The administration of 5-FU as the first chemotherapeutic agent for colorectal cancer, showed difficulties including short half-life and the development of resistance. One prominent approach to overcome these restrictions, is administration of 5-FU in conjunction with nanoparticles, particularly magnetic nanoparticles. In this study, Fe3O4 nanoparticles were prepared by the green synthesis and coated with polylactic acid-hyaluronic acid (PLA-HA) copolymer. Then, the HCT116 colorectal cancer cell line was used to assess the cytotoxicity and effectiveness of PLA/Fe3O4 and PLA-HA/Fe3O4 nanoparticles for the delivery of 5-FU medication. The characteristics of these copolymers were investigated by 1H-NMR, FTIR and Thermogravimetric analysis. The nanoparticles were prepared using solvent diffusion technique and then characterized with different techniques like dynamic light scattering (DLS), TEM images, FTIR, UV-Vis spectroscopy, and VSM (Vibrational Sample Magnetometer). Ultimately, an assessment of drug encapsulation efficacy, the release profile and an in vitro analysis of cytotoxicity were performed to investigate the efficacy of drug delivery to HCT116 cells. The results of NMR, FTIR and TGA analysis confirmed the successful synthesis of copolymers. A zeta potential of -18 mV and a spherical shape with an average size of 235 nm were characteristics of the synthesized PLA-HA/Fe3O4/5-FU nanoparticles. The encapsulation of Fe3O4 nanoparticles in PLA-HA copolymer decreased their magnetic saturation, and VSM analysis showed that the nanoparticles possessed superparamagnetic properties. Additionally, the 5-FU encapsulation efficiency was 42%, and it demonstrated a burst and sustained release pattern. It was discovered that the acidic pH was more effective. The MTT assay proved the low toxicity and biocompatibility of drug-free nanocarriers'. Remarkably, compared to PLA/Fe3O4/5-FU micelles, the viability of HCT116 cells was found to be significantly reduced by PLA-HA/Fe3O4/5-FU micelles. This phenomenon can be explained by the unique way that hyaluronic acid interacts with overex CD44 receptors. One potential strategy for targeted drug delivery and HCT116 cell line control is to encapsulate 5-FU in magnetite nanoparticles (Fe3O4) made by the green synthesis method and use HA as cell-surface receptors to create PLA-HA/Fe3O4/5-FU nanoparticles. Nanocarriers favorable physicochemical characteristics and potent apoptotic effects make them promising agents for precisely delivering drugs to colon cancer cells. • Drug delivery efficiency is significantly improved while utilizing different ligands are functionalized on the surface of nanoparticles. • Encapsulation of Fe3O4 nanoparticles into the PLA-HA/Fe3O4/5-FU micelles and PLA-HA/Fe3O4 nanoparticles leads to the production of nanoparticles or micelles with appropriate magnetic properties. • Acidic environments cause more drug release than neutral ones, and since cancer cells have a lower pH than healthy cells, this can cause less drug release in healthy cells and ultimately fewer negative effects on healthy cells.
The inappropriate use of antibiotics increases the costs of treatment, antibiotic resistance, increased disease length and duration of hospital stay. The aim of this study was investigating the pattern of use and effectiveness of the Linezolid in COVID-19 hospitalized patients. In this retrospective cross-sectional analytical study was carried out from February 2020 (from the beginning of the pandemic in Iran) to the end of September 2020, 32 COVID-19 patients that used Linezolid were included. The data retrieved from medical document's unit and analysis was performed by SPSS statistical software version 20. According to the three elements of the 1- culture of resistant bacteria 2-the correct daily dose and 3-adequate duration of the drug, consumption pattern of Linezolid was irrational in 24 (75%) COVID-19 patients and it was rational only in 8 (25%) patients. Twenty-three (71.9%) patients received sufficient doses of the drug and 9 (28.1%) patients did not receive the required minimum dose. Four (50%) patients who rationally received Linezolid improved and the remaining 4 died. Leukopenia occurred in 1 patient (3.1%), anemia appeared in 24 individuals (75%), and 15 patients (46.9%) developed thrombocytopenia. We suggest that the prescription of Linezolid is in accordance with the standard instructions and the stewardship antibiotic program to reduce the medication costs, drug side effects, and the prevalence of antibiotic resistance.
Rituximab (RTX) is one of the treatment options for refractory myasthenia gravis (MG), yet the optimal dosing schedule remains undetermined. Our study aims to explore this issue and offer a valuable reference for clinical dosing. This is a single-arm meta-analysis. Studies in adults with myasthenia gravis published before 31 December 2023 were searched in PubMed, Web of Science, and other databases. Two primary effectiveness outcomes were analyzed: (1) Proportion of patients achieving minimal manifestation status (MMS) or better, (2) Change in Quantitative MG Score (QMGs) after RTX treatment. Safety outcomes included the incidence and description of serious adverse events (SAEs) and adverse events (AEs). Forest plots were generated to provide an overview and detailed combined effects. Publication bias was evaluated using funnel plots and the Egger test. Conventional dose refers to an RTX regimen similar to that used for the treatment of B-cell lymphoma: 375 mg/m2 per week for 4 weeks or 1000 mg for Weeks 1 and 3. Dosing regimens below the conventional dose in a treatment cycle are defined as low dose. A total of 1037 MG patients received RTX treatment. Overall, 59.0% (95% CI: 48.2-69.8%, n = 599) of patients achieved MMS or better, with a mean decrease in QMGs of 6.81 (95% CI, -9.27 to -4.35, n = 222). The low-dose group showed a higher proportion of patients achieving MMS or better (76.6% vs 51.6%) and a more significant decrease in QMGs from baseline (-9.04 vs -3.62) compared to the conventional dose group (P < 0.01). Differences in the incidence of SAEs and AEs between the two groups were not significant (P > 0.05). Univariate meta-regression analyses showed that the dose administered was significantly associated with the proportion of MMS or better and the change in QMGs, whereas the proportion of Musk patients was not significantly associated with any of the outcomes. Stepwise logistic regression analyses showed that non-refractory MG, mild disease severity (MGFA classification), and low-dose were significant predictors for achieving an MMS or better prognosis, whereas for achieving improvement or better, only low dose was an independent predictor. RTX can improve clinical symptoms, reduce QMGs in MG patients and the use of oral glucocorticoids and other immunosuppressants. The efficacy of low-dose RTX in treating MG patients is more effective than conventional-dose RTX and demonstrates a better safety profile. Mild disease severity, non-refractory MG, low dose, and MuSK-MG over AChR-MG predict better efficacy. Large randomized controlled trials are necessary to evaluate the efficacy and safety of RTX in MG patients and its various subtypes.
The effectiveness of PD-1 inhibitors for treating endometrial cancer (EC) remains a topic of debate. Guidelines lack consistency regarding the preferred treatments for advanced cases, as well as for patients experiencing metastasis or recurrence. Thus, our goal was to assess the efficacy of Dostarlimab, a PD-1 inhibitor, in EC by incorporating data from clinical trials to create a more comprehensive database. We conducted a thorough and systematic search of the Scopus, Medline, Embase, and Web of Science databases, identifying all eligible studies on Dostarlimab's efficacy in endometrial cancer. Our data demonstrated that the hazard ratio of OS in the pooled proportion of participants was 43%. The hazard ratio of PFS in the pooled proportion of EC patients was 0.39 (95% CI: 0.31-0.49). The overall analysis generated a probability of remaining in response of 72.71% (95% CI: 60.94-84.49%). In addition, pooling the results from both subgroups of EC patients, including proficient mismatch repair (pMMR) and deficient mismatch repair (dMMR), yielded an ORR of 33.93% (95% CI: 21.49-46.37%) and a DCR of 51.73% (95% CI: 37.0-66.42%). Overall, the deficient mismatch repair group compared to the proficient mismatch repair group showed better outcomes. Finally, the dMMR subgroup showed a median PFS of 7.86 months (95% CI: 4.46-11.26). Dostarlimab demonstrated limited efficacy in patients with pMMR EC, but it represented better outcomes in those with dMMR EC.
Amphotericin B (AMB) is a drug used to treat vulvovaginal candidiasis (VVC), which is a fungal infection affecting the vagina and vulva. Nevertheless, the substance's limited capacity to dissolve in water leads to poor absorption when taken orally, hence diminishing its therapeutic efficacy. In order to address this limitation, β-cyclodextrin (βCD) was used to create AMB in the form of an inclusion complex. This study aims to enhance the solubility and bioavailability of AMB by formulating it into an inclusion complex with βCD. Subsequently, we developed dissolvable microarray patches (DMP) as a novel drug delivery system, optimizing the formulation for improved retention, penetration, and controlled release of AMB. The stability of the AMB-βCD inclusion complx (IC) structure has been confirmed by employing molecular docking studies. The formulation of DMP involved the incorporation of IC with polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP). The mechanical strength, ability to be inserted, and propensity to irritate Amphotericin B-Inclusion Complex-Dissolvable Microarray Patches (IC-DMP) were evaluated by laboratory experiments utilizing the porcine vaginal mucosal layer. Further investigations, such as Differential Scanning Calorimetry (DSC), were performed to assess the physicochemical characteristics of the IC. The solubility of the pure medication was greatly enhanced up to fourfold by the inclusion complex. The assessment of IC-DMP exhibited exceptional mechanical robustness and insertion abilities, with no indications of discomfort. Among the formulas tested in ex vivo vaginal kinetic experiments, Formula F3 had the most effective retention in the porcine vaginal mucosal layer. It had an AUC value of 208.02 ± 0.33 h.µg/cm3 and the highest Cmax value of 20.05 ± 0.06 µg/cm3. Therefore, Formula F3 was the most efficient formula in terms of vaginal drug delivery. The integration of IC into the DMP system significantly enhances the solubility and bioavailability of AMB, facilitating its absorption in the circulatory system when applied intravaginally for vulvovaginal candidiasis treatment. These promising initial findings support further clinical evaluation of this novel drug delivery system.
Rosa damascena Mill. has been studied in clinical trials for the treatment of diverse gastrointestinal diseases. The aim of this study is to conduct a systematic review and meta-analysis of clinical trials using R. damascena in the management of gastrointestinal disorders. PubMed, Web of Science, Embase, Scopus, and Google Scholar were searched up to Jun 30, 2024. Clinical trials utilizing R. damascena for gastrointestinal disorders were included in the study. The study protocol was registered in PROSPERO (CRD42024519644). The main keywords for the search were R. damascena, gastrointestinal, digestive system, and clinical trials. The Cochrane RoB 2.0 tool was employed for quality assessment of randomized controlled trials. A summary of intervention effects for each study was provided by calculating standardized mean differences and accompanying 95% confidence intervals using a random-effects model. Weighted mean differences and heterogeneity between studies were assessed using Hedges's method and Cochran's Q test, respectively. Additionally, the risk ratio (RR) index was utilized to investigate the effect of R. damascena. Thirteen studies were included for systematic review. The results showed that the use of R. damascena significantly improves the Quality of life (SMD: 0.84, CI95%: 0.03 to 1.65, P = 0.041) and mean defecation frequency per week (SMD: 0.86, CI95%:0.14 to 1.58, P = 0.018) in patients with constipation. However, no improvement was observed in the Bristol stool form scale in patients with constipation, and this relationship was not statistically significant either (SMD: -1.34, CI95%: -4.39 to 1.71, P = 0.388). Also, the rate of incomplete evacuation significantly improved in patients with constipation (RR: 0.78, CI95%: 0.63 to 0.94, P = 0.035). Based on the results of this study, R. damascena could have promising effects on symptoms of patients with functional constipation and their quality of life. Future studies should focus on standardizing methodologies, exploring different dosage levels, and investigating its effects on a wider range of gastrointestinal conditions.
Lactose intolerance affects a significant portion of the global population. Among the proposed treatments for the disease, the main strategy is the use of Lactase, beta-galactosidase, and enzyme before consuming dairy products. The beta-galactosidase enzyme loses its activity in the acidic environment of the stomach before reaching the small intestine environment. In this study, a pH sensitive tablet of beta-galactosidase enzyme with local drug delivery was made for the treatment of lactose intolerance through the hydrogel formulation in the core compartment of the 3D-printed shell of the tablet. The tablets were characterized in terms of morphology, chemical interaction, mechanical properties, dissolution test and pharmacopeial physiochemical requirements. The best polymer weight percentages were selected during the 3D printing of the tablet so that less than 11% release of enzyme within 2 h inside the stomach environment (pH = 1.2) and about 100% enzyme release in the intestinal environment (pH = 6.8) within 6 h was achieved. It should be noted that the enzyme release was confirmed by SDS-PAGE. The recovery of the enzyme activity in tablet was 94%, compared to the activity of the free enzyme. SEM analysis showed smooth, uniform, and continuous layers and the results of FTIR analysis showed no covalent interactions between different materials in the manufacturing process. Furthermore, acceptable tolerances were obtained for pharmacopeial tests including weight variation, content uniformity and assay. According to the results, incorporation of hydrogel into melt extrusion-based 3D printing could be used for producing tailored tablets containing beta-galactosidase enzyme amounts with a delayed release formulation and local oral drug delivery to treat lactose intolerance.
Tacrolimus is a critical calcineurin inhibitor used in the management of liver transplant recipients. Currently, several pharmaceutical companies have developed and introduced generic formulations of Tacrolimus. Most studies on the use of generic Tacrolimus have focused on the conversion from branded to generic versions in stable patients. The aim of this study is to assess the efficacy and safety of Suprotac® compared to Prograf®, over a 12-month period in de novo adult liver transplant recipients. This randomized clinical trial was conducted among adult liver transplant recipients at the Shiraz Transplant Center from October 2022 to June 2024. All patients over 18 years of age, with Tacrolimus as part of their post-transplant immunosuppressive regimen, were included in the study. Patients were randomly assigned to two groups: those receiving Suprotac® and those receiving Prograf® for 12 months in de novo manner. All patients were followed up for 12 months post-transplant. The incidence of rejection, graft loss, liver enzyme fluctuations, safety profile, and adverse events were evaluated between the two groups. A total of 152 patients participated in this study. The rejection rates were 5.88% in the Suprotac® group and 14.28% in the Prograf® group (p-value:0.093). Mortality rates were 22.05% in the Suprotac® group and 10.71% in the Prograf® group (p-value: 0.056. Additionally, 10 patients experienced graft loss. No significant differences were found between the two groups regarding fluctuations in liver enzymes and renal function. The most commonly reported adverse events in both groups were neurological complications such as headache, and insomnia. The findings of this study indicate that de novo use of Suprotac®, compared to Prograf®, offers comparable efficacy in preventing rejection and a similar one-year safety profile in adult liver transplant recipients.
Non-Hodgkin lymphoma, a major cancer type, is usually treated with radiotherapy but encounters challenges with resistance and toxicity. Therefore, the treatment of non-Hodgkin lymphoma needs agents to be very effective while protecting healthy cells. Blueberry extract, rich in micronutrients, flavonoids, and bioactive compounds, may inhibit cancer cell growth and induce apoptosis without harming normal cells. This study investigates the efficacy of blueberry extract in combination with radiotherapy as a radiosensitizer on Raji cells, a model for highly invasive non-Hodgkin lymphoma. First, Raji cells were treated with blueberry extract alone and in combination with a single dose of 2 Gy radiotherapy. The effects of blueberry extract on inhibiting proliferation and induction of apoptosis in Raji cells were investigated by MTT assay, flow cytometry (Annexin-V-FITC), cell cycle analysis, and quantitative gene expression analysis of BAX, BCL-2 and XPA. Its role in improving the efficacy of radiotherapy on cancer cells was also investigated. Treated cells with blueberry extract alone and in combination with radiotherapy showed reduced viability, increased induction of apoptosis and a higher proportion of cells in the SUB-G1 cell cycle phase was detected. Additionally, gene expression analysis indicated upregulation of the pro-apoptotic gene BAX expression and decreased anti-apoptotic gene BCL-2 expression, along with elevated expression of XPA as an indicator of DNA damage after radiotherapy. The study suggests that blueberry extract stimulates apoptosis in Raji cells and could serve as an anti-cancer drug. Furthermore, the combination of this extract with radiotherapy could be used as a radiosensitizer.
Metoprolol, a widely used β-blocker, is administered as a racemic mixture, with (S)-metoprolol being more pharmacologically active. Its metabolism by CYP2D6 exhibits significant inter-individual variability due to genetic polymorphisms. While enantioselective pharmacokinetics have been studied in single-dose trials, data on long-term therapy in hypertensive patients is limited. This study examines urinary enantiomer profiles to assess variability in metabolism and excretion. This study investigates the enantiomeric profile of metoprolol in urine samples collected from hypertensive patients receiving long-term racemic metoprolol therapy. The research aims to improve the analytical performance of the method to explore the enantioselective metabolism and excretion of the drug, focusing on the variation in enantiomer ratios among patients and the potential implications for clinical practice. Urine samples were collected from 30 hypertensive patients treated with racemic metoprolol. The samples were analyzed using capillary electrophoresis (CE) with clarithromycin as a chiral selector. Prior to CE analysis, liquid-liquid extraction was performed to isolate metoprolol from urine. The CE method employed an online preconcentration method and had a detection limit of 0.015 µg mL-1 for each enantiomer, a linear range of 0.05 to 2.0 µg mL-1, and demonstrated intra-day and inter-day precision below 6.3%, with accuracy within 5.6%. Metoprolol enantiomers were quantified in patients' urine samples, with enantiomer ratios varying among individuals. The enantiomer ratio (S/R) exceeded 1 in most patients, reflecting higher (S)-metoprolol concentrations. However, in approximately 40% of patients, the ratio was less than 1, suggesting possible enantioselective renal excretion. The study confirms that there is substantial inter-individual variability in the enantioselective metabolism and excretion of metoprolol among hypertensive patients. The findings emphasize the need to consider enantioselective pharmacokinetics in clinical practice, especially for chiral drugs like metoprolol. The results also suggest that the duration of treatment may affect the metabolism and excretion of enantiomers, warranting further investigation into the effects of long-term drug administration on enantiomeric ratios.
New psychoactive substances (NPS) pose a rapidly evolving public health challenge due to their diverse chemical structures and psychoactive effects, necessitating a comprehensive understanding of their classification, mechanisms of action, and detection. Recognizing critical gaps in the understanding and management of NPS, this review aimed to synthesize current liter-ature. Specifically, we sought to elucidate the evolving classifications of NPS, delineate their underlying molecular mechanisms of action to inform therapeutic strategies, and critically evaluate existing detection methodologies to ad-dress current analytical limitations, thereby providing an essential, integrated perspective on this rapidly changing landscape. A narrative literature review was conducted to analyze NPS classification, molecular mechanisms, and detection techniques. Searches were performed across Web of Science, Scopus, PubMed, and Elsevier, using keywords such as "synthetic cathinones", "designer drugs", "new psychoactive substance(s)", "detection of new psychoactive sub-stances" and "toxicology." Inclusion criteria prioritized studies primarily focused on NPS with clearly defined com-pounds (e.g., UNODC, EMCDDA classifications) and published within the last four years. Eligible publications en-compassed in vivo and in vitro studies, original research, and various review types. Exclusion criteria involved liter-ature outside the specified timeframe and studies on established drugs of abuse or licit substances, unless a direct comparative analysis with NPS was presented. The review synthesized a classification framework for NPS, detailed the molecular mechanisms underlying their psychoactive effects, and summarized current detection methodologies. Furthermore, it underscored the significant health risks associated with NPS use, including addiction, psychological disturbances, organ toxicity, and fatal outcomes. The continued emergence and proliferation of NPS necessitate ongoing research to fully characterize their specific effects and associated risks. This review provides a foundational synthesis of current knowledge, not only supporting the development of evi-dence-based interventions to mitigate their public health impact, but also serving as a catalyst for new research direc-tions aimed at a deeper understanding and more effective management of these evolving compounds.
Electroceuticals refers to the constantly growing disciplines of bioelectric and bioelectronic medication. These include a broad variety of devices that have been invented and are now being utilized in medical implants, wearable medical electronics, and bioelectronics. The primary aim of this study is to encompass several facets of electroceuticals, their applications, and recent advancements in the field of medical challenges. A complete literature study was conducted, which included a comprehensive review of globally recognized scientific research databases. The progressive refinement and diminution of technology, in conjunction with swift advancements in comprehending the role of electrical pathways in the human body, have rendered it progressively viable to manipulate these pathways for therapeutic purposes. Electrical stimulation impacts and modifies biological functioning and pathological processes in the body. In the contemporary era of medicine, health care practitioners from a variety of fields utilize electricity to cure disease or injury or to assess and diagnose using a variety of electrically driven medical tools.
A recent body of evidence has suggested regular exercise as a promising complementary therapeutic strategy in the management of epilepsy and its related cognitive impairments. To put it to the test, our study aimed to comparatively examine the effects of physical exercise, low and high doses of levetiracetam, or the combination of both on amygdala electrical kindling-induced epilepsy in rats, as well as the consequent learning and memory impairments. Male Wistar rats were randomly divided into ten groups (n = 7 per group) as the following: (I) Control (without kindling and exercise), (II) Lev (rats were received 54 mg/kg of levetiracetam without kindling and exercise), (III) Ex (rats were subjected to exercise without kindling), (IV) Ex-K (rats were subjected to preventive exercise before kindling), (V) K (rats were subjected to kindling without any intervention), (VI) K-Ex (rats were subjected to exercise after kindling), (VII) K-L lev (rats were received 27 mg/kg levetiracetam after kindling), (VIII) K-H lev (rats were received 54 mg/kg levetiracetam after kindling), (IX) K-Ex-L lev (subjected to exercise and receiving a low dose of levetiracetam after kindling), and (X) K-Ex-H lev (rats were subjected to exercise and receiving a high dose of levetiracetam after kindling). After the kindling procedure and interventions, the seizure parameters, including dADD, S1L, S2L, S3L, S4L, S5L, Max S5D, and Max ADD, were recorded, and seizure-related behavioral changes were evaluated using the MWM test. Our findings showed that in all therapeutic interventional groups, including Ex, L lev, H lev, and their combination (Ex-L lev and Ex-H lev), there was a substantial reduction in parameters, including seizure stages, seizure duration, and dADD. In contrast, there was a significant increase in the mean delay time or latency from electrical stimulation to the onset of stages 1, 2, and 3 of seizure (S1L, S2L, and S3L), and all groups were significantly different from the kindling group. Moreover, the kindling-induced spatial memory and learning deficit was remarkably ameliorated by preventive exercise, Ex, L lev, H lev, and their combination. Our study reveals that, in conjunction with levetiracetam, regular exercise can ameliorate the intensity and frequency of amygdala electrical kindling-induced epileptic seizures, as well as the consequent spatial memory and learning impairments.
Fluoxetine, an antidepressant, has shown potential anticancer effects. However, its therapeutic efficacy is limited by its poor bioavailability and rapid metabolism. Nanotechnology is advancing medicine, particularly in developing suitable drug delivery systems to improve therapeutic effects and reduce drug side effects. This study aims to synthesize chemically conjugated fluoxetine-dextran nanoparticles (FLX-DEX NPs) to improve the pharmacokinetic profile in plasma and brain to improve antidepressant and anticancer activity against glioma and breast cancer. Besides this, it also targets to reduce the side effects of the drug via delivering the payload to pathological cells. Fluoxetine was conjugated to aldehyde-functionalized dextran to give pH stimulus release from its nanoparticles. The spectral and morphological characterization was performed using dynamic light scattering (DLS), atomic force microscopy (AFM), UV, FTIR and 1HNMR. The stability was determined using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) to evaluate thermal stability and phase transitions of the fluoxetine-dextran nanoparticles. Non-compartmental model was employed to compare the pharmacokinetics of FLX and its nanoparticles in the plasma and various parts of Sprague-Dawley rats. Furthermore, the in vitro safety profile, cytotoxic activity on MCF-7 breast cancer and U87 glioma cell lines and antidepressant effects were measured using various animal models. The levels of dopamine and serotonin in brain were monitored after a fortnight treatment of FLX and its NPs. The nanoparticles were found to be round to slightly elliptical, having size less than 50 nm and charge -15-20 mV. These nanoparticles were more stable to the drug as depicted by thermoanalysis. The particles showed a controlled and pH stimuli released. The Cmax, Tmax, t1/2, volume of distribution and plasma elimination values were 5.23, 2, 15 h, 1.94 and 0.045, respectively, on oral administration of 30 mg/ kg/day. They passed 20% and 18% viability against MCF-7 and glioma cancer at 10 mg/kg/day dose without retarding its anti-depressant effect. FLX-DEX NPs offer dual therapeutic benefits, enhancing anticancer activity and antidepressant effects. The extended half-life and controlled fluoxetine release improved the pharmacokinetics and therapeutic outcomes, suggesting a promising nanotechnology-based approach for cancer and depression treatment.
Some forms of breast cancer such as triple-negative phenotype, are serious challenge because of high metastatic cases, high mortality and resistance to conventional therapy motivated the search for alternative treatment approaches. Nanomaterials are promising candidates and suitable alternatives for improving tumor and cancer cell treatments. Biosynthesis of ZnO NPs by help of Berberis integerrima fruit extract, has been done. Analysis of Zinc Oxide NPs using DLS, FTIR, SEM, and EDS techniques have been performed. Moreover, biological activities of ZnO NPs evaluated through MTT method, Flow cytometry, and real time PCR methods. Biocatalytic and apoptotic activity of ZnO NPs on healthy HFF (human fibroblast cell line), MDA-MB 231, and MDA-MB 468 (triple negative breast cancer cell lines, (TNBC)) evaluated. Furthermore, Bax, Bcl-2 and caspase-3 apoptotic genes expression changes in cancer cells assessed in compare to GAPDH as a house keeping gene. Physico-chemical investigation demonstrated ZnO NPs were confirmed by Berberis integerrima fruit extract for the first time. The MTT assay and Flow cytometry results indicated biocompatibility of the ZnO NPs in normal cell line and high anticancer potential against TNBC MDA-MB-231 and MDA-MB-468 cell lines. The IC50 of ZnO NPs were 104.4 and 44.86, 20.96 after 24 hours for HFF, MDA-MB-231 and MDA-MB-468 cells, respectively. The current research showed a fast, cost effective and ecofriendly method for ZnO NPs nanoparticle synthesis. Furthermore, In vitro data analysis demonstrated biocompatibility and highly anticancer effects of biosynthesized ZnO NPs against TNBC cancerous cells.
Esophageal squamous cell carcinoma (ESCC) is a prevalent and lethal cancer, with traditional treatments often ineffective. This study investigates the anti-proliferative and anti-metastatic effects of natural compounds Urolithin A (UA) and Urolithin B (UB) on ESCC cell lines KYSE-30 and YM-1. KYSE-30 and YM-1 ESCC cells were treated with UA and UB, and their viability assays, cell cycle arrest, apoptosis, expressions of mRNA linked to apoptosis and metastasis, generation of reactive oxygen species (ROS), activity of MMP-2 and MMP-9, along with mRNA expressions of MMP-2 and MMP-9, and migration were assessed. The results showed that UA (which had lower IC50 than UB) and UB reduced the viability of both KYSE-30 and YM-1 cells. Furthermore, UA and UB exhibited lower toxicity towards normal HFF cells compared to ESCC cells. Both UB and the more effective UA induced apoptosis and caused G2/M cell cycle arrest in KYSE-30 and YM-1 cells. Additionally, UA and UB elevated ROS production and led to a decrease in Bcl-2 expression while increasing the expression of Bax and p21 genes. A decrease in the mRNA expression and enzymatic activity of MMP-2 and MMP-9 was observed following treatment with UA and UB. UB and, more potently, UA show the potential to induce apoptosis while reducing metastatic properties and migration of ESCC cells, suggesting them as promising candidates for new anti-ESCC therapies; however, further preclinical and clinical research is needed to fully understand their anti-cancer effects and mechanisms.
Doxorubicin (Dox) is a chemotherapy medication used in the therapy of cancers. However, despite its killing of cancer cells, Dox is toxic to the heart and can lead to heart failure. This outcome in turn poses a therapeutic challenge given the limited treatment options available to these individuals. This study examines how CeO₂ nanoparticles, through oxidative stress, inflammation, apoptosis, and mitochondrial function, reduced Dox toxicity in human cardiac myocyte (HCM) cells. Following detection of the optimal doses of CeO₂ nanoparticles using the MTT assay, HCM cells were treated with Dox (8.25 µM) and CeO₂ nanoparticles for 24 h. Then, the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) and the activity of superoxide dismutase (SOD) were determined. Furthermore, the mitochondrial membrane potential, mitochondrial swelling, and mitochondrial cytochrome c release were analyzed. The level of gene expression of IL-1β, IL-6, and TNF-α, as well as apoptosis, was also examined. The data of this work demonstrated that Dox significantly elevated levels of ROS and MDA and reduced GSH level and SOD activity, which is modified by CeO₂ nanoparticles. Also, Dox meaningfully increased inflammation markers and apoptosis and induced mitochondrial malfunction, which were meaningfully reduced by CeO₂ nanoparticles in a dose-response manner in HCM cells. According to the present study results, CeO₂ nanoparticles, through a reduction in oxidative stress, inflammation, apoptosis, and mitochondrial malfunction, can have therapeutic potential in HCM cells toxicity induced by Dox.
The co-delivery of two therapeutic agents within a single nanoparticle platform offers a potential strategy to improve treatment efficacy while minimizing adverse effects. Albumin as a biocompatible carrier could facilitate simultaneous delivery of cargos to the tumoral region based on passive targeting gained by enhanced permeability and retention (EPR). This study aimed to develop, characterize, and assess a dual-drug delivery system incorporating rapamycin and SN38, utilizing the nanoparticle albumin bound technique, for the treatment of breast cancer. Albumin bound NPs of SN38 and rapamycin were prepared using probe sonication method. NPs were characterized using dynamic light scattering (DLS) and field emission scanning electron microscopy (FESEM) techniques to confirm their hydrodynamic diameter and structural properties. Drug loading (DL) and entrapment efficiency (EE) were measured using validated reverse phase high performance liquid chromatography (RP-HPLC) methods. Cellular cytotoxicity assay, cellular internalization, quantitatively cellular uptake, colony formation assay, and sphere formation assay were performed. To track NPs destiny as a 24 h follow up in the biodistribution part, NPs were intravenously injected to the BALB/c tumor bearing mice. Blank NPs showed hydrodynamic diameter of about 121 nm, drug incorporation resulted in sizes around 200 nm. No toxicity was observed by MTT assay for blank albumin NPs. MTT assay of drug loaded NPs showed higher toxicity for dual drug loaded NPs compared to single drug loaded NPs. Confocal images and flow cytometry showed high accumulation of NPs in cytoplasmic space of 4T1 cells. All of the experimental groups showed significant decrease in colony formation and sphere formation in comparison to the control group. NPs were also preferentially accumulated in the tumoral region in vivo due to their suitable size. In conclusion, the designed drug delivery system proposes great potential for breast cancer treatment.
Bile salts enriched nanovesicles (bilosomes) have been attention worthy in the past few years due to their distinctive effect on the enhancement of drug delivery through various physiological administration routes. Oral delivery of multifunctioning phytochemical curcumin has faced a lot of difficulties due to its scarce solubility and poor oral bioavailability. The current investigation aimed to develop curcumin loaded bilosomes for improvement of oral curcumin bioavailability with maximum efficiency and safety. The effect of formulation variables (type of span, SDC % to total lipid content Span/Cholesterol molar ratio) on physicochemical characterization and in vitro drug release in simulated intestinal fluid was investigated. Furthermore, in-vivo protective effect of bilosomes on hepatic and renal functions was also studied. and conclusion. The results revealed that the best curcumin loaded bilosomal formulation showed spherical nanovesicular morphology with particle size 145.1 ± 19.42 nm with highly reasonable %EE (93%), Zeta potential (≥ -30mv), prominent controlled in-vitro release reaching 55.18 ± 1.10 after 96 h. The formulation also showed good storage stability with negligible differences in physical features and content. The IC50 values of bilosomal, niosomal, and free curcumin were 216.50, 211.44, and 121.63 mmol/ml, respectively revealing that the unencapsulated curcumin displayed high toxicity on Caco2 cell line (nearly 2 folds). Additionally, the prepared bilosomes showed significant in-vivo hepatic and renal protection in liver cirrhosis induced rats with conservation to all liver and renal markers and histopathological morphology. The study assumes the effectiveness and safety of oral delivery of curcumin loaded bile salts stabilized nanovesicles and its powerful commandment for further investigations.
Cancer drug resistance is a multifaceted phenomenon. The present review article aims to comprehensively analyze the cellular and molecular aspects of drug resistance in cancer and the strategies employed to overcome it. A systematic search of relevant literature was conducted using electronic databases such as PubMed, Scopus, and Web of Science using appropriate key words. Original research articles and secondary literature were taken into consideration in reviewing the development in the field. Cancer drug resistance is a pervasive challenge that causes many treatments to fail therapeutically. Despite notable advances in cancer treatment, resistance to traditional chemotherapeutic agents and novel targeted medications remains a formidable hurdle in cancer therapy leading to cancer relapse and mortality. Indeed, a majority of patients with metastatic cancer experience are compromised on treatment efficacy because of drug resistance. The multifaceted nature of drug resistance encompasses various factors, such as tumor heterogeneity, growth kinetics, immune system, microenvironment, physical barriers, and the emergence of undruggable cancer drivers. Additionally, alterations in drug influx/efflux transporters, DNA repair mechanisms, and apoptotic pathways further contribute to resistance, which may manifest as either innate or acquired traits, occurring prior to or following therapeutic intervention. Several strategies such as combination therapy, targeted therapy, development of P-gp inhibitors, PROTACs and epigenetic modulators are developed to overcome cancer drug resistance. The management of drug resistance is compounded by the patient and tumor heterogeneity coupled with cancer's ability to evade treatment. Gaining further insight into the mechanisms underlying medication resistance is imperative for the development of effective therapeutic interventions and improved patient outcomes.