Drug Research最新文献

Diabetic retinopathy, the most common microvascular complication of diabetes mellitus, is the leading cause of vision impairment worldwide. Flavonoids with antioxidant properties have been shown to slow its progression. Myricetin, a flavonoid polyphenolic compound, possesses antioxidant properties, but its clinical use in ocular delivery is limited by poor aqueous solubility, stability, and bioavailability. Recently, in situ gels have gained interest as ocular drug delivery vehicles due to their ease of installation and sustained drug release. This study aimed to develop a myricetin-loaded thermoresponsive in situ nanoemulgel to enhance its efficacy in treating diabetic retinopathy. Nanoemulsions were developed via aqueous phase titration using Sefsol 218 as the oil phase, Kolliphore RH40 as the surfactant, and PEG 400 as the co-surfactant. Physicochemical evaluations identified formulation batch ISG17, consisting of 10% oil phase, 30% S_mix (1:2), and 60% distilled water, as the optimal formulation. The developed in situ nanoemulgel showed significant enhancement in corneal permeation and retention, which was further confirmed by fluorescence microscopy. Ocular tolerability was demonstrated through corneal hydration tests and histopathology investigations. The antioxidant potential of the myricetin-loaded nanoemulgel was assessed using the DPPH assay. Myricetin was found to be an efficient antioxidant, as indicated by its IC₅₀ values compared to ascorbic acid. The MTT cell viability assay results showed that the developed formulation effectively inhibits the proliferation of Y79 retinoblastoma cells, demonstrating comparable efficacy to the standard marketed preparation Avastin (Bevacizumab injection). In conclusion, the nanoemulsion formulation containing a thermoresponsive polymer for in situ gelling presents a promising drug delivery system, offering superior therapeutic efficacy and better patient compliance for the treatment of diabetic retinopathy.

One of the most widespread arboviral diseases in the world, dengue virus disease (DVD) is primarily found in tropical and subtropical regions, affecting 129 countries. The main way that the dengue virus (DENV) spreads is through the bite of a female Aedes aegypti mosquito. Symptomatic therapy and supportive care are the primary methods of managing patients with DENV infection as there is currently no approved antiviral medication for this condition. Since the guidelines from the AYUSH Ministry, Government of India, recommend 10 ml of carica papaya leaf extract (CPLE) twice daily for seven days, to treat dengue fever clinically, we plan to review the potential of carica papaya in managing DENV infection.Using terms like dengue, dengue fever, dengue hemorrhagic fever, dengue shock syndrome, and carica papaya, the literature was searched in databases like Medline/PubMed Central/PubMed, Google Scholar, Science Direct, EBSCO, Scopus, Web of Science, EMBASE, Directory of open access journals (DOAJ), and reference lists to find articles relevant to the clinical, in-vivo, in-vitro, and in-silico studies evaluating the efficacy of carica papaya in the management of dengue viral infection. This review included English-language publications that supported the use of carica papaya in the treatment of dengue fever, but it excluded publications that were duplicates.Numerous preclinical and clinical investigations, such as in-vitro, in-vivo, and in-silico studies, have identified carica papaya's anti-dengue potential. The pleiotropic effects of carica papaya, including its anti-thrombocytopenic activity, immunomodulatory effects, and larvicidal property against the Aedes aegypti mosquito species, have also been confirmed by numerous in-vitro and in-vivo studies. These effects can help patients with dengue fever by elevating their platelet count and alleviating other symptoms.To hasten recovery and reduce hospital stays, patients with DENV infection may take carica papaya leaf extract (CPLE) in addition to supportive care and symptomatic treatment. Additional randomized controlled clinical trials would be necessary to confirm the safety and effectiveness of CPLE in patients with DENV infection.

WEE1 is a key tyrosine kinase involved in the cell cycle regulation with potent anticancer effects in various cancer types including colorectal cancer. Recent studies have focused on the potential of combinational inhibition of Ataxia Telangiectasia and Rad-3-related protein (ATR) and WEE1 in increasing apoptosis in cancer cells. Therefore, this study investigates the effects of inhibiting WEE1, by employing AZD1775, on colorectal cancer cells' susceptibility to VE-822-induced DNA damage and apoptosis.SW-480 and HT-29 cells were treated with AZD1775 and VE-822, alone and in combination. MTT assay was used to assess cell proliferation and viability. The mRNA levels of ATR, checkpoint kinase 1 (CHK1), WEE1, ribonucleotide reductase (RR) catalytic subunit M1 (RRM1) and RRM2 were measured by qRT-PCR. Cellular γ-(H2A histone family member X) H2AX levels were measured by Western blot. Analyses were conducted using ELISA to assess 8-Oxo-2'-deoxyguanosine (8-oxo-dG) levels. Lactate dehydrogenase (LDH) and ELISA death assays were used to assess apoptosis.The SW-480 and HT-29 cells have low proliferation rate when treated with VE-822 and AZD1775. The IC50 value for VE-822 was 1.3 μM and 1.6 μM in SW480 and HT-29, respectively. Also, this value for AZD1775 in SW480 was 140 nM and in HT-29 was 185 nM. The expression levels of ATR, CHK1, WEE1, RRM1, and RRM2 were significantly downregulated in both cell lines treated with combination of VE-822 and AZD1775 (P<0.05). DNA damage markers, including γ-H2AX and 8-oxo-dG were upregulated in these cells. Simultaneous treatment with VE-822 and AZD177 increased apoptosis capacity of both cell lines.The inhibition of WEE1 via AZD1775 potentiated the anticancer effects of ATR inhibitor, VE-822, in combating colorectal cancer via targeting DNA damage.

This study aims to explore the therapeutic potential of thymoquinone (TQ) in DR by assessing its effects on Müller cell apoptosis through modulation of the miR-29b/SP1 pathway in a diabetic animal model.Healthy C57BL/6 mice (25 g) were used in the study. Retinal samples were collected from both normal and diabetic mice subjected to various treatments: TQ (1 mg/kg/day), glibenclamide (GLB, 250 mg/kg/day), sitagliptin (STG, 10 mg/kg/day), and metformin (MET, 5 mg/kg/day) over a period of 28 days. The study measured miR-29b and SP1 mRNA levels using qRT-PCR. Protein expressions of SP1, Bax, and bcl-2 were analyzed through western blotting, while Caspase-3 activity using an ELISA assay kit, and apoptosis levels by annexin V.TQ administration resulted in a 52% reduction in blood glucose levels. Similarly, GLB, STG, and MET treatments reduced blood glucose by 60%, 57%, and 61%, respectively (p<0.05). In addition, TQ upregulated miR-29b by 51.28% and downregulated SP1 mRNA by 32.52% (p<0.05). Bax protein expression levels were decreased by 64.99%, while Bcl-2 protein expression increased by 62.92% in the TQ treatment group as compared to the untreated diabetic controls. Furthermore, Caspase-3 activity was downregulated by 40.03% with TQ treatment (p<0.05). Interestingly, the effect TQ on SP1 mRNA expression was inhibited by a miR-29b blocker (p<0.05), while an miR-29b mimic enhanced this effect; this was associated with a mitigation of apoptosis of retinal Müller cells as measured by flow cytometry (p<0.05).These results indicate that TQ might be a possible option for DR via its effect on the miR-29b/SP1 pathway; and therefore, playing a significant role in the mechanism against cell death.

Tolerance to the antinociceptive effects of opioids is a major concern. Studies have shown that chronic use of non-steroidal anti-inflammatory (NSAIDs) causes significant tolerance and cross-tolerance to morphine. Chronic NSAIDs use can increase the risk of certain diseases, such as peptic ulcers, and exacerbate others, like heart failure. Therefore, developing novel pharmacological approaches could provide considerable benefits for chronic therapeutic procedures. Isovaline with a chemical structure similar to glycine and GABA induce a significant analgesic effect through GABA-B receptors. In this study, we investigated the impact of both short-term and long-term use of isovaline on the immediate response to pain, as well as the development of analgesic tolerance through daily injection (i.p.) of isovaline (100 mg/kg) for 5 days in male Balb/c mice. Additionally, on day 6, we examined the potential for cross-tolerance between isovaline and sodium salicylate (300 mg/kg) or morphine (5 mg/kg). The findings showed that isovaline injection resulted in a delayed onset of analgesic effect, a lowered peak effect, and less cumulative pain relief compared with sodium salicylate and morphine. This analgesic effect gradually decreased over the five days of isovaline injection. When sodium salicylate was injected into isovaline-tolerant mice, the antinociceptive effect decreased, suggesting cross-tolerance to sodium salicylate. However, no such tolerance was observed following morphine injection. Accordingly, it seems that chronic isovaline may interact with the sodium salicylate analgesic pathway but not with morphine.

Fragment based novel drug identification and its validation through use of molecular dynamics and simulations.Comparing primary microcephaly genes with glioblastoma expression profiles reveals potential oncogenes, with proteins that support growth and survival in neural stem/progenitor cells likely retaining critical roles in glioblastoma. Identifying such proteins in familial and congenital microcephalic disorders offers promising targets for brain tumor therapy. Among these, KIF11, a kinesin motor protein (KSP), stands out as a significant oncogene. Expression analyses across various cancer types, including glioblastoma, demonstrate its overexpression in brain tumor patients. Using a targeted fragment-based drug discovery approach, we explored alternative small molecule inhibitors for KIF11. Existing drugs, such as ispinesib, are limited by side effects and multidrug resistance. Through molecular docking and simulations, we identified three candidate drug fragments. Further analysis confirmed that Mol-121026 exhibits a more stable interaction with KIF11 compared to ispinesib. Detailed analyses indicate that Mol-121026 binds to the same active site as the reference drug, effectively inhibiting KIF11's mechano-chemical activity. Importantly, Mol-121026, a derivative of 3-phenyl-1H-pyrazol-5-carboxylic acid, offers a promising alternative due to its lower molecular complexity, ability to target allosteric sites, and potential for optimization into a potent and effective drug candidate. Our findings identified Mol-121026 as a top candidate with a docking score of -10.2 kcal/mol and MM/GBSA binding energy of -19.10 kcal/mol. Molecular dynamics simulations revealed stable interactions with key residues GLU116 and GLU118, supporting its potential as a promising KIF11 inhibitor.

To investigate the effect of 1α,25(OH)₂D₃ on hepatic stellate cells and the mechanism of the TGF-β1/Smad signaling pathway.LX2 cells were treated with TGF-β1 and different concentrations of 1α,25(OH)₂D₃. Cell proliferation was assessed using the CCK8 assay to determine the optimal concentration of 1α,25(OH)₂D₃ activity. The cell cycle and apoptotic rates were evaluated using flow cytometry. The expressions of Samd2, Samd3, Samd4, and Samd7 was assessed by western blotting, whereas the expression of MMP1, MMP13, and TIMP-1 was detected by qPCR.Compared with the control group, the 1α,25(OH)₂D₃ group had a higher apoptotic rate of LX2 cells, the cell cycle was blocked from the G1 stage to the S stage, the expressions of Samd2, Samd7, MMP1, and MMP13 increased, while the expressions of Samd3, Samd4, and TIMP-1 decreased.1α,25(OH)₂D₃ inhibits hepatic stellate cell activation and exerts anti-hepatic fibrosis effects by downregulating the expression of Samd3, Samd4, TIMP-1 and upregulating the expression of Samd2, Samd4, MMP1, and MMP13.

The targeted delivery of drugs is vital in breast cancer treatment due to its ability to produce long-lasting therapeutic effects with minimal side effects. This study reports the successful development of doxorubicin hydrochloride (DOX)-loaded colloidal gold nanoparticles stabilized with acacia gum (AG). Optimization studies varied AG concentrations (0.25% to 3% w/v) to determine optimal conditions for nanoparticle synthesis. The resulting acacia stabilized gold nanoparticles (AGNPs) were characterized using various techniques including high-resolution transmission electron microscopy (HR-TEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), ultraviolet-visible spectroscopy, Fourier-transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FE-SEM), and selected area electron diffraction (SAED). In vitro drug release studies demonstrated a higher release rate of DOX in sodium acetate buffer (pH 5.0) compared to phosphate buffer saline (pH 7.4), suggesting an enhanced therapeutic efficacy in acidic tumor environments. Cytotoxicity of DOX-AGNPs and free DOX was assessed in human breast cancer cells (MDA-MB-231). The DOX-AGNPs exhibited significantly greater cytotoxicity, indicating enhanced efficacy in targeting cancer cells. This enhancement suggests that adsorbing DOX on the surface of gold nanoparticles can improve drug delivery and effectiveness, potentially reducing side effects compared to pure DOX and traditional delivery methods. Stability tests conducted over six months at 25±1°C showed significant changes in particle size and PDI, suggesting limited stability under these conditions. Overall, the acacia-stabilized gold nanoparticles synthesized in this study exhibit promising characteristics for drug delivery applications, particularly in cancer therapy, with effective drug loading, controlled release, and favorable physicochemical properties.

Background: Psoriasis is a chronic skin condition that is associated with persistent inflammation and skin lesions. Topical therapy has been a promising approach to the alleviation of psoriasis through the application of anti-inflammatory agents. Phosphatidylserine (PS) administration has shown anti-inflammatory effects in the trials. Consequently, the objective of this study was to evaluate the effects of topical PS on the potential improvement of an imiquimod (IMQ)-induced psoriasis model. Additionally, cyclosporine A was utilized as a comparative anti-psoriatic agent in our study.

Methods: The psoriasis model was established by topically applying IMQ to the dorsal skin of mice once daily for five consecutive days. The efficacy of topical PS was assessed using the Psoriasis Area and Severity Index (PASI) score to evaluate skin lesions. Subsequently, the skin samples were analyzed using Baker's scoring system, Masson's trichrome staining, immunohistochemistry, and real-time PCR analysis.

Results: IMQ-induced plaque-type psoriasis resulted in a significant increase (P<0.05) in dermal thickness, hyperkeratosis, PASI score, and inflammatory cytokines at the lesion site. The topical PS and cyclosporine A significantly (P<0.05) reduced PASI score and dermal thickness, while also alleviating erythema and scaling when compared to untreated mice. Furthermore, biomolecular assessments revealed that PS significantly (P<0.05) inhibited the gene expression of IL-17, IL-23, and TNF-α cytokines in the IMQ-induced lesions.

Conclusion: Topical PS may pointedly alleviate psoriasis through the inhibition of inflammation. The beneficial effects of the PS recommend further investigation in both experimental and clinical studies in the control of skin psoriasis.

Tyrosine Kinase inhibitor (TKI) is a class of drugs that interfere with protein kinases' signal transduction pathways through an array of inhibitory mechanisms. Tyrosine kinases (TK) have an inevitable role in downstream signal transduction and the proliferation of tumour cells. Hence, tyrosine kinase inhibitors (TKIs) are frequently employed as anti-neoplastic agents in the treatment of colon, breast, kidney, and lung cancers. They can be used as single or combination therapy with other targeted therapies. It is understood that TKIs pose a risk of developing proteinuria in some patients as it can primarily result in dysfunction of the split diaphragm, constriction or blockage of capillary lumens mediated by the basement membrane, acute interstitial nephritis, or acute tubular necrosis. This paper reviews the mechanism of action of TKIs, the pathophysiological mechanism of TKI-induced proteinuria, and its management Fig. 1.