Future Journal of Pharmaceutical Sciences最新文献

In the twenty-first century, in vitro models of excitotoxic injury, leveraging advanced cellular and molecular technologies, offer a promising alternative to animal studies. These models provide a more precise understanding of injury mechanisms. Method: This study utilizes kainic acid (KA), a potent glutamate receptor agonist, to induce excitotoxicity, oxidative stress, and mitochondrial dysfunction, resulting in motor neuron (MN) degeneration. Mature, differentiated NSC-34 MNs were exposed to different concentrations of KA (0.1, 0.5, and 1 mM) to induce neurodegeneration and apoptosis. Following KA treatment, cells were either treated with MLC901 (NeuroAiD™ II) or left untreated. The effects were assessed through cell viability assays, immunocytochemistry with antibiotic staining, and analysis of key markers in the PI3K/AKT signaling pathway. KA exposure resulted in significant neurodegeneration and apoptosis, as indicated by a reduction in cell viability, a decrease in Tubulin beta-III expression, and downregulation of regenerative markers, including AKT, p-AKT, and GAP43. Additionally, the apoptotic marker p-GSK3β was upregulated in KA-treated cells. In contrast, MLC901 treatment alleviated these detrimental effects. MLC901 restored Tubulin beta-III expression and reversed the downregulation of PI3K/AKT signaling markers (AKT, p-AKT, GAP43). Furthermore, MLC901 treatment led to a reduction in the apoptotic marker p-GSK3β. This study demonstrates that KA induces necrotic and apoptotic cell damage, mimicking secondary injury mechanisms typical of neurodegenerative diseases. MLC901 shows promise as a neuroprotective agent, counteracting KA-induced excitotoxicity and highlighting its potential therapeutic application in neuroprotection.

Background

Alzheimer's (AD) is a neurological disorder that worsens the quality of life and raises the need for caretakers with no available curative medication for the illness. Therefore, there is a growing concern about the use of herbal medicine, as it is cost-effective, has minimal side effects, and could slow AD progression and enhance patients' quality of life, making it a viable adjuvant therapy. Pithecellobium dulce (Roxb.) Benth F. Leguminosae is widely consumed in several countries to treat various illnesses. This study used in vitro, in vivo, and in silico studies to investigate the potential use of P. dulce leaves' methanolic extract in treating and preventing Alzheimer's disease.

Results

The in vitro study showed that the extract inhibited 77% of the acetylcholinesterase (AChE) activity, and the IC₅₀ value was 19.23 ± 1.02 µg/ml. The in vivo study of scopolamine-induced Alzheimer's confirmed the result by significantly inhibiting AChE, dopamine, noradrenaline, and malondialdehyde levels and increasing acetylcholine, and glutathione levels. A phytochemical analysis of the leaves methanolic extract using UPLC-ESI–MS/MS revealed 67 compounds of different chemical classes, 22 flavonoids, 17 phenolic and organic acids, 8 fatty acids, 3 sterols, 6 amino acids and alkaloids, 5 coumarins, and 2 anthraquinones, 1 sugar, 1 lignin, 1 terpene, and 1 hydrocarbon. It was found that 5, 7, 3′, 4′, 5′-pentahydroxy-3, 6, 8-tri-methoxy flavone had the strongest binding affinity for AChE (− 18.8 kcal/mol). Different computational modeling methods were employed, including principal component analysis, ligand-residue interaction, dynamics cross-correlation matrices analysis, and thermodynamics calculation. The binding of 5, 7, 3′, 4′, 5′-pentahydroxy-3, 6, 8-tri-methoxy flavone to ACh protein decreased the fluctuation and influenced the ligand optimum orientation on the AChE protein conformational space. Additionally, the drug binding energy of AChE and the residue correlation in the 5, 7, 3′, 4′, 5′-pentahydroxy-3, 6, 8-tri-methoxy flavone-AChE system was increased.

Conclusion

The P. dulce extract contains secondary metabolites that could promisingly be a safe and effective natural treatment for Alzheimer's complications through the antioxidant activity, acetylcholinesterase, dopamine, and noradrenaline inhibition activities and also by increasing the acetylcholine level in the brain.

Graphical abstract

Background

Procalcitonin (PCT) was first described in the early 1960s as a precursor of calcitonin that is synthesized mainly in the thyroid and lung tissues. It is an immediate biosynthetic product in response to bacterial toxins and the pro-inflammatory cytokines, which in turn makes it a distinctive biomarker for bacterial infections. The present analysis deals with the study on the biochemical characteristics, production pathways, and clinical uses of PCT as a diagnostic tool.

Methods

During March and June 2024, a cross-sectional study was performed, among 357 patients with the proper characteristics who were admitted to the hospital and got their PCT levels, there were those who had respiratory, cardiac, gastrointestinal, and systemic infections. The exclusion criteria were the hospital stay of less than 24 h and a few noninfectious diseases.

Results

The higher PCT levels (> 0.5 ng/mL) reliably informed about the presence of bacterial infections like pneumonia, endocarditis, urinary tract infections, and sepsis. PCT levels demonstrated trivial increase in viral as well as fungal infections. The study ratified the significant relationship between PCT levels and the severity of bacterial infections, thus backing its usefulness in the diagnosis and treatment control.

Conclusion

Procalcitonin is increasingly emerging as a trustworthy biomarker for bacterial infections, thus helping in the early diagnosis, guiding targeted antibiotic therapy, and reducing inappropriate antibiotic use. Its high specificity for bacterial etiology has largely contributed to the success and potency of antibiotic stewardship programs.

Background

The current studies involve the development of a liquid chromatographic method that is highly effective (HPLC) for the Lumateperone Tosylate method that is simple, rapid, accurate, precise, and economical, all made possible by analytical quality by design (AQbD). The HPLC method’s experimental settings were multivariately optimised by using the design of experiments to determine critical method parameters, and the Ishikawa diagram was used for risk assessment. A two-factor, three-level design was used for the factor screening investigations. Mathematical models were created using two independent factors: the buffer’s pH and the composition of the mobile phase. The response surface methodology and the impacts of these independent aspects were thoroughly examined using central composite design, which allowed for the evaluation of the critical method attributes (CMAs). The parameters of method robustness include retention time, peak area, and symmetry factor. Utilising the desirability function, the optimisation of the CMAs took place at the same time.

Results

According to the contour diagram’s optimised data, 10 mM ammonium acetate buffer (pH = 3.2): acetonitrile (80:20 v/v) was selected as a mobile phase with a 1 mL/min flow rate. A Zorbax SB C18 250 × 4.6 mm, 5 μ chromatographic column with a UV detector at 230 nm was used and oven temperature was maintained at 25 °C. Lumateperone Tosylate showed linearity in the concentration range of 25–250 µg/mL (r² = 0.9921). % RSD for interday and intraday precision was found to be 0.25–0.52 and 0.12–0.32, respectively. The % assay of drug content was found to be 100.01 ± 0.06, and accuracy was found to be 100.30–100.65%. In compliance with ICH recommendations, the optimised assay conditions were validated.

Conclusion

Therefore, it was clearly shown from the results that the AQbD methodology could be effectively used to optimise the HPLC method for Lumateperone Tosylate analysis. The technique was used to assess the Lumateperone Tosylate content in capsules as well.

Background

The present study aimed at investigating the effectiveness of zeinmersomes (ZMS)-based nano-formulation to enhance icariin (ICA) cytotoxicity in colon cancer cells. The prepared ICA-ZMS was characterized with respect to particle size, entrapment efficiency, and in vitro release.

Results

ICA-ZMS showed higher cytotoxicity in HCT-116 cells compared to HT-29 and Caco-2 cells with almost no cytotoxicity in normal HCoEpC colon cells. In this regard, ICA-ZMS exhibited potentiated cytotoxicity as compared to ICA-raw. In HCT-116 cells, ICA loaded on ZMS exhibited better cellular penetration compared to ICA-raw. The accumulation of HCT-116 in the S phase was identified using cell cycle analysis. Annexin V staining highlighted a potent pro-apoptotic activity of the prepared ICA-ZMS. This with confirmed by the observed up-regulated Bax and down-regulated Bcl-2 mRNA expression. Further, mRNA expression of p53, cytochrome C, and caspase-3 was significantly increased by exposing cells to ICA-ZMS. This was associated with a detectable decline in mitochondrial membrane potential. These data were confirmed by the ability of ICA-ZMS to significantly enhance the life span of Ehrlich ascites carcinoma-bearing mice.

Conclusion

This study suggests that the loading of ICA on ZMS nanoparticles enhances its cytotoxic and pro-apoptotic activities. This involves modulation of p53-dependent mitochondrial signaling.

Background

Steroid-induced hypergluconeogenesis is a significant contributor to hyperglycemia, often complicating the therapeutic use of steroids. This study investigates the potential of quercetin, a naturally occurring flavonoid, to mitigate steroid-induced hypergluconeogenesis in Saccharomyces cerevisiae. The levels of glucose, total proteins, free amino acids, pyruvate, lactate and antioxidants were assessed in the quercetin-treated yeast cells induced with betamethasone at different time intervals. The glucose uptake potential of yeast cells treated with quercetin was also studied and also the effect of steroids and quercetin on cell viability was analyzed.

Results

Our results show that quercetin effectively reduces gluconeogenesis by normalizing the levels of metabolites involved in the process and alleviates the hyperglycemic effects associated with steroid exposure. Quercetin-treated yeast cells also demonstrated a better uptake of glucose. Additionally, quercetin was found to improve the overall cell viability highlighting its role in modulating glucose metabolism.

Conclusion

These outcomes suggest that quercetin can serve as a promising adjunct therapy for managing steroid-induced metabolic disturbances, providing a natural and effective approach to counteracting steroid-induced hyperglycemia.

Background

The concurrent measurement of emtricitabine, tenofovir, and rilpivirine was achieved using UPLC, employing Analytical Quality by Design (AQbD) principles, which encompass response surface methodology (RSM) and Box–Behnken design (BBD). This approach offers a systematic and efficient method for improving analytical procedures and ensuring reliable results.

Results

Analyte separation was accomplished using an Endoversil C 18 (2.1 × 50 mm, 1.7 µm) column as the stationary phase. The mobile phase consisted of a mixture of 80% orthophosphoric acid (0.1%) and 20% acetonitrile, with a flow rate of 0.4 ml/min and a column temperature of 30 °C. A photodiode array detector was used for detection at 270 nm. The peak area response-concentration curve exhibited linearity across ranges of 50–250 µg/ml (emtricitabine), 100–500 µg/ml (tenofovir), and 10–50 µg/ml (rilpivirine). Quantitation limits were determined to be 0.099 µg/ml (emtricitabine), 0.165 µg/ml (tenofovir), and 0.066 µg/ml (rilpivirine). The method was successfully validated for the simultaneous determination of emtricitabine, tenofovir, and rilpivirine in combined tablet dosage form. Percentage recoveries were 99.89%, 99.52%, and 100.20%, with relative standard deviations of 0.415%, 0.268%, and 0.559% for emtricitabine, tenofovir, and rilpivirine, respectively.

Conclusion

The performance of the proposed method was evaluated against reported RP-UPLC methods and found to be rapid and cost-effective. The developed and validated stability indicating RP-UPLC method proved suitable for quality control and drug analysis.

Background

Chemotherapy-induced peripheral neuropathy (CIPN) is a detrimental outcome of various antineoplastic drugs, such as paclitaxel (PTX), vincristine (VCR), oxaliplatin (L-OHP), and bortezomib (BOR). CIPN results in pain and disability, thereby reducing quality of life and discontinuation of chemotherapy. Currently, the only effective treatment for CIPN is using duloxetine. Therefore, development of new treatments is necessary. Extract of Lentinula edodes mycelia (LEM) improves the quality of life for individuals undergoing chemotherapy treatment. As treatment with LEM may attenuate CIPN after chemotherapy, this study was conducted to determine whether treatment with LEM abrogates L-OHP-, PTX-, VCR-, and BOR-evoked cold and mechanical allodynia in mice.

Results

We found that LEM exhibits protective effects against cold and mechanical allodynia in mice treated with L-OHP, PTX, VCR, or BOR. We also found that the administration of L-OHP, PTX, VCR, and BOR elevated mRNA expression of Cav3.2, Cav3.3, and NR2A in the DRG of mice, whereas treatment with LEM abrogated L-OHP-, PTX-, VCR-, and BOR-induced Cav3.2 and NR2A mRNA expression. In addition, LEM treatment abrogated L-OHP-, PTX-, VCR-, and BOR-induced ERK1/2 phosphorylation in the DRG and spinal cord of mice. Furthermore, treatment with LEM reversed symptoms in mice that developed cold and mechanical allodynia after receiving L-OHP, PTX, VCR, or BOR.

Conclusion

These findings suggest that the attenuation of expression of phosphorylated ERK1/2, Cav3.2, and NR2A upon LEM treatment may be an effective prophylactic and therapeutic strategy against L-OHP-, PTX-, VCR-, and BOR-induced cold and mechanical allodynia.

Background

Honey’s medical values have been extensively recorded in literature. Yemeni Sidr honey was reported to treat many ailments like stomach and respiratory disorders. ESKAPE and other multidrug-resistant pathogens are considered one of the top three risks to global public health, so alternative strategies become critical demand against such pathogens or their biofilms. The current study aimed to explore the antibacterial and antioxidant potential of the Yemeni Sidr honey extracts. The antibacterial activity of the two Yemeni Sidr honey extracts (ST and SM) was assessed against different pathogenic strains. The antioxidant activity was also evaluated using ORAC, ABST, 5-LOX, and DPPH. Furthermore, 2D HSQC data of both ST and SM honey extracts were collected uploaded to the SMART platform to identify the possible metabolites in these extracts. The identified metabolites were analyzed using docking and molecular dynamic simulations (MDS) to identify the key players in the antibacterial action.

Results

The antibacterial activity revealed that ST and SM extracts have similar activity against all tested pathogens. ST extract exhibited superior antibiofilm effect against P. aeruginosa and C. albicans by 68.2% and 62.6%, respectively, exceeding the reference standards. Moreover, ST extract displayed the highest antioxidant power against all assays except the DPPH assay. SMART dereplication of the HSQC data of ST extract revealed the annotations of five carbohydrates (fructose, glucose, mannose, maltose, and sucrose); while, SM extract showed three major phenolic compounds (chrysin, ellagic acid, and caffeic acid), in which chrysin and ellagic acid were likely the key players in the antibacterial action, based on MDS.

Conclusions

The study confirmed the effectiveness of Sidr honey against the tested multidrug-resistant pathogens. Additionally, our observations shed the light on the main secondary constituents in Yemini Sidr honey extracts, and their effective role in multidrug-resistant pathogens growth inhibition.

Background

In conjunction with other antiviral medicines, sofosbuvir (SOF) is an essential therapy for chronic hepatitis C. There is some debate over its influence on hepatic fibrosis. The use of nanotechnology in treatment has gained popularity, with the goal of delivering therapeutic substances to the liver to increase efficacy and decrease adverse effects. The aim of this study was to demonstrate the protective effect of sofosbuvir and the efficacy of incorporating nanoparticle galactosylated taurocholate bilosomal formula to SOF on thioacetamide-induced liver fibrosis.

Methods

Rats were divided into 7 groups: normal control, SOF, SOF encapsulated in galactosylated taurocholate bilosomal formula (nano-SOF), galactosylated taurocholate bilosomal formula (nanoparticle), thioacetamide (TAA), TAA-SOF and TAA-nano-SOF. Liver fibrosis was induced by TAA (200 mg/kg) intraperitoneal injection twice per week for 8 weeks. SOF, nanoparticle and nano-SOF were given (40 mg/Kg/day) orally from day one of the study. Serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and tissue transforming growth factor beta (TGF-β) were assessed. Also, histopathological assessment of hepatic tissue was done.

Results

Administration of SOF and TAA to normal rats resulted in significant increase in serum AST, ALT, ALP and tissue TGF-β₁ levels with variable degree of liver fibrosis. Additionally, rats in TAA group that received SOF therapy did not exhibit improved liver functions, TGF-β₁ level and liver fibrosis score. However, administering nano-sofosbuvir prophylactically to TAA-treated rats resulted in a considerable improvement in liver function tests, TGF-1 levels, with liver fibrosis score regression.

Conclusion

In contrast to free sofosbuvir, SOF encapsulated in galactosylated taurocholate bilosomal formula (nano-SOF) displayed hepatoprotective effects in rat with thioacetamide-induced hepatic fibrosis. These findings strongly support the concept that galactoylatedbilosomes are promising nanocarrier for the targeted delivery of sofosbuvir to the liver.