduction in mice treated with the drug combination. These results highlight the combined treatment with PIN1 and HDAC inhibitors as a promising therapeutic approach for these aggressive tumors.

Dual targeting of histone deacetylases and MYC as potential treatment strategy for H3-K27M pediatric gliomas

Diffuse midline gliomas (DMGs) are aggressive and fatal pediatric tumors of the central nervous system that are highly resistant to treatments. Lysine to methionine substitution of residue 27 on histone H3 (H3-K27M) is a driver mutation in DMGs, reshaping the epigenetic landscape of these cells to promote tumorigenesis. H3-K27M gliomas are characterized by deregulation of histone acetylation and methylation pathways, as well as the oncogenic MYC pathway. In search of effective treatment, we examined the therapeutic potential of dual targeting of histone deacetylases (HDACs) and MYC in these tumors. Treatment of H3-K27M patient-derived cells with Sulfopin, an inhibitor shown to block MYC-driven tumors in vivo, in combination with the HDAC inhibitor Vorinostat, resulted in substantial decrease in cell viability. Moreover, transcriptome and epigenome profiling revealed synergistic effect of this drug combination in downregulation of prominent oncogenic pathways such as mTOR. Finally, in vivo studies of patient-derived orthotopic xenograft models showed significant tumor growth reduction in mice treated with the drug combination. These results highlight the combined treatment with PIN1 and HDAC inhibitors as a promising therapeutic approach for these aggressive tumors.

Review on endobronchial therapies-current status and future.

There is a growing demand for lung parenchymal-sparing localized therapies due to the rising incidence of multifocal lung cancers and the growing number of patients who cannot undergo surgery. Lung cancer screening has led to the discovery of more pre-malignant or early-stage lung cancers, and the focus has shifted from treatment to prevention. Transbronchial therapy is an important tool in the local treatment of lung cancers, with microwave ablation showing promise based on early and mid-term results. To improve the precision and efficiency of transbronchial ablation, adjuncts such as mobile C-arm platforms, software to correct for computed tomography (CT)-to-body divergence, metal-containing nanoparticles, and robotic bronchoscopy are useful. Other forms of energy such as steam vapor therapy, pulsed electric field, and photodynamic therapy are being intensively investigated. In addition, the future of transbronchial therapies may involve the intratumoral injection of novel agents such as immunomodulating agents, gene therapies, and chimeric antigen receptor T cells. Extensive pre-clinical and some clinical research has shown the synergistic abscopal effect of combination of these agents with ablation. This article aims to provide the latest updates on these technologies and explore their most likely future applications.

Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma.

Neurofibromatosis type 2 is a genetic disorder that results in the formation and progressive growth of schwannomas, ependymomas, and/or meningiomas. The NF2 gene encodes the Merlin protein, which links cell cortical elements to the actin cytoskeleton and regulates a number of key enzymes including Group I p21-activated kinases (PAKs), the Hippo-pathway kinase LATS, and mTORC. While PAK1 and PAK2 directly bind Merlin and transmit proliferation and survival signals when Merlin is mutated or absent, inhibition of Group 1 PAKs alone has not proven sufficient to completely stop the growth of NF2-deficient meningiomas or schwannomas in vivo, suggesting the need for a second pathway inhibitor. As the Hippo pathway is also activated in NF2-deficient cells, several inhibitors of the Hippo pathway have recently been developed in the form of YAP-TEAD binding inhibitors. These inhibitors prevent activation of pro-proliferation and anti-apoptotic Hippo pathway effectors. In this study, we show that PAK inhibition slows cell proliferation while TEAD inhibition promotes apoptotic cell death. Finally, we demonstrate the efficacy of PAK and TEAD inhibitor combinations in several NF2-deficient Schwannoma cell lines.

Investigating the properties and agronomic benefits of onion peel and chicken feather-derived biochars

Biochar production from unconventional biomass, specifically onion peel (OP) and chicken feathers (CF), was investigated in this study. Two distinct biochars were produced by doping each biomass with the other, with the aim of exploring the synergistic effects of different feedstock combinations on biochar properties. The biochar production process was conducted using a retort heating method and characterized using several techniques. A yield of 36 % was obtained for OP-doped biochar (OP92CF8-BC) and 23 % for CF-doped biochar (F92OP8-BC). Fourier Transform Infrared Spectroscopy analysis revealed characteristic functional groups from cellulose, hemicellulose, and lignin in OP92CF8-BC, while CF92OP8-BC displayed keratin-related peaks. Scanning Electron Microscopy imaging showed surface morphology differences, with OP92CF8-BC exhibiting a rougher and more porous structure compared to CF92OP8-BC. Energy-Dispersive X-ray Spectroscopy analysis confirmed the elemental composition, with OP92CF8-BC having higher carbon, calcium, and sulfur contents and CF92OP8-BC having higher nitrogen and oxygen contents. The biochar had specific surface areas of 342.4 and 200.80 m2/g for OP92CF8-BC and CF92OP8-BC, respectively. According to the results, using biochar treatments-more especially, CF92OP8-BC-can significantly enhance cob weight. This could be good for agricultural productivity. These findings highlight the influence of feedstock composition on the properties of biochar and provide insights for its potential applications in soil amendment and pollutant removal.

Synergistic effect of osthole and notopterol combination against Alzheimer's disease and osteoporosis by applying zebrafish AD/OP comorbidity model

Alzheimer's disease (AD) and osteoporosis (OP) are both serious degenerative diseases, with the potential for concurrent occurrence in clinical settings, and they share certain pathological correlations. Osthole (OST) and notopterol (NOT) are the main active ingredients in traditional Chinese medicine, Angelica pubescens and Notopterygium incisum, respectively, and they exhibit neuroprotective and osteoprotective effects. However, whether the combination of OST and NOT produces a synergistic effect against AD and/or OP remains unclear. The aim of this study was to investigate whether the combination of OST and NOT could produce synergistic anti-AD and/or OP effects using the previously constructed zebrafish AD/OP comorbidity model. Active compounds with anti-AD and OP effects were screened from Angelica pubescens and Notopterygium incisum through network pharmacology, identifying OST and NOT, respectively. Then, the AlCl3-induced (Aluminum chloride, AlCl3) AD combined with OP zebrafish model, in conjunction with the Chou-Talalay synergy evaluation model, was employed to assess whether the OST and NOT combination produced synergistic effects against AD and/or OP. Furthermore, a CuSO4-induced (Copper sulfate, CuSO4) inflammation zebrafish model was used to investigate whether the combination of OST and NOT produced synergistic anti-inflammatory effects, thereby resulting in synergistic anti-AD and/or OP effects. The results demonstrated that the OST-NOT combined treatment produced a synergistic anti-AD and OP effect. Moreover, the combined treatment of OST and NOT significantly inhibited nitric oxide (NO) and reactive oxygen species (ROS) release more effectively than OST or NOT alone, indicating a synergistic anti-inflammatory effect of the OST and NOT combined treatment.

Nanoliposomal in situ gel of fluoxetine and embelin as a potent intervention for depression via the intranasal route in CUMS animal model

Due to the intricate mechanism of depression, slow therapeutic effect, and intolerable side effects, fluoxetine does not treat its many symptoms. To address monotherapy's limitations, novel and synergistic therapies are needed. This study delves into the potential of thermosensitive nanoliposomal gel loaded with fluoxetine and embelin (FXT-EMB NLs in situ gel) to manage depression via the intranasal route in a chronic unpredictable mild stress (CUMS) animal model. FXT-EMB NLs were prepared using thin-film hydration, optimized by a central composite design, and loaded into an in situ gel containing Poloxamer-407 and HPMC polymers. The optimized NLs had satisfactory vesicle size (92.6 ± 1.3 nm), TEM, SEM, PDI (0.22 ± 0.01), zeta potential (35.1 ± 0.2 mV), and entrapment efficiency (87.09 and 73.26 % for FXT and EMB) results. DSC, FTIR, and XRD confirmed the purity of APIs, compatibility, and loading efficiency of the in situ gel. The in vitro release showed sustained release, whereas the ex vivo permeation and CLSM studies demonstrated enhanced permeation across goat nasal mucosa (19.351 and 19.6 μg/cm2/h). DPPH assay confirmed the antioxidant potential of the NLs and was non-irritant according to the nasal toxicity and HET-CAM studies. The N2a neuroblastoma cell line revealed cell viability and the synergistic effect of the drug combination (CI < 1). The in vivo study found that NLs significantly enhanced SOD and CAT levels in Wistar rats, and reduced IL-6, TNF-α levels, and immobility time in the CUMS model of depression (p < 0.001). The combination and synergistic antioxidant action of FXT and EMB-loaded NLs in situ gel could be beneficial for effectively treating depression.