High-dose Treatment Research Articles

Dose-Dependent Effect of a New Biotin Compound in Hippocampal Remyelination in Rats.

Demyelination is commonly observed in neurodegenerative disorders, including multiple sclerosis (MS). Biotin supplementation is known to stabilize MS progression. To reduce the effective dose of biotin, we synthesized a new and superior form of biotin, a complex of magnesium ionically bound to biotin (MgB) and compared its dose-dependent effect with biotin alone after inducing demyelination using lysolecithin (LPC) in rats. Myelination was assessed using luxol fast blue staining and immunostaining against MBP protein, revealing that the most significant remyelination occurred in the MgB groups. Additionally, both biotin and MgB-treated animals showed dose-dependent improvements in spatial memory. Moreover, we detected a decrease in inflammatory proteins in both treatment groups, which was more prominent in high-dose MgB-treated animals and correlated with decreased expression of NF-κB p65, OP, and MMP-9 proteins. Further analysis of biotin-related proteins demonstrated that both biotin and, notably, MgB reversed the demyelination-dependent reduction of these proteins. Furthermore, biotin, particularly MgB, improved neuronal transmission proteins, Synapsin-1, PSD-93, and PSD-95. Additionally, both treatment groups exhibited increased BDNF, GAP43, and ICAM levels, with significant increments observed in high-dose MgB-treated animals. Increased GFAP, indicative of reactive gliosis, was observed in LPC-treated animals, and this effect was notably reversed by high-dose MgB treatment. The current data emphasize the dose-dependent beneficial effect on the remyelination process. Furthermore, the combination of biotin with Mg resulted in a more potent effect compared to biotin by itself. The strong influence of MgB encourages proof-of-concept studies using MgB in patients with MS.

Interleukin-10 exhibit dose-dependent effects on macrophage phenotypes and cardiac remodeling after myocardial infarction

IntroductionInterleukin-10 (IL-10) is a potent immunomodulatory cytokine widely explored as a therapeutic agent for diseases, including myocardial infarction (MI). High-dose IL-10 treatment may not achieve expected outcomes, raising the question of whether IL-10 has dose-dependency, or even uncharted side-effects from overdosing. We hypothesized that IL-10 has dose-dependent effects on macrophage (Mφ) phenotypic transition and cardiac remodeling after MI.MethodsUsing RAW264.7 monocyte models, we examined whether administering differential doses of exogenous IL-10 (0–1,000 ng/mL) perturbs classic M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes of polarized Mφ or even alters the phenotypic transition of prospective M1 and M2 polarization. We then investigated the impact of single intramyocardial IL-10 administration on cardiac function, structure, and inflammation post-MI, using a mouse MI model.ResultsCompared with 0-ng/mL control, 250-ng/mL IL-10 had the strongest overall effects in decreasing M1 and increasing M2 phenotypes on polarized Mφ while ≥500-ng/mL IL-10 dampened M1 polarization and augmented native IL-10 secretion more effectively than low doses in vitro. Echocardiography revealed that the 250-ng group had consistently higher contractile function and lower left ventricular (LV) dilatation than the saline control over 6 weeks while ≥1,000-ng groups exhibited transient lower LV ejection fraction at 5 days post-MI in vivo. Moreover, different doses of IL-10 differentially modulated myocardial gene expression, phagocytic cell infiltration at the infarct, LV fibrosis, and revascularization post-MI, with some, but not all, doses exerting beneficial effects.DiscussionOur study suggested that IL-10 has an effective dose range on Mφ phenotypes, and intramyocardial IL-10 treatment may trigger cardioprotective or unwanted effects post-MI in a dose-dependent manner.

Dynamic impact of polyethylene terephthalate nanoplastics on antibiotic resistance and microplastics degradation genes in the rhizosphere of Oryza sativa L.

This study examined the effects of polyethylene terephthalate (PET) nanoplastics on the rhizosphere of Oryza sativa L., focusing on dynamic changes and interactions among microbial communities, antibiotic resistance genes (ARGs) and microplastic degradation genes (MDGs). PET exposure altered the structure and function of soil microbial, enabling specific microbial groups to thrive in polluted environments. High-dose PET treatments markedly increased the abundance and dissemination of ARGs, primarily via resistance mechanisms such as antibiotic efflux and target alteration. By providing additional carbon sources and surfaces for microbial attachment, PET stimulated the growth of microorganisms harboring MDGs, resulting in an increase in MDGs abundance. The elevated expression of MDGs facilitated the propagation of ARGs, with overlapping host microorganisms suggesting that certain microbial groups exhibit dual metabolic capabilities, enabling them to endure both antibiotic and microplastic pressures. Toxic byproducts of microplastic degradation, such as mono-ethylhexyl phthalate, further promoted ARGs dissemination by increasing horizontal gene transfer frequency. Structural equation modeling revealed that PET indirectly influenced ARGs and MDGs expression by altering soil C/N ratio, available phosphorus, and enzyme activities. Thus, nanoscale PET exacerbates ecological risks to soil microbial communities by driving co-propagation of ARGs and MDGs, highlighting the persistent threat of composite pollution to agroecosystems.

Exposure to triphenyl phosphate during pregnancy: The role of gut-bile acids-liver axis on lipid metabolism in male offspring.

The widespread use of Triphenyl phosphate (TPhP) as a substitute flame retardant in various commercial products has raised global concerns for its health risks. Previously, we found that gestational and lactational TPhP exposure disturbed lipid metabolism and gut microbiota in offspring sex-dependently. In this study, we further explored the prenatal TPhP exposure on lipid metabolism in male offspring, and the role of gut-bile acids-liver axis in it. The results showed that gestational TPhP exposure would induce hyperlipidemia in male offspring, it dose-dependently increased the weight of body and liver, levels of serum lipid, and enlarged lipid droplets in white adipose tissue. The expression of lipid metabolism-related genes was significantly changed in the liver and adipose tissue. The gut microbiome of male offspring was also altered, with different profiles between the low and high dose treatment group. Target bile acids (BAs) metabolites analysis revealed a significant increased levels of primary BAs cholic acid (CA), but decreased levels of chenodeoxycholic acid (CDCA), and decreased levels of the secondary BAs deoxycholic acid (DCA), hyodeoxycholic acid (HDCA), ursodeoxycholic acid (UDCA), and lithocholic acid (LCA) in TPhP treatment group. Measurements of gene expression along the gut-BAs-liver axis showed that the TPhP treatment group had an increase in cholesterol-7alpha-hydroxylase (CYP7A1) and a decrease in apical sodium-dependent bile acid transporter (ASBT), with only the low-dose group exhibiting an increase in carbohydrate response element binding protein (ChREBP). Correlation and mediation analysis highlighted associations of Burkholderiaceae in low-dose treatment group and Erysipelotrichaceae in high dose group with lipid metabolism and BAs metabolites. No consistent correlations were observed in two treatment group. Additionally, Mantel tests did not reveal a consistent correlation between the microbiome network community and lipid metabolism or the gut-bile acids-liver axis. Overall, our findings indicate that gestational TPhP exposure induces hyperlipidemia in male offspring, and while the gut-BAs-liver axis plays a role, other mechanisms warrant further investigation.

Exploring the promising potential of alcohol extract from the aerial part of dill in ameliorating DSS-induced ulcerative colitis in mice.

Dill (Anethum graveolens L.) is a typical Uyghur medicine. It is traditionally used to treat sticky and stagnant dampness, hiccups and food stagnation, intestinal obstruction, and anorectal diseases. Our study is designed to investigate the potential of alcohol extract from the aerial part of dill in ameliorating ulcerative colitis induced by Dextran Sulfate Sodium Salt (DSS) in mice. In this paper, the chemical composition of the aerial part of dill was speculated from the data obtained by LC-MS and determined by comparing with 10 standards through HPLC. The aerial part of fresh dill was dried, crushed, sieved, and then extracted with 70% ethanol to obtain DE. The lipopolysaccharide (LPS)-induced RAW264.7cells were used to test the anti-inflammatory activity of DE in vitro. The impact of DE on UC was also studied in vivo. UC was induced by drinking 2.5% DSS to C57BL/6 mice for 6 days. The positive control group received 5-aminosalicylic acid (5-ASA) by gavage, and the low and high-dose treatment groups were respectively given 200mg/kg and 400mg/kg of DE by gavage daily for 7 days from the first day. DE significantly reduces the disease activity index (DAI) and colon histopathological damage. DE can also alleviate oxidative stress and inflammation in UC mice by reducing IL-6, IL-1β, MDA, and MPO levels and increasing CAT and GSH levels in colonic tissues. DE can protect the integrity of the colonic mucosal barrier by reducing damage to goblet cells, increasing the levels of mucin MUC2, and regulating the expression of tight junction proteins such as ZO-1, Occludin, Claudin-1, and Claudin-2. In addition, DE improves the ratio of beneficial and harmful bacteria, thus further alleviating the imbalance of intestinal flora. DE has anti-inflammatory activity in vitro and an ameliorative effect on DSS-induced UC in mice by alleviating oxidative stress and inflammation, protecting the integrity of the intestinal barrier, and regulating intestinal flora.

Acephate Exposure Induces Transgenerational Ovarian Developmental Toxicity by Altering the Expression of Follicular Growth Markers in Female Rats.

Acephate is an organophosphate foliar and soil insecticide that is used worldwide. In this study, the transgenerational ovarian developmental toxicity caused by acephate, along with its in utero reprogramming mechanisms, were explored. Thirty female virgin Wistar albino rats were randomly assigned to three groups: one control group and two acephate treatment groups. The treatment groups received daily low or high doses of acephate (34.2 mg/kg or 68.5 mg/kg body weight, respectively) from gestational day 6 until spontaneous labor, resulting in F1 offspring. At 28 days, a subgroup of F1 females were euthanized. The ovaries were extracted, thoroughly cleaned, and weighed before being fixed for further analysis. The remaining F1 females were mated with normal males to produce the F2 generation. The F1 female offspring presented reduced fertility and body weight, whereas the ovarian weight index and sex ratio increased in a dose-dependent manner. Structural analysis revealed altered follicular abnormalities with ovarian cells displaying pyknotic nuclei. Additionally, the gene and protein expression of Cyp19 decreased, whereas that of Gdf-9 increased in the high-dose treatment group (68.5 mg/kg). We also observed significantly increased expression levels of ovarian estrogen receptor 1 (Esr1) and insulin-like growth factor 1 (Igf1), whereas Insl3 expression was significantly decreased. The F2 female offspring presented reproductive phenotype alterations similar to those of F1 females including decreased fertility, reduced Cyp19 gene and protein expression, and structural ovarian abnormalities similar to those of polycystic ovary syndrome (PCOS). In conclusion, acephate induced ovarian developmental toxicity across two generations of rats, which may be linked to changes in the ovarian Cyp19, Gdf9, Insl3, and Igf1 levels.

Stackelberg Evolutionary Games of Cancer Treatment: What Treatment Strategy to Choose if Cancer Can be Stabilized?

AbstractWe present a game-theoretic model of a polymorphic cancer cell population where the treatment-induced resistance is a quantitative evolving trait. When stabilization of the tumor burden is possible, we expand the model into a Stackelberg evolutionary game, where the physician is the leader and the cancer cells are followers. The physician chooses a treatment dose to maximize an objective function that is a proxy of the patient’s quality of life. In response, the cancer cells evolve a resistance level that maximizes their proliferation and survival. Assuming that cancer is in its ecological equilibrium, we compare the outcomes of three different treatment strategies: giving the maximum tolerable dose throughout, corresponding to the standard of care for most metastatic cancers, an ecologically enlightened therapy, where the physician anticipates the short-run, ecological response of cancer cells to their treatment, but not the evolution of resistance to treatment, and an evolutionarily enlightened therapy, where the physician anticipates both ecological and evolutionary consequences of the treatment. Of the three therapeutic strategies, the evolutionarily enlightened therapy leads to the highest values of the objective function, the lowest treatment dose, and the lowest treatment-induced resistance. Conversely, in our model, the maximum tolerable dose leads to the worst values of the objective function, the highest treatment dose, and the highest treatment-induced resistance.

Safety and Efficacy of Moderate-Dose Denosumab in Fibrous Dysplasia: Observational Results from a Phase 2 Clinical Trial.

Fibrous dysplasia (FD) is a rare skeletal mosaic disease associated with fractures and disability. A phase 2 trial of the RANKL inhibitor denosumab (NCT03571191) reported profound reductions in lesion activity and increased lesional mineralization after 6-months of high-dose treatment. Denosumab was well-tolerated, however discontinuation was associated with severe hypercalcemia. Investigate safety and efficacy of moderate-dose denosumab (120 mg/3 months) compared to the standard high-dose regimen. Clinical Research Center. Adults with FD. Eight adults received high-dose denosumab for 6 months (120mg/month with loading doses on weeks 2 and 3) followed by 8-months post-treatment observation. The protocol was amended to restart moderate-dose denosumab (120 mg/3 months) if clinically indicated. Bone turnover markers, 18F-NaF PET/CT, lesion biopsies. In 6 subjects who restarted moderate-dose treatment, changes in serum markers at initial and final dose were comparable (P1NP -82% and -91%, CTX -86% and -86% for moderate- and high-dose, respectively). There was no difference in 18F-NaF PET/CT lesional activity or absolute change in avid lesion volume between moderate- and high-dose regimens. Sequential tissue histological analyses in 1 subject demonstrated progressive lesional mineralization and reduced cellularity with moderate-dose treatment. Bone turnover markers on moderate-dose treatment showed sustained decline in 4 subjects, however 2 severely affected subjects developed rebound between doses, with recurrent hypercalcemia in 1 subject. Moderate-dose denosumab may provide clinical benefits comparable to the high-dose regimen in adults with FD, while potentially lowering associated risks. However, discrepancies in duration of efficacy are an important potential safety concern.

Antiparasitic and antioxidant effects of selenium nanoparticles on parasitic Trichinellaspiralis.

This study presents a comprehensive methodology for the synthesis, characterization, and evaluation of selenium nanoparticles (SeNPs) for their anthelmintic properties against Trichinella spiralis. SeNPs were synthesized via a chemical reduction method, with a color change from clear white to brownish-red indicating nanoparticle formation. X-ray diffraction (XRD) analysis revealed broad peaks at 2θ ranges of 20-33° and 48-58°, confirming the semi-crystalline nature of the nanoparticles. UV-Vis absorption spectroscopy identified a characteristic peak at around 295nm. High-resolution transmission electron microscopy (HRTEM) showed spherical, monodispersed SeNPs with smooth surfaces, ranging from 30 to 106nm in size, with an average diameter of 69nm. Forty-two male rats were divided into six groups, including healthy controls and T. spiralis-infected rats treated with varying doses of SeNPs. Body and organ weight indexes were assessed at the start, during the intestinal and muscular phases. Significant body weight increases were observed during the intestinal phase, particularly in the positive control group. Organ weight analysis showed a significant decrease in liver weight in the high-dose SeNP group compared to controls. SeNP treatment significantly reduced the number of adult worms in the intestines and encysted larvae in muscles. The high-dose group reduced adult worms and encysted larvae more than the low-dose group. Scanning electron microscopy (SEM) revealed morphological alterations in adult T. spiralis worms, including wrinkled architecture, torn cuticles, and severe sloughing in high-dose treated worms. During the muscular phase, significant decreases in hemoglobin and red blood cell count were observed in the positive control group, while SeNP treatment restored these levels. Liver enzyme activities (AST, ALT, and ALP) were elevated in infected untreated groups but were enhanced with SeNP treatment. Antioxidant enzyme activities (CAT, and SOD) increased in SeNP-treated groups, with higher doses showing greater efficacy in reducing oxidative stress markers (MDA) and inflammatory markers (TNF-α, and IL-6). Histological analysis showed significant restoration of normal intestinal architecture in high-dose SeNP-treated infected rats, including the reduction of villus atrophy and leukocyte infiltration. In diaphragm muscles, high-dose SeNP treatment minimized encysted larval deposition and restored normal muscle architecture. We can conclude that the study demonstrates the potential of SeNPs as an effective anthelmintic agent against T. spiralis, highlighting their synthesis, characterization, and therapeutic efficacy.

Outcome of lupus nephritis patients treated with an anti-CD40 monoclonal antibody according to kidney biopsy features.

A phase II trial tested different doses of the anti-CD40 monoclonal antibody BI655064 as add-on therapy to the standard of care in class III or IV Lupus Nephritis (LN) patients with active disease. A post-hoc analysis showed a potential benefit of the higher tested doses (180mg/240mg) versus low dose (120mg)/placebo. We investigated whether the treatment effect of BI655064 on kidney outcomes may be modified by the presence of glomerular monocytes, a target for this drug with a well-known role in LN pathogenesis. 101 renal biopsies of LN patients enrolled in the BI655064 trial were scored centrally. eGFR and spot urine protein/urine creatinine ratio (UP/UC) and Complete Renal Response (CRR) were evaluated over 52 weeks. Patients were divided according to a "Better" or "Worse" performance than the average of all patients in the cohort, predicted by a mixed model for repeated measurements. Logistic regression models adjusted for potential confounders assessed the association between different treatment doses and outcomes according to the presence or absence of monocytes. A higher BI655064 dose (180/240mg) was associated with better outcomes of UP/UC and CRR when glomerular monocytes were present in kidney biopsies (OR 3.66[1.09-12.3], P=0.04; OR 4.58[1.24-16.9], P=0.02). A trend toward improved eGFR was also observed in these patients (P 52-weeks=0.08). In LN kidney biopsies with glomerular monocytes, high-dose BI655064 treatment improved proteinuria at 52 weeks and resulted in a higher CRR compared to biopsies without glomerular monocytes. Histologic features may guide the choice of treatment for individual LN patients.

Assessment of dimethoate and malathion mediated toxicity on Solanum lycopersicum L.

Nowadays organophosphate-based chemicals are most commonly used insecticides worldwide which are applicable to a wide range of crop plants. In this study, the effect of organophosphate insecticides, dimethoate (DM) and malathion (MT), was investigated on Solanum lycopersicum L. The seeds were germinated under in vivo conditions and after 1month of germination, they were transferred to separate pots. Insecticides were applied in three different concentrations (X, 2X, and 4X) using a nozzle spray at 7-day intervals for 21days where X was the recommended dose. After 21days of treatment, the toxicological responses of plants were confirmed by evaluating the growth patterns, anatomical, photosynthetic pigments, expression of proteins, and antioxidant enzymes catalase (CAT), guaiacol peroxidase (GPX), and ascorbate peroxidase (APX). The study findings demonstrated that both DM and MT treatment resulted in adverse growth effects even at the initial recommended dose (X) of application. However, compared to MT, at 4X concentrations of DM, maximum decrease in plant height (43.43%), leaf length (43.16%), leaf width (41.09%), and total numbers of leaves per plant (50.57%) was observed. Plants subjected to higher doses of DM and MT showed a gradual reduction in chlorophyll a, chlorophyll b, total chlorophyll, and carotenoids (67.25, 50.00, 62.03, and 41.04%, respectively, for DM and 61.75, 55.72, 59.87, and 41.04%, respectively, for MT). In addition, higher doses of these insecticides greatly disturbed micromorphology and protein contents. At high dose (4X) of treatment, the activities of CAT, GPX, and APX were found to increase by 14.01, 3.62, and 2.21 times the control value, respectively, for DM and 5.17, 2.53, and 1.46 times, respectively, for MT. Additionally, increased isoenzymes of CAT, GPX, and APX were demonstrated by nondenaturing PAGE and were also dependent on the concentrations of DM and MT. These results suggest that the isoforms of the antioxidant enzymes newly developed due to DM and MT excess may be used as biochemical markers for other crop plants grown under insecticide stress. This study provides insights into the biochemical mechanism associated with the toxicity caused to plants by the test insecticides.

Oral supplementation with Nicotinamide Riboside treatment protects RGCs in DBA/2J mouse model.

The aim of this study was to test whether oral administration of nicotinamide riboside (NR), the nicotinamide adenine dinucleotide (NAD+) precursors, protect retina ganglion cells (RGCs) from neurodegeneration in DBA/2J (D2) mice, which is a widely used mouse model of age-related inherited glaucoma. Oral NR or NAM administration (NR low dose: 1150mg/kg; NR high dose: 4200mg/kg; NAM low dose group: 500mg/kg; NAM high dose: 2000mg/kg of body weight per day) essentially started when D2 mice were 4 or 9 months old and continued up to 12 months old. Control cohort identically received food/water without NAM or NR. Intraocular pressure (IOP) was measured every month until experiment completion. Pattern electroretinography (PERG) was recorded. Retinas were harvested for whole mount immunofluorescence staining with RGCs marker Brn3a and imaged by fluorescent confocal microscopy. Optic nerves were harvested for axon staining and quantification. Retinal NAD+ levels were enzymatically assayed. NR oral supplementary treatment started at 4 months old robustly increased retinal NAD+ levels in D2 mice (NRHigh vs. vehicle: 273.7±23.59% vs. 108.70±12.10%, p<0.001). In aged vehicle group (12 months old), there was significantly diminution of the P1 and N2 components of PERG response compare with naïve group (naïve vs. vehicle: P1: 7.82± 0.70uV vs 1.63± 0.17uV, p<0.0001; N2: -13.29± 0.83uV vs. -3.22± 0.27uV, p<0.0001; Kruskal-Wallis test with Dunn's multiple comparison test). NR treatment preserved aged D2 visual function when mice were 9 and 12 months old. In addition, long-term NR high dose treatment significantly protected against total RGCs loss and optic nerve atrophy (RGC: NRHigh vs. vehicle: 1412±62.00vs 475.2±94.68 cells/field, p<0.00001; axon numbers: NRHigh vs. vehicle: 23990±1159 vs 8573±1160, n=41-53, p<0.0001). Furthermore, long-term NR supplementation prevent iris depigmentation and delayed IOP elevation. NR oral supplementary treatment significantly preserved RGC and axon numbers, potentially preserves retinal function via elevated retinal NAD+ level in aged D2 mice. Interestingly, NR treatment also prevented iris atrophy, delayed IOP elevation associated with this glaucoma model. NR oral supplementation thus treated several aspects of murine pigment dispersion glaucoma. Given parallels between this model and glaucoma in human, out data indicate that NR is worth exploring as a therapeutic candidate in treatment of glaucoma.

Refractory hypoglycemia is sensitive to octreotide therapy: is it triggered by sorafenib or hepatocellular carcinoma?

Hypoglycemia is a medical emergency with a multitude of potential causes. Paraneoplastic hypoglycemia represents a rare cause of this condition. Hepatocellular carcinoma (HCC) can result in paraneoplastic hypoglycemia through extensive tumor infiltration and the presence of insulin-like growth factor 2 precursors. In this article, a patient whose persistent hypoglycemia did not improve despite long-term intravenous glucose and high-dose steroid treatment and who was successfully treated with octreotide is described. A 50-year-old male patient with a diagnosis of metastatic HCC was admitted to the emergency department due to symptomatic hypoglycemia. His blood glucose level was found to be 40 mg/dl and he was hospitalized in our clinic for treatment. The patient, who had been on sorafenib treatment for 2 weeks due to HCC, was started on intravenous dextrose for hypoglycemia and steroid, glucagon, and octreotide treatments, respectively. The patient's sorafenib treatment was discontinued and a second-line palliative chemotherapy was initiated. The patient responded dramatically to octreotide treatment and the need for intravenous glucose gradually decreased. Following approximately six weeks after hospitalization, the patient's requirement for intravenous glucose was no longer necessary. HCC and its treatment is a complex process involving the activation or inhibition of various mechanisms, and refractory hypoglycemia may rarely be seen in patients with HCC. But the cause of hypoglycemia may not always be identified. In cases where the cause is not understood, other treatment options for hypoglycemia, such as increasing caloric intake, intravenous glucose administration, high-dose steroids, glucagon, and octreotide, should be considered.

Evaluation of Drug Effectiveness and Controlled Release Profiles of Clay Minerals Loaded with Anti-Carcinogenic Agent as a Drug Delivery System on Leukemia.

Myeloid leukemia is a stem cell disease with high mortality due to the challenges of high-dose treatments and side effects. Innovative nanoparticle drug delivery systems are being explored to enhance efficacy and tissue-targeted therapy. This study investigates the potential of Bentonite (BNT)-based nanoparticles (NPs) as drug carriers for azacitidine (AZA) in treating THP-1 and K562 myeloid leukemia (AML) cell lines, aiming to improve drug stability, bioavailability, and therapeutic efficacy while ensuring controlled release. Bentonite clay morphology was analyzed using Scanning Electron Microscopes. The BNT-AZA combination was tested in THP-1 and K562 cell cultures via in vitro proliferation tests, CCK-8 assays, and drug release tests with dialysis membranes. Apoptosis and internalization were evaluated using Annexin V-FITC and fluorescence methods, respectively. The BNT-AZA exhibited controlled release over 8hours, with 50% released within 2hours, 90% by the 4th hour, and prolonged release beyond 8hours. This profile reduces side effects while increasing efficacy in target cells. Bentonite demonstrated significant drug-loading capacity, controlled release, and tumor-targeting capabilities. At concentrations of 10, 25, 50, and 100µg/mL, BNT showed dose-dependent antiproliferative effects, maintaining low cytotoxicity at lower concentrations. The combination of azacytidine and bentonite exhibited a synergistic effect in inhibiting cell proliferation, with significant decreases in cell viability in the 1µM azacytidine + 10µg/mL bentonite, 5µM azacytidine + 10µg/mL bentonite, and 10µM azacytidine + 10µg/mL bentonite groups compared to the controls. The combination of 1µM AZA with 10µg/mL BNT achieved similar efficacy to 10µM AZA alone, suggesting a potential for dose reduction and improved safety. BNT nanoparticles are promising carriers for AZA, enhancing targeted delivery, reducing side effects, and potentially lowering the required dose for leukemia treatment. These findings support further investigation into the clinical application of BNT-AZA in hematologic cancers.

Lily extract ameliorate mouse pneumonia by modulating ciliary function

This study explores the biological effects and mechanisms of Lily extract on LPS-induced pneumonia mice. Research has found that after 48 h of treatment with low-dose and high-dose lily extract (100 mg/kg, 200 mg/kg), there was a significant reduction in inflammatory cell infiltration, mRNA expression levels of pro-inflammatory factors (IL-6, IL-1β, TNF-α), protein levels of inflammation-related proteins (IL-6, NF-κB P65) in the lung tissue. In addition, lily extract significantly improved the function of cilia assembly and movement. The expression levels of cilia-related genes (Ttc21a, Cfap45, etc.) and proteins were significantly upregulated. Among them, the high-dose treatment group had tightly arranged cilia and good growth conditions, which was significantly better than the LPS pneumonia model and low-dose treatment group. This found providing novel insights into the pathogenesis and progression of pneumonia. This has important implications for the prevention and treatment of pneumonia, as well as the development of natural agents.

Protective role of polysaccharide from the roots of Millettia speciosa Champ in mice with ulcerative colitis induced by dextran sulphate sodium

This study investigated the therapeutic mechanism of Millettia Speciosa Champ. polysaccharide (MSCP), also known as Niu Dali polysaccharide, in treating ulcerative colitis (UC) using a dextran sulphate sodium (DSS) induced colitis model in C57BL/6 mice. Mice were randomly assigned to four groups: control, DSS model, and low- and high-dose MSCP treatment groups (50, 100 mg/kg/day, respectively). MSCP administration began concurrently with DSS induction. Throughout the intervention, changes in body weight and disease activity index were monitored. On day 44, colonic tissues were collected for analysis after measuring their lengths. Results demonstrated that MSCP effectively ameliorated DSS-induced chronic colitis by suppressing proinflammatory cytokine secretion, enhancing anti-inflammatory cytokine production, restoring intestinal epithelial barrier integrity, and downregulating TLR4 expression.

The Use of Acetazolamide to Prevent Acute Kidney Injury in Patients with Cancer on High-Dose Methotrexate Treatment: A Retrospective Pilot Analysis.

Background: High-dose methotrexate (HDMTX) chemotherapy is associated with a significant risk of acute kidney injury (AKI). Acetazolamide is thought to increase methotrexate solubility via urinary alkalinisation, potentially reducing the risk of crystalline nephropathy. A tertiary hospital has included acetazolamide in its HDMTX protocols, although data on the risks and benefits are limited. This study evaluated the role of acetazolamide in managing patients receiving HDMTX and identified risk factors for AKI. Methods: The retrospective cohort pilot study included consecutive hospital patients who received HDMTX (≥500 mg/m2). Data collected from digital medical records included demographics, comorbidities, methotrexate dosages and serum concentrations, and pathology results. The development of AKI was defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Relationships between variables and AKI were initially assessed using Mann-Whitney U-tests and chi-square tests, and significant variables were further analysed using logistic regression to identify independent predictors of AKI. Results: Among 66 HDMTX treatment cycles in 31 patients, AKI occurred in 0/7 cycles with acetazolamide versus 14/59 cycles without (p = 0.33). Increasing age, the presence of hypertension, and concurrent use of beta-lactam antibiotics were associated with the development of AKI. Age was identified as the strongest independent risk factor for AKI (odds ratio 1.12, p = 0.034). Conclusions: Optimising management protocols, especially for older patients, is essential to reduce AKI risk during HDMTX therapy. While acetazolamide did not appear to reduce the risk of AKI, this pilot study was limited by a small sample size. Large randomised controlled trials are needed to assess efficacy and patient outcomes.

Enhanced Inhibition of Triple-Negative Breast Cancer Metastases with High-Dose Rujifang Treatment Assessed by Optical Flow Cytometry In Vivo

Enhanced Inhibition of Triple-Negative Breast Cancer Metastases with High-Dose Rujifang Treatment Assessed by Optical Flow Cytometry <i>In Vivo</i>

Semen Cuscutae flavonoids activated the cAMP-PKA-CREB-BDNF pathway and exerted an antidepressant effect in mice.

Semen Cuscutae flavonoids (SCFs) constitute a class of metabolites of Semen Cuscutae, a botanical drug that was recently found to have an anti-depression effect. This study aimed to evaluate the anti-depression effects of SCFs in chronic unpredictable mild stress (CUMS)-induced mice and to interrogate the underlying mechanisms. The CUMS mice were used for assessing the effects of SCFs treatments on depression. Mice were randomly divided into five groups. Four groups were subjected to the CUMS induction and concomitantly administered orally with either the vehicle or with a high-, medium-, and low-dose of SCFs, once per day for 4weeks. One group was kept untreated as a control. The mice were then assessed for their statuses of a number of depression-related parameters, including body weight, food intake, sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), and forced swim test (FST). In addition, a day after the completion of these tests, biopsies from the hippocampus were harvested and used to perform metabolomics by HPLC-MS/MS and to assess the levels of cAMP by ELISA and the levels of PKA, CREB, p-CREB, and BDNF by Western blot analyses. SCFs resulted in significant increases in both body weight and food intake and in the amelioration of the depressive-like behaviors in CUMS mice. A high-dose SCFs treatment led to significant alterations in 72 metabolites, of which 26 were identified as potential biomarkers for the SCFs treatment. These metabolites are associated with lipid, amino acid, and nucleotide metabolism. Among 26 metabolites, cAMP was positively correlated with body weight, SPT, OFT-total distance, and OFT-central residence time, while negatively correlated with immobility time in TST and FST, linking a change in cAMP with the SCFs treatment and the significant improvement in depressive symptoms in CUMS mice. Further analyses revealed that the levels of cAMP, PKA, CREB, p-CREB, and BDNF were reduced in the hippocampus of CUMS mice but were all increased following the SCFs treatments. SCFs could ameliorate hippocampal metabolic disturbances and depressive behaviors and cause the activation of the cAMP-PKA-CREB-BDNF signaling pathway in the hippocampus of CUMS mice.

Adjuvant Effect of Lactobacillus paracasei in Sublingual Immunotherapy of Asthmatic Mice.

Background: Sublingual immunotherapy (SLIT) has shown promise in mitigating allergic asthma symptoms; nevertheless, its high dose and prolonged duration of treatment raise safety concerns. This study explored the potential of Lactobacillus paracasei (L. paracasei) to enhance the effectiveness of SLIT in a mouse model of allergic asthma. Methods: Allergic asthma was induced in Balb/c mice following sensitization and challenge with a house dust mite (HDM) allergen. Subsequently, the mice were subjected to SLIT (66 and 132 µg) either alone or in combination with L. paracasei supplementation. Asthma-associated parameters, including rubbing frequency, IgE level, cytokine profiles, and histological changes, were evaluated to assess treatment efficacy. Results: mice that received SLIT 132 µg combined with the probiotic (combined 132) demonstrated a significant reduction in allergic symptoms (rubbing). This treatment strategy led to a marked IgE and eosinophil level decrease in serum; an increase in anti-inflammatory cytokines like IFN-γ and IL-10; and a reduction in pro-inflammatory cytokines IL-17 and TNF-α. The combination therapy also mitigated lung inflammation and supported the restoration of the structural integrity of the colon, promoting the recovery of goblet cells and mucus secretion. Probiotic treatment alone also effectively reduced IgE levels, increased IFN-γ, and decreased levels of IL-17 and TNF-α. Conclusions: The adjuvant effect of L. paracasei in enhancing SLIT represents a promising approach for improving asthma treatment efficacy.