Combined Treatment Research Articles

Combination of Etoposide and Quercetin-Loaded Solid Lipid Nanoparticles Potentiates Apoptotic Effects on MDA-MB-231 Breast Cancer Cells

BackgroundBreast cancer is a major global cancer, for which radiation and chemotherapy are the main treatments. Natural remedies are being studied to reduce the side effects. Etoposide (ETO), a chemo-drug, and quercetin (QC), a phytochemical, are considered potential factors for adaptation to conventional treatments. ObjectivesThe anticancer effect of the synergy between ETO and Quercetin-loaded solid lipid nanoparticles (QC-SLNs), was investigated in MDA-MB-231 cells. MethodsWe developed QC-SLNs for efficient cellular delivery, characterizing their morphology, particle size, and zeta potential. We assessed the cytotoxicity of QC-SLNs and ETO on breast cancer cells via the MTT assay. Effects on apoptosis intensity in MDA-MB-231 cells have been detected utilizing annexin V-FITC, PI, and caspase activities. Real-time PCR assessed Bax gene and Bcl-2 gene fold change expression, while Western blot analysis determined p53 and p21 protein levels. ResultsSpherical, negatively charged QC-SLNs, when combined with ETO, significantly enhanced inhibition of MDA-MB-231 cell proliferation compared to ETO or QC-SLNs alone. The combined treatment also notably increased the apoptosis pathway. QC-SLNs + ETO increased the Bax/Bcl-2 gene ratio, elevated p53 and p21 proteins, and activated caspase 3 and 9 enzymes. These results indicate the potential for QC-SLNs + ETO as a strategy for breast cancer treatment, potentially overcoming ETO-resistant breast cancer chemoresistance. ConclusionThese results suggest that QC-SLN has the potential to have a substantial impact on the breast cancer cure by improving the efficacy of ETO. This enhancement could potentially help overcome chemoresistance observed in ETO-resistant breast cancer.

Dexmedetomidine hydrochloride plus sufentanil citrate inhibits glucose metabolism and epithelial‑mesenchymal transition in human esophageal squamous carcinoma KYSE30 cells by modulating the JAK/STAT3/HIF‑1α axis.

Dexmedetomidine hydrochloride (DEX-HCl) and sufentanil citrate (SFC) are commonly used anesthetic drugs for esophageal cancer (EC) surgery. The present study was performed to investigate the effect of DEX-HCl and SFC treatment on glucose metabolism and epithelial-mesenchymal transition in EC. Cell counting kit-8 (CCK8), clonogenic, wound healing and Transwell migration assays were performed to assess the effects of the DEX-HCl and SFC on KYSE30 cell proliferation, invasion and migration. Changes in lactate and glucose levels in KYSE30 cells were also detected. Western blot analysis was used to determine the protein expression levels of the JAK/STAT signaling pathway and glucose metabolism-related proteins. The results of CCK8, clonogenic and wound healing assays demonstrated that DEX-HCl and SFC inhibited KYSE30 cell proliferation, invasion and migration. Similarly, the combined DEX-HCl and SFC treatment significantly reduced lactate production, ATP production and glucose levels in KYSE30 cells. Western blotting indicated that DEX-HCl and SFC could reduce JAK/STAT and metastasis-related protein expression. Demonstrating a reduction in Hexokinase 2, matrix metallopeptidase 2 and 9, N-cadherin and lactate dehydrogenase A protein expression levels. The effects of DEX-HCl and SFC combined treatment were counteracted by the addition of JAK/STAT pathway activator RO8191, which suggested that DEX-HCl and SFC could serve a role in mediating the JAK/STAT signaling pathway in KYSE30 cells.

Effects of sinomenine on a rat orthotopic liver carcinoma model.

Liver carcinoma is a common malignant tumor. In this study, an orthotopic liver carcinoma model was established by B-ultrasound, and the therapeutic effect of sinomenine (Sin) on the disease was investigated. SD rats were randomly divided into control, Sin, Sorafenib (Sor), and combination (Sin+Sor) groups (n=8). An orthotopic liver carcinoma model was established by inoculating N1-S1 cells into the rat liver by B-ultrasound-guided, and tumor volume was monitored three times by B-ultrasound after inoculation. After drug treatment, the tumor tissues were stained with HE and TUNEL, and the levels of inflammatory cytokines, ALT and AST were detected by ELISA. The numbers of erythrocytes, leukocytes and platelets were detected. Immunohistochemistry and immunofluorescence were used to detect the expression of Ki-67, CD44, VEGF and CD31. The levels of cell cycle, apoptosis-related proteins were detected by western blot. B-ultrasound monitoring found that Sin reduced tumor volume. Moreover, Sin improved tissue lesions, and promoted cancer cell apoptosis. Sin decreased the levels of inflammatory cytokines, AST and ALT, and decreased the numbers of erythrocytes, leukocytes and platelets. Simultaneously, the expressions of Ki-67, CD44, VEGF and CD31 were decreased in the Sin group. Furthermore, Sin decreased the Bcl-2, Cyclin D1, CDK4, CDK6 and Survivin levels, but increased Bax, Cleaved-caspase3/pro-caspase3, P21 and P27 levels. More importantly, the combination of Sin and Sor treatment was more effective than treatment alone. A rat orthotopic liver carcinoma model was established under the guidance of B-ultrasound, and Sin had a therapeutic effect on orthotopic liver carcinoma.

The use of mouthwash containing trimetaphosphate as an adjunct therapy to fluoridated toothpaste reduces enamel demineralization

IntroductionThe decline in dental caries has been attributed to the widespread use of fluoride (F). Two forms of presentation are fluoridated toothpaste (FT) and mouthwash (MW), widely used by the population. Materials and methodsThis study aimed to evaluate in vitro the effects of combining FT and MW, whether supplemented with sodium trimetaphosphate (TMP) or not, on dental enamel demineralization. Bovine enamel blocks (n = 60) were selected based on initial surface hardness (SHi) and divided into 5 experimental groups (n = 12 each): I) Placebo Toothpaste (without F/TMP); II) 1100 ppm F Toothpaste (FT); III) 1100F associated with a MW at 100 ppm F (FT + MW 100F); IV) 1100F associated with a MW at 225 ppm F (FT + MW 250F); and V) 1100F associated with a MW at 100 ppm F supplemented with 0.4% TMP (FT + MW 100F-TMP). The blocks were treated twice a day, undergoing 5 pH cycles over 7 days. Thus, the percentage change in surface hardness (%SH), integrated subsurface hardness loss (ΔKHN), and the concentration of F, phosphorus (P), and calcium (Ca) in the enamel were determined. The data were submitted to ANOVA and Student-Newman-Keuls test (p < 0.001). ResultsThe 1100F group was statistically inferior to the groups associated with MW for %SH, ΔKHN, and the concentration of P and Ca in the enamel (p < 0.001). Blocks treated with FT + MW 225F and FT + MW 100F-TMP showed significantly lower %SH compared to the other groups (p < 0.001). The FT + MW 100F - TMP group exhibited the lowest depth mineral loss (ΔKHN), and higher concentration de P in enamel (p < 0.001). ConclusionThe adjunct use of MW with FT produces a greater protective effect in inhibiting enamel demineralization, and the supplementation of TMP to the MW with 100F provides a superior effect compared to MW with 225F. Clinical significanceThis combination of treatments could be regarded as one of several alternative fluoride supplements for subjects at elevated risk of caries.

Long-term suppression of turfgrass insect pests with native persistent entomopathogenic nematodes

Entomopathogenic nematodes (EPNs) can control several important turfgrass insect pests including white grubs, weevils, cutworms, and sod webworms. But most of the research has focused on inundative releases in a biopesticide strategy using EPN strains that may have lost some of their ability to persist effectively over years of lab maintenance and / or selection for virulence and efficient mass-production. Our study examined the potential of fresh field isolate mixes of endemic EPNs to provide multi-year suppression of turfgrass insect pests. In early June 2020, we applied isolate mixes from golf courses of the EPNs Steinernema carpocapsae, Heterorhabditis bacteriophora, and their combination to plots straddling fairway and rough on two golf courses in central New Jersey, USA. Populations of EPNs and insect pests were sampled on the fairway and rough side of the plots from just before EPN application until October 2022. EPN populations increased initially in plots treated with the respective species. Steinernema carpocapsae densities stayed high for most of the experiment. Heterorhabditis bacteriophora densities decreased after 6 months and stabilized at lower levels. Several insect pests were reduced across the entire experimental period. In the fairway, the combination treatment reduced annual bluegrass weevil larvae (59 % reduction) and adults (74 %); S. carpocapsae reduced only adults (42 %). White grubs were reduced by H. bacteriophora (67 %) and the combination (63 %). Black turfgrass ataenius adults were reduced in all EPN treatments (43–62 %) in rough and fairway. Sod webworm larvae were reduced by S. carpocapsae in the fairway (75 %) and the rough (100 %) and by H. bacteriophora in the rough (75 %). Cutworm larvae were reduced in the fairway by S. carpocapsae (88 %) and the combination (75 %). Overall, our observations suggest that inoculative applications of fresh field isolate mixes of endemic EPNs may be a feasible approach to long-term suppression of insect pests in turfgrass but may require periodic reapplications.

Phytol and α-Bisabolol Synergy Induces Autophagy and Apoptosis in A549 Cells and Additional Molecular Insights through Comprehensive Proteome Analysis via Nano LC-MS/MS.

Non-Small Cell Lung Cancer (NSCLC) is a malignancy with a significant prevalence and aggressive nature, posing a considerable challenge in terms of therapeutic interventions. Autophagy and apoptosis, two intricate cellular processes, are integral to NSCLC pathophysiology, each affecting the other through shared signaling pathways. Phytol (Phy) and α -bisabolol (Bis) have shown promise as potential anticancer agents individually, but their combined effects in NSCLC have not been extensively investigated. The present study was to examine the synergistic impact of Phy and Bis on NSCLC cells, particularly in the context of autophagy modulation, and to elucidate the resulting differential protein expression using LCMS/ MS analysis. The A549 cell lines were subjected to the patented effective concentration of Phy and Bis, and subsequently, the viability of the cells was evaluated utilizing the MTT assay. The present study utilized real-time PCR analysis to assess the expression levels of crucial apoptotic genes, specifically Bcl-2, Bax, and Caspase-9, as well as autophagy-related genes, including Beclin-1, SQSTM1, Ulk1, and LC3B. The confirmation of autophagy marker expression (Beclin-1, LC3B) and the autophagy-regulating protein SQSTM1 was achieved through the utilization of Western blot analysis. Differentially expressed proteins were found using LC-MS/MS analysis. The combination of Phy and Bis demonstrated significant inhibition of NSCLC cell growth, indicating their synergistic effect. Real-time PCR analysis revealed a shift towards apoptosis, with downregulation of Bcl-2 and upregulation of Bax and Caspase-9, suggesting a shift towards apoptosis. Genes associated with autophagy regulation, including Beclin-1, SQSTM1 (p62), Ulk1, and LC3B, showed significant upregulation, indicating potential induction of autophagy. Western blot analysis confirmed increased expression of autophagy markers, such as Beclin-1 and LC3B, while the autophagy-regulating protein SQSTM1 exhibited a significant decrease. LC-MS/MS analysis revealed differential expression of 861 proteins, reflecting the modulation of cellular processes. Protein-protein interaction network analysis highlighted key proteins involved in apoptotic and autophagic pathways, including STOML2, YWHAB, POX2, B2M, CDA, CAPN2, TXN, ECHS1, PEBP1, PFN1, CDC42, TUBB1, HSPB1, PXN, FGF2, and BAG3, emphasizing their crucial roles. Additionally, PANTHER pathway analysis uncovered enriched pathways associated with the differentially expressed proteins, revealing their involvement in a diverse range of biological processes, encompassing cell signaling, metabolism, and cellular stress responses. The combined treatment of Phy and Bis exerts a synergistic inhibitory effect on NSCLC cell growth, mediated through the interplay of apoptosis and autophagy. The differential protein expression observed, along with the identified proteins and enriched pathways, provides valuable insights into the underlying molecular mechanisms. These findings offer a foundation for further exploration of the therapeutic potential of Phy and Bis in the management of NSCLC.

Excimer and Tacrolimus in the treatment of acral vitiligo

Vitiligo is an acquired circumscribed hypomelanosis with a worldwide incidence of 1-2%, with no gender predilection. Acral lesions of vitiligo are typically resistant to conventional treatments, leading to a significant reduction in affected individuals' quality of life. The objective of the study is to evaluate the efficacy of combined tacrolimus and 308 nm excimer laser therapy in treating acral vitiligo lesions. Results indicate repigmentation observed in all patients (100%), with a rate exceeding 75% in 8 out of 10 patients, particularly in those with isolated acral involvement evolving for less than 6 months. Adverse events are limited, with good tolerance. The combined treatment demonstrates statistically significant efficacy, achieving a repigmentation rate of at least 75%. Previous studies suggest tacrolimus alone may induce repigmentation, but comparative studies are needed to confirm these findings. Photodynamic therapies may offer improved outcomes by combining treatments, such as using topical tacrolimus with the 308 nm excimer laser, potentially accelerating repigmentation with sustained results.

Active targeted delivery of theranostic thermo/pH dual-responsive magnetic Janus nanoparticles functionalized with folic acid/fluorescein ligands for enhanced DOX combination therapy of rat glioblastoma.

Doxorubicin (DOX), a chemotherapy drug, has demonstrated limited efficacy against glioblastoma, an aggressive brain tumor with resistance attributed to the blood-brain barrier (BBB). This study aims to overcome this challenge by proposing the targeted delivery of magnetic Janus nanoparticles (MJNPs) functionalized with folic acid ligands, fluorescent dye, and doxorubicin (DOX/MJNPs-FLA). The properties of these nanoparticles were comprehensively evaluated using bio-physiochemical techniques such as Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), zeta potential analysis, high-resolution transmission electron microscopy (HR-TEM), vibrating sample magnetometry (VSM), fluorescence microscopy, MTT assay, hemolysis assay, and liver enzyme level evaluation. Dual-controlled DOX release was investigated under different pH and temperature conditions. Additionally, the impact of DOX/MJNPs-FLA on apoptosis induction in tumor cells, body weight, and survival time of cancerous animals was assessed. The targeted delivery system was assessed using C6 and OLN-93 cell lines as representatives of cancerous and healthy cell lines, respectively, alongside Wistar rat tumor-bearing models. Results from Prussian blue staining and confocal microscopy tests demonstrated the effective targeted internalization of MJNPs-FLA by glioblastoma cells. Additionally, we investigated the biodistribution of the nanoparticles utilizing fluorescence imaging techniques. This enabled us to track the distribution pattern of MJNPs-FLA in vivo, shedding light on their movement and accumulation within the biological system. Furthermore, the combination of chemotherapy and magnetic hyperthermia exhibited enhanced efficacy in inducing apoptosis, as evidenced by the increase of the pro-apoptotic Bax gene and a decrease in the anti-apoptotic Bcl-2 gene. Remarkably, this combination treatment did not cause any hepatotoxicity. This study highlights the potential of DOX/MJNPs-FLA as carriers for therapeutic and diagnostic agents in the context of theranostic applications for the treatment of brain malignancies. Additionally, it demonstrates the promising performance of DOX/MJNPs-FLA in combination treatment through passive and active targeting.

Ising’s Roots and the Transfer-Matrix Eigenvalues

Today, the Ising model is an archetype describing collective ordering processes. As such, it is widely known in physics and far beyond. Less known is the fact that the thesis defended by Ernst Ising 100 years ago (in 1924) contained not only the solution of what we call now the ‘classical 1D Ising model’ but also other problems. Some of these problems, as well as the method of their solution, are the subject of this note. In particular, we discuss the combinatorial method Ernst Ising used to calculate the partition function for a chain of elementary magnets. In the thermodynamic limit, this method leads to the result that the partition function is given by the roots of a certain polynomial. We explicitly show that ‘Ising’s roots’ that arise within the combinatorial treatment are also recovered by the eigenvalues of the transfer matrix, a concept that was introduced much later. Moreover, we discuss the generalization of the two-state model to a three-state one presented in Ising’s thesis, which is not included in his famous paper of 1925 (E. Ising, Z. Physik 31 (1925) 253). The latter model can be considered as a forerunner of the now-abundant models with many-component order parameters.

Clinical Efficacy of Megadose Vitamin C in Sepsis: Protocol for a Multicenter Randomized Single-Blind Placebo-Controlled Clinical Trial

Abstract Introduction Sepsis is a severe disease with a complex pathogenesis and is an important factor in the mortality of patients in intensive care units (ICUs). The administration of vitamin C and its combination treatment in sepsis was not supported by the results of multiple randomized controlled clinical trials. However, the efficacy of a higher vitamin C dose in treating patients with sepsis remains unclear. Therefore, the effectiveness of administering a larger dosage of vitamin C to patients with sepsis remains unclear. Methods and Analysis The Clinical Efficacy of Megadose Vitamin C in Sepsis (CEMVIS) trial is a multicenter, single-blind, randomized, placebo-controlled trial with 234 individuals with sepsis. The following adult patients will be enrolled: those with procalcitonin (PCT) ≥ 2 ng/mL and sepsis 3.0 diagnostic criteria. Patients will be randomly assigned to receive 12 g vitamin C or the same volume of 5% glucose injection intravenously pumped every 12 h for 4 days or up to the moment they are discharged from ICU. The primary outcome will be the mortality within 28 days. Secondary outcomes will mainly include protection and support of organ functions, improvement in inflammatory status, and length of ICU stay. Moreover, adverse events and serious adverse events will be meticulously recorded. Ethics This study was approved by the Clinical Ethics Committee of Zhujiang Hospital of Southern Medical University (2020-KY-069-05). The trial results will be published in peer-reviewed journals or at national or international conferences. Trial registration clinicaltrials.gov, NCT05194189, Registered 3 January 2022, URL: https://www.clinicaltrials.gov.

Performance of Blackgram as Influenced by Water Soluble Fertilizers and PGPR under Rainfed Situation

Lower production potential of blackgram grown under rainfed situation due to lack of proper nutrition during critical crop growth stages. So, investigation was carried out with an objective to study the effect of water-soluble fertilizers and PGPR on performance of blackgram during Kharif-2019, a field study was carried out at University of Agricultural and Horticultural Sciences, Shivamogga which comes under Southern Transition Zone of Karnataka. Experimental design was laid out in randomized complete block design with thirteen treatments and replicated thrice. Treatments include combination of 19:19:19, monopotassium phosphate @ different dosage foliar spray with and without PGPR treatment along with package of practices. Water soluble fertilizers viz., 19:19:19 (N: P: K) and mono potassium phosphate (0:52:34) were used in treatment combinations along with PGPR. The Results revealed that, foliar application of 19:19:19 and mono potassium phosphate @ 1 per cent each at 30 and 45 days after sowing + PGPR along with a package of practice recorded significantly higher plant height, number of branches per plant, leaf and stem dry weight, crude protein (26.54 %), seed yield (1167 kg ha-1) and haulm yield (2019 kg ha-1) over package of practice treatment and also positive correlation was found between growth and yield parameters with seed yield and haulm yield.

Physiochemical interaction between osmotic stress and a bacterial exometabolite promotes plant disease

Various microbes isolated from healthy plants are detrimental under laboratory conditions, indicating the existence of molecular mechanisms preventing disease in nature. Here, we demonstrated that application of sodium chloride (NaCl) in natural and gnotobiotic soil systems is sufficient to induce plant disease caused by an otherwise non-pathogenic root-derived Pseudomonas brassicacearum isolate (R401). Disease caused by combinatorial treatment of NaCl and R401 triggered extensive, root-specific transcriptional reprogramming that did not involve down-regulation of host innate immune genes, nor dampening of ROS-mediated immunity. Instead, we identified and structurally characterized the R401 lipopeptide brassicapeptin A as necessary and sufficient to promote disease on salt-treated plants. Brassicapeptin A production is salt-inducible, promotes root colonization and transitions R401 from being beneficial to being detrimental on salt-treated plants by disturbing host ion homeostasis, thereby bolstering susceptibility to osmolytes. We conclude that the interaction between a global change stressor and a single exometabolite from a member of the root microbiome promotes plant disease in complex soil systems.

Janus kinase inhibitor overcomes resistance to immune checkpoint inhibitor treatment in peritoneal dissemination of gastric cancer in C57BL/6J mice.

Cancer immunotherapy aims to unleash the immune system's potential against cancer cells, providing sustained relief for tumors responsive to immune checkpoint inhibitors (ICIs). While promising in gastric cancer (GC) trials, the efficacy of ICIs diminishes in the context of peritoneal dissemination. Our objective is to identify strategies to enhance the impact of ICI treatment specifically for cases involving peritoneal dissemination in GC. The therapeutic efficacy of anti-PD1, CTLA4 treatment alone, or in combination was assessed using the YTN16 peritoneal dissemination tumor model. Peritoneum and peritoneal exudate cells were collected for subsequent analysis. Immunohistochemical staining, flow cytometry, and bulk RNA-sequence analyses were conducted to evaluate the tumor microenvironment (TME). A Janus kinase inhibitor (JAKi) was introduced based on the pathway analysis results. Anti-PD1 and anti-CTLA4 combination treatment (dual ICI treatment) demonstrated therapeutic efficacy in certain mice, primarily mediated by CD8 + T cells. However, in mice resistant to dual ICI treatment, even with CD8 + T cell infiltration, most of the T cells exhibited anexhaustion phenotype. Notably, resistant tumors displayed abnormal activation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway compared to the untreated group, with observed infiltration of macrophages, neutrophils, and Tregs in the TME. The concurrent administration of JAKi rescued CD8 + T cells function and reshaped the immunosuppressive TME, resulting in enhanced efficacy of the dual ICI treatment. Dual ICI treatment exerts its anti-tumor effects by increasing tumor-specific CD8 + T cell infiltration, and the addition of JAKi further improves ICI resistance by reshaping the immunosuppressive TME.

Risk versus Benefit of Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma: ASystematic Review and Meta-Analysis of Randomized Controlled Trials.

Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.

Systemic Inflammation in Oncologic Patients Undergoing Systemic Treatment and Receiving Whey Protein-Based Nutritional Support

There is increasing evidence about the role of inflammation in sarcopenia and tumor progression; thus, its modulation would represent a valuable strategy for improving clinical outcomes in patients with cancer. Several studies have reported that whey protein has significant anti-inflammatory and antioxidant characteristics in humans. We aimed to evaluate the effects of whey protein-based oral nutritional support on circulating cytokines in patients with solid tumors undergoing systemic treatment. Forty-six patients with solid tumors of different origin and undergoing systemic treatment were evaluated. Nutritional support with two daily whey protein-based oral supplements was administered. Circulating levels of IL-6, IL-8, IL-10, MCP-1 and IP-10 were determined. Nutritional evaluation included anthropometric, instrumental and biochemical parameters. Over 63% of the evaluated patients underwent surgery, 56.5% required chemotherapy and almost 50% received combined treatment. Patients with resected primary tumor presented with lower baseline IL-6 (p &lt; 0.05) and IP-10 (p &lt; 0.001); after three months of nutritional support, they presented with lower IL-8 (p &lt; 0.05) and tended to present lower IL-6 and IP-10 (p = 0.053 and 0.067, respectively). Significant positive correlations between circulating cytokines, C-reactive protein and ferritin were observed; similarly, negative correlations with anthropometric and biochemical nutritional parameters were noticed (p &lt; 0.05). We did not observe significant changes in circulating cytokine levels (IL-6, IL-8, IL-10, MCP-1 and IP-10) in patients with cancer undergoing systemic treatment after three months of nutritional support with whey protein-based oral supplements. According to a univariate analysis in our cohort, circulating IL-8 was associated with mortality in these patients, additionally, MCP-1 and IP-10 tended to correlate; but an age- and sex-adjusted multivariate analysis revealed that only baseline MCP-1 was significantly associated with mortality (OR 1.03 (95% CI: 1.00–1.05)). In conclusion, surgery of the primary solid tumor and combination treatment allow significant reduction in circulating cytokine levels, which remained stable while patients received nutritional support with whey protein-based oral supplements over three months. The role of MCP-1 as an independent factor for mortality in these patients should be further evaluated.

Optimization of nutmeg (Myristica fragrans) grafting using multiple rootstock and scion types

The rootstock number and scion types can be used to optimize grafting success. This study aimed to determine the effect of rootstock number, scion type, and its interaction on the success of nutmeg grafting. The research was conducted at the Seed Breeding Site in Layeni Village, Central Maluku Regency, Maluku. The research started in November 2022 and ended in August 2023. The experiment used a two-factor completely randomized design. The first factor was the rootstock number, i.e., single, double, and triple rootstocks. The second factor was the scion type, i.e., Myristica fragrans Houtt, Myristica argentea Warb, and Myristica sp. The 9 treatment combinations were replicated six times, resulting in a total of 54 experimental units. The result of the study concluded that grafting success was influenced by the rootstock number and the scion types, and there was no interaction between rootstock and scion. The highest success was achieved by using a single rootstock with a success rate of 60%. The use of Myristica sp. scions gave the highest grafting percentage of 76.66%. Successful nutmeg grafting was characterized by the presence of a fusion between the rootstock and the scion, based on anatomical observations. Failed nutmeg grafting was characterized by the absence of fusion between rootstock and scion. The rootstock number and scion type affected shoot emergence time, linked stem diameter, shoot length, and leaf number, while the scion type affected the shoot number. Double rootstock tended to have higher parameters than single and triple rootstock for shoot emergence and leaf number, but the number of failed grafting was still challenging. Keywords: anatomical; double rootstock; compatibility; incompatibility; linked stem diameter

Essential oils in post-harvest disease management: Metabolic impact on Narince (Vitis vinifera L. cv) grapes against Botrytis cinerea

There is an urgent need for alternative, environmentally friendly post-harvest disease management solutions because of the growing concern over the use of chemical fungicides in agriculture and their detrimental impact on human health and the environment. This study examines the effects of thymol, eugenol, and 1,8-cineole essential oils on the sugar, organic acid, and amino acid profiles of 'Narince' grape berries as well as their effectiveness against gray mold (Botrytis cinerea). Our study has noted that the application of EOs, particularly eugenol, significantly alters the metabolic profile of 'Narince' grapes, enhancing sugar content and modifying the levels of organic acids and amino acids, which suggests a potential for improving grape quality and resistance to Botrytis cinerea. The combined use of eugenol with other EOs and fungicides, as indicated by the treatments OF and OSF, not only displayed a synergistic effect in elevating the concentration of key metabolites but also appeared to be more effective in combating fungal infection compared to individual EO applications. The PCA analysis and subsequent heatmap visualization revealed distinct metabolic clustering among the treatments, with combined EO treatments, especially those including eugenol, markedly influencing the amino acid profile of the berries. Our investigation's results suggest that EOs may offer a viable, eco-friendly alternative to traditional fungicides. Our study also adds to the body of knowledge supporting the advancement of integrated pest management strategies that are efficacious yet environmentally considerate, aligning with the global shift towards more sustainable practices in agriculture and food security.

A novel combinatorial approach usingsulforaphane- and withaferin A-rich extracts for prevention of estrogen receptor-negative breast cancer through epigenetic and gut microbial mechanisms.

Estrogen receptor-negative [ER(-)] mammary cancer is the most aggressive type of breast cancer (BC) with higher rate of metastasis and recurrence. In recent years, dietary prevention of BC with epigenetically active phytochemicals has received increased attention due to its feasibility, effectiveness, and ease of implementation. In this regard, combinatorial phytochemical intervention enables more efficacious BC inhibition by simultaneously targeting multiple tumorigenic pathways. We, therefore, focused on investigation of the effect of sulforaphane (SFN)-rich broccoli sprouts (BSp) and withaferin A (WA)-rich Ashwagandha (Ash) combination on BC prevention in estrogen receptor-negative [ER(-)] mammary cancer using transgenic mice. Our results indicated that combinatorial BSp + Ash treatment significantly reduced tumor incidence and tumor growth (~ 75%) as well as delayed (~ 21%) tumor latency when compared to the control treatment and combinatorial BSp + Ash treatment was statistically more effective in suppressing BC compared to single BSp or Ash intervention. At the molecular level, the BSp and Ash combination upregulated tumor suppressors (p53, p57) along with apoptosis associated proteins (BAX, PUMA) and BAX:BCL-2 ratio. Furthermore, our result indicated an expressional decline of epigenetic machinery HDAC1 and DNMT3A in mammary tumor tissue because of combinatorial treatment. Interestingly, we have reported multiple synergistic interactions between BSp and Ash that have impacted both tumor phenotype and molecular expression due to combinatorial BSp and Ash treatment. Our RNA-seq analysis results also demonstrated a transcriptome-wide expressional reshuffling of genes associated with multiple cell-signaling pathways, transcription factor activity and epigenetic regulations due to combined BSp and Ash administration. In addition, we discovered an alteration of gut microbial composition change because of combinatorial treatment. Overall, combinatorial BSp and Ash supplementation can prevent ER(-) BC through enhanced tumor suppression, apoptosis induction and transcriptome-wide reshuffling of gene expression possibly influencing multiple cell signaling pathways, epigenetic regulation and reshaping gut microbiota.

Combined Biologic and Surgical Interventions for Hidradenitis Suppurativa: A Systematic Review

Introduction. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent painful or suppurative lesions due to follicular occlusion. Biologics and other treatment modalities such as surgical excision are commonly used in the treatment of severe HS. However, despite the frequent use of biologics and surgical interventions in the treatment of patients with HS, an assessment of their combined effects is lacking. This systematic review aims to qualitatively analyze the efficacy of combined biologic and surgical treatment for HS. Methods. The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed. The databases PubMed (MEDLINE), Embase, Cochrane (CENTRAL), ClinicalTrials.gov, MedRxiv.org, and the International Clinical Trial Registry were searched from inception until May 1, 2023. Results. A total of 1,145 studies were screened, with eight studies included for data extraction. Patients receiving combined biologic and surgical treatment showed greater improvement in the severity measurements of HS, including HS Impact Assessment, HS Physician Global Assessment, HS Sartorius Score, International Hidradenitis Suppurative Severity Score, HS recurrence rate, and Dermatology Life Quality Index. However, three studies reported a prolongation of wound healing with combined biologic and surgical treatment. Conclusion. Our systematic review highlights the additive effects of using biologics and surgery together to treat HS compared to either treatment alone. However, when both treatment modalities are used simultaneously, the potential risk of prolonged wound healing must be considered. Due to the limited number and heterogeneity of the included studies, more clinical trials are needed to establish diagnostic conclusions.

Exosome-sheathed porous silica nanoparticle-mediated co-delivery of 3,3′-diindolylmethane and doxorubicin attenuates cancer stem cell-driven EMT in triple negative breast cancer

BackgroundTherapeutic management of locally advanced and metastatic triple negative breast cancer (TNBC) is often limited due to resistance to conventional chemotherapy. Metastasis is responsible for more than 90% of breast cancer-associated mortality; therefore, the clinical need to prevent or target metastasis is immense. The epithelial to mesenchymal transition (EMT) of cancer stem cells (CSCs) is a crucial determinant in metastasis. Doxorubicin (DOX) is the frequently used chemotherapeutic drug against TNBC that may increase the risk of metastasis in patients. After cancer treatment, CSCs with the EMT characteristic persist, which contributes to advanced malignancy and cancer recurrence. The latest developments in nanotechnology for medicinal applications have raised the possibility of using nanomedicines to target these CSCs. Hence, we present a novel approach of combinatorial treatment of DOX with dietary indole 3,3′-diindolylmethane (DIM) which is an intriguing field of research that may target CSC mediated EMT induction in TNBC. For efficient delivery of both the compounds to the tumor niche, advance method of drug delivery based on exosomes sheathed with mesoporous silica nanoparticles may provide an attractive strategy.ResultsDOX, according to our findings, was able to induce EMT in CSCs, making the breast cancer cells more aggressive and metastatic. In CSCs produced from spheres of MDAMB-231 and 4T1, overexpression of N-cadherin, Snail, Slug, and Vimentin as well as downregulation of E-cadherin by DOX treatment not only demonstrated EMT induction but also underscored the pressing need for a novel chemotherapeutic combination to counteract this detrimental effect of DOX. To reach this goal, DIM was combined with DOX and delivered to the CSCs concomitantly by loading them in mesoporous silica nanoparticles encapsulated in exosomes (e-DDMSNP). These exosomes improved the specificity, stability and better homing ability of DIM and DOX in the in vitro and in vivo CSC niche. Furthermore, after treating the CSC-enriched TNBC cell population with e-DDMSNP, a notable decrease in DOX mediated EMT induction was observed.ConclusionOur research seeks to propose a new notion for treating TNBC by introducing this unique exosomal nano-preparation against CSC induced EMT.Graphical