Advanced pharmaceutical bulletin最新文献

Purpose: This review aims to elucidate the role of estrogen-sensitive microRNAs (miRNAs) in modulating brain functions and disorders, highlighting the protective effects of estrogen on the central nervous system.

Methods: A comprehensive literature review was conducted, examining the relationship between estrogen, miRNAs, and cognitive health. The study focused on experimental data comparing cognitive impairments between genders and the mechanisms of estrogen's effects on brain function.

Results: Cognitive impairments are less prevalent in women of reproductive age compared to men, indicating estrogen's neuroprotective role. Estrogen modulates gene expression through specific receptors, while miRNAs regulate approximately 30% of protein-coding genes in mammals. These miRNAs play critical roles in synaptic plasticity and neuronal survival. The review identifies several estrogen-sensitive miRNAs and their potential involvement in brain disorders.

Conclusion: The interplay between estrogen and miRNAs offers valuable insights into the molecular mechanisms underlying cognitive health and disease. Understanding these relationships may lead to novel therapeutic strategies for addressing various brain disorders, particularly those associated with hormonal changes and aging.

Purpose: Currently, there is a crucial need for alternative strategies to control leishmaniasis, which threatens more than 1 billion people worldwide. The simultaneous use of combination therapy and nanostructured lipid carriers aimed to assess the leishmanicidal activity of silver and dapsone niosomes co-administration in vitro and in silico.

Methods: After preparing the niosomal formulations of dapsone and silver using the film hydration method, Span 40 and Tween 40/cholesterol with a 7/3 molar ratio was selected as the optimal formulation. Consequently, the arrays of experimental approaches were conducted to compare the anti-leishmaniasis efficacy of ready niosomes with amphotericin B and obtain a deeper understanding of their possible mechanisms of action.

Results: Our findings showed higher potency of silver-loaded and dapsone-loaded niosomes co-administration compared to amphotericin B as a positive control group. The results of isobologram and combination index (CI) analyses confirmed the synergic potential of this mixture. This combination triggered anti-leishmanial pathways of macrophages, which promoted the expression level of Th1 cell-related genes, and the downregulated expression of the phenotypes related to Th2 cells. Furthermore, a high level of antioxidant and apoptotic profiles against the parasite provides a rational basis and potential drug combination for cutaneous leishmaniasis. Moreover, the outcomes of the molecular docking showed a high binding affinity between dapsone and iNOS, stimulating the immune response in Th1 direction.

Conclusion: In general, the multifunctional leishmanicidal activity of dapsone and silver-niosomes co-administration should be considered for further in vivo and clinical studies.

Serum creatinine (SCr) is widely regarded as a standard biomarker for assessing glomerular filtration rate (GFR) and is commonly used to guide dose adjustments for renally eliminated drugs. However, the application of SCr as a marker for evaluating GFR and drug dosing in kidney injury has significant limitations that are often overlooked in clinical practice. This oversight can result in subtherapeutic drug concentrations or adverse drug reactions due to inappropriate dosing adjustments based on SCr levels alone. This review aimed to highlight the factors affecting serum creatinine (SCr) and the challenges associated with using SCr as a biomarker for assessing GFR and adjusting drug doses with regard to its limitations and variability. The findings of this review underscore the complexity of SCr regulation, which is affected by its synthesis, metabolism, and excretion processes (glomerular filtration, tubular secretion, tubular reabsorption and extra-renal elimination), and disease states (such as trauma-induced hyperfiltration and HIV) and the use of medications (drug-creatinine interactions) lead to altered renal excretion of creatinine, either increasing or decreasing its levels. Additionally, the renal excretion pathways for drugs and creatinine are not entirely the same, making it difficult to use creatinine to evaluate drug renal excretion. In conclusion, SCr is an imperfect index of GFR and adjusting drug dosing, and the development of multi-biomarker panels, incorporating biomarkers from different excretory pathways-particularly those involving tubular transport-holds promise for improving the evaluation of renal excretory function and ensuring safer and more effective drug dosing.

Purpose: It seems that maternal intervention, which may involve epigenetic mechanisms, can affect cerebral ischemia in offspring. Metformin consumption by the mother activates the AMP-activated protein kinase (AMPK) pathway. Metformin has also induced the AMPK and protected neurons in cerebral ischemia. This study investigates the effect of maternal metformin administration, which activates the AMPK pathway, on cerebral ischemia in offspring.

Methods: Animals were separated into four groups: sham, 2-vessels occlusion (2VO), Met+2VO, Met+compound c (CC)+2VO. Female rats were administrated with metformin at a dose of 200 mg.kg^-1 body weight for 2 weeks prior to mating. After the final metformin injection, each female rat was paired with an intact adult male to allow for mating. Sixty-days old offspring underwent cerebral ischemia and then memory-related tests were done.

Results: Current data revealed that the neurological deficits score was reduced Met+2VO group (P<0.001), and the memory increased (P<0.001) in comparison to the 2VO. The Bcl-2/Bax ratio declined in the metformin group (P<0.001) while the brain-derived neurotropic factor (BDNF), c-fos, p-AMPK/AMPK ratio and Histone H3K9 acetylation in the hippocampus augmented significantly compared to the 2VO group (P<0.001).

Conclusion: These findings indicated that the metformin intervention via AMPK activation could improve the movement disability, enhance spatial memory, increase neural plasticity, and augment the bioenergetics state and histone acetylation in the hippocampus of the offspring.

Purpose: In the present research, a green technique (an ultrasonic method) was used to synthesize menadione sodium bisulfite (MSB) niosome (Menasome) which is used to improve dermal delivery and increase anti-melanogenesis activities.

Methods: Various cholesterol: surfactant (Chol: Sur) ratios were investigated to optimize the Menasomes. Photon correlation spectroscopy, attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), transmission electron microscopy (TEM), and differential scanning calorimetry (DSC) were employed to characterize the solid state of MSB in nanoparticle form. Additionally, the optimized formulation was used to investigate ex-vivo skin absorption, in vivo skin irritation, in vitro cell survival, and anti-melanogenesis activity.

Results: The results exhibited that increasing cholesterol declined the average size of the Menasomes from 653.766±25.171 nm to 298.133±8.823 nm and increased entrapment efficiency 30.237±3.4204% to 83.616±2.550 %. The rat skin permeation study indicated that Menasome gel administered more MSB in dermal layers (439.000±36.190 μg/cm² or 23.827±1.964%) than MSB plain gel (286.200±22.6 μg/cm² or 15.53±1.227%). In both the in vivo skin irritation test and the in vitro cytotoxicity experiment, the extended-release behavior of the enhanced Menasome demonstrated a minimal side effect profile. Furthermore, optimum Menasome inhibited melanin formation (37.426±1.644% at 15μM) greater than free MSB (57.383±1.654%) considerably (P<0.05). Furthermore, Menasome 7 prevented L-dopa auto-oxidation in higher levels (95.140±2.439%) than pure MSB solution (83.953±1.629%).

Conclusion: According to the study's findings, the prepared Menasome could be employed as a viable nanovehicle for MSB dermal delivery, a promising solution for the management of human hyperpigmentation disorders.

Purpose: Warfarin is one of the most widely used anticoagulants that functions by inhibiting vitamin K epoxide reductase. Warfarin overdose, whether intentional or unintentional, can cause life-threatening bleeding. Here, we present a novel warfarin adsorbent based on mesoporous silica that could serve as an antidote to warfarin toxicity.

Methods: Amino-functionalized mesoporous silica (MS-NH₂) was synthesized based on the co-condensation method through a soft template technique followed by template removal. The prepared structure and functional group were studied by Fourier transform infrared spectroscopy (FT-IR), and X-ray diffraction (XRD). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) checked the morphology. The capacity of MS-NH₂ in the adsorption of warfarin was evaluated in vitro, at pH=7.4 and pH=1.2. In vivo evaluations were performed in control and warfarin-overdosed animal models. Overdosed animals were treated with MS-NH₂ by oral gavage. Biomarkers of organ injury were assessed in animal serum.

Results: The MS-NH₂ was relatively uniform, spherical with defined diameters (400 nm) and porous structure. Synthesized particles had a large surface area (1015 m₂ g^-1) and mean pore diameter of 2.4 nm which led to considerable adsorption capacity for warfarin 1666 mg/g. In vivo studies revealed that oral administration of MS-NH₂ in mice poisoned with warfarin caused a significant difference (P<0.05) in the International Normalized Ratio (INR) and prothrombin time (PT). Moreover, the warfarin with MS-NH₂ group demonstrated a notable decrease in biomarkers associated with tissue damage, such as bilirubin, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST).

Conclusion: The results confirm that MS-NH₂ administration can be an effective treatment for warfarin toxicity and could potentially mitigate the adverse effects of warfarin poisoning.

Purpose: Autophagy, governed by genes with dual roles in cell death and survival, plays a crucial role in cancer persistence. Arsenic trioxide (ATO), carboplatin (CP), and cyclophosphamide (CY) are used to treat various cancers. ATO impedes cell proliferation and triggers apoptosis in cancer cells. CP, a platinum-based drug, damages cancer cell DNA, while CY acts as an alkylating agent, disrupting cell proliferation. This study investigates the combined effects of ATO, CP, and CY on inducing apoptosis and modulating autophagy in triple-negative breast cancer (TNBC) cell lines, BT-20 and MDA-MB-231.

Methods: The cytotoxic effects of ATO, CP, and CY, alone and in combination, were evaluated using the MTT assay on BT-20 and MDA-MB-231 cells. Apoptosis and cell cycle progression were analyzed by annexin-V FITC/PI staining and flow cytometry. Gene expression of autophagy-and apoptosis-related markers, including Beclin 1, LC3, caspase 3, and BCL2, was quantified using RT-PCR. Data were analyzed using GraphPad Prism 4.0 with one-way ANOVA followed by Dunnett's test.

Results: The combination of ATO, CP, and CY significantly reduced cell viability and enhanced apoptosis, evidenced by increased caspase-3 activity and reduced BCL2 expression. Cell cycle arrest in the G1 phase was observed, alongside elevated autophagy markers Beclin 1 and LC3.

Conclusion: The combination of ATO, CP, and CY induces synergistic effects in promoting apoptosis and autophagy in TNBC cell lines. These findings suggest that this combination therapy could be a promising approach to enhancing treatment efficacy in aggressive breast cancers, offering new insights into potential therapeutic strategies.

Purpose: The clinical use and efficacy of phytomolecules are often hampered as their complex structure, poor aqueous solubility and low biological stability restricts their intestinal permeability which results in low oral bioavailability. Rutin (RT), quercetin (QU), thymoquinone (TQ) are few of such potent and therapeutically versatile phytomolecules that await maximal utilization. To address this lacuna, an attempt was made to develop a single strategy for enhanced intestinal permeation that can be applied to diverse phytomolecules.

Methods: A simple idea with easy-to-apply method was developed that involved preparing nanoparticles of the phytomolecules RT, QU, TQ using Eudragit matrix (RT-PNP, QU-PNP, TQ-PNP) and examined for particle characteristics, EE, in vitro release and kinetics. Phytomolecule loaded nanoparticle (PNPs) were encapsulated in HPMC grade capsule shell and evaluated for intestinal permeability by everted gut sac method.

Results: The average particle sizes of RT-PNP, QU-PNP, TQ-PNP were 446±0.152, 39.6±0.006 and 186±0.513 nm, polydispersity indices were<0.5 with negative zeta potential. The % release of respective phytomolecule from RT-PNP, QU-PNP, TQ-PNP was significantly higher (P<0.05) at pH 6.8 than pH 1.2. PNPs followed Higuchi kinetics with non-Fickian diffusion mechanisms. The apparent intestinal permeability (Papp) of RT-PNP, QU-PNP, TQ-PNP were 14.45±4.85, 12.96±1.73 and 30.87±8.75 µg/cm², respectively, significantly (<0.5) greater vs RT, QU, TQ, respectively. CLSM confirmed significantly higher (P<0.05) intestinal permeation of RT-PNP, QU-PNP, TQ-PNP vs RT, QU, TQ, respectively.

Conclusion: Developed PNPs appear to be a good approach to increase the permeability of hydrophobic phytomolecules.