Research in Pharmaceutical Sciences
Volume:19 Issue: 1, Feb 2024

Alzheimer's disease (AD) is a common neurodegenerative disease and the fifth leading cause of death among the elderly. The development of drugs for AD treatment is based on inhibiting cholinesterase (ChE) activity and inhibiting amyloid-beta peptide and tau protein aggregations. Many in vitro findings have demonstrated that thiazole- and thiazolidine-based compounds have a good inhibitory effect on ChE and other elements involved in the AD pathogenicity cascade.

Experimental approach: 

In the present review, we collected available documents to verify whether these synthetic compounds can be a step forward in developing new medications for AD. A systematic literature search was performed in major electronic databases in April 2021. Twenty-eight relevant in vitro and in vivo studies were found and used for data extraction.

Findings demonstrated that thiazole- and thiazolidine-based compounds could ameliorate AD's pathologic condition by affecting various targets, including inhibition of ChE activity, amyloid-beta, and tau aggregation in addition to cyclin-dependent kinase 5/p25, beta-secretase-1, cyclooxygenase, and glycogen synthase kinase-3β.

Conclusion and implications: 

Due to multitarget effects at micromolar concentration, this review demonstrated that these synthetic compounds could be considered promising candidates for developing anti-Alzheimer drugs.

Diabetes mellitus is a persistent hyperglycemic condition. Thai cuisine and medicine incorporate spices: nutmeg, mace, clove buds, cardamom, cinnamon, and coriander. The in vitro impacts of these spices on anti-diabetic, antioxidant, anti-inflammatory, and total phenolic and flavonoid content were assessed.

Experimental approach: 

Alpha-amylase and alpha-glucosidase inhibition assays were conducted. Antioxidant potential was measured through DPPH and ABTS assays. Anti-inflammatory activity was determined by inhibiting nitric oxide generation in RAW 264.7 cells. Total phenolic content was quantified using the Folin Ciocalteu method, while total flavonoid content was estimated via the aluminum chloride colorimetric method.

Ethanolic and aqueous extracts of a blend of spices (Siam cardamom, nutmeg, mace, and clove buds), denoted as 4-GlurE and 4-GlurA, displayed concentration-dependent inhibition of alphaglucosidase, with IC50 values of 0.373 and 0.435 mg/mL, respectively. 4-GlurE and 4-GlurA exhibited antioxidant activity, by ABTS•+ radical and DPPH scavenging capabilities. 4-GlurE demonstrated antiinflammatory potential by reducing nitric oxide generation (IC50: 43.95 ± 2.47 μg/mL). 4-GlurE and 4-GlurA possessed total phenolic content (TPC) of 122.47 ± 1.12 and 148.72 ± 0.14 mg GAE/g, respectively. 4-GlurE exhibited a higher total flavonoid content (TFC) compared to the aqueous extract (340.33 ± 4.77 and 94.17 ± 3.36 mg QE/g). Cinnamon and clove aqueous extracts were more potent than acarbose in alpha-glucosidase inhibition with the highest antioxidant activity. Polyphenol levels (TPC and TFC) exhibited strong correlations with antioxidant capacity.

Conclusions and implications: 

Findings are consistent with the traditional use of 4-Glur, with cinnamon, for diabetes prevention and treatment.

Coronavirus disease (COVID-19) is one of the greatest challenges of the twentieth century. Recently, in silico tools help to predict new inhibitors of SARS-CoV-2. In this study, the new compounds based on the remdesivir structure (12 compounds) were designed.

Experimental approach: 

The main interactions of remdesivir and designed compounds were investigated in the 3CLpro active site. The binding free energy of compounds by the MM-GBSA method was calculated and the best compound (compound 12 with the value of -88.173 kcal/mol) was introduced to the molecular dynamics simulation study.

The simulation results were compared with the results of protein simulation without the presence of an inhibitor and in the presence of remdesivir. Additionally, the RMSD results for the protein backbone showed that compound 12 in the second 50 nanoseconds has less fluctuation than the protein alone and in the presence of remdesivir, which indicates the stability of the compound in the active site of the Mpro protein. Furthermore, protein compactness was investigated in the absence of compounds and the presence of compound 12 and remdesivir. The Rg diagram shows a fluctuation of approximately 0.05 Å, which indicates the compressibility of the protein in the presence and absence of compounds. The results of the RMSF plot also show the stability of essential amino acids during protein binding .

Conclusion and implications: 

Supported by the theoretical results, compound 12 could have the potential to inhibit the 3CLpro enzyme, which requires further in vitro studies and enzyme inhibition must also be confirmed at protein levels.

The insulin-like growth factor binding protein 3 (IGFBP-3) and its novel death receptor (IGFBP-3R) have been exhibited to have tumor suppressor effects. Despite their prognostic value in some cancers, they have not been elucidated in gastric cancer.

Experimental approach: 

We collected 68 samples from patients with gastric cancer. IGFBP-3 and IGFBP- 3R expression levels were evaluated with quantitative real-time polymerase chain reaction (RT-PCR) and western blotting in patients. The relationship between prognostic factors and IGFBP-3/IGFBP-3R expression was also evaluated.

Our results showed that IGFBP-3 and IGFBP-3R expression was reduced significantly in tumor tissues. We found that there was an association between the reduction of IGFBP-3 with lymph node metastasis and tumor-node-metastasis (TNM) staging. Besides, IGFBP-3R expression was associated with tumor size, lymph node metastasis, differentiation, and TNM classification. Interestingly, we presented that the downregulation of IGFBP-3R was stage-dependent. In survival analysis, our findings showed that low levels of IGFBP-3R mRNA expression exhibited a close correlation with survival rate.

Conclusion and implications: 

The findings of this study showed that the expression levels of IGFBP-3 and IGFBP-3R are valuable prognostic factors. Despite the potential of IGFBP-3, IGFBP-3R plays a significant role as a prognostic factor in gastric cancer. However, these findings need to be developed and confirmed by further studies.

Ovarian cancer is the deadliest gynecological cancer. Bromodomain and extra terminal domain (BET) proteins play major roles in the regulation of gene expression at the epigenetic level. Jun Qi (JQ1) is a potent inhibitor of BET proteins. Regarding the short half-life and poor pharmacokinetic profile, JQ1 was loaded into newly developed nano-carriers. Chitosan nanoparticles are one of the best and potential polymers in cancer treatment. The present study aimed to build chitosan-JQ1 nanoparticles (Ch-J-NPs), treat OVCAR-3 cells with Ch-J-NPs, and evaluate the effects of these nanoparticles on cell cycle and apoptosis-associated genes.

Experimental approach: 

Ch-J-NPs were synthesized and characterized. The size and morphology of Ch-J-NPs were defined by DLS and FE-SEM techniques. OVCAR-3 cells were cultured and treated with Ch-J-NPs. Then, IC50 was measured using MTT assay. The groups were defined and cells were treated with IC50 concentration of Ch-J-NPs, for 48 h. Finally, cells in different groups were assessed for the expression of genes of interest using quantitative RT-PCR.

IC50 values for Ch-J-NPs were 5.625 μg/mL. RT-PCR results demonstrated that the expression of genes associated with cell cycle activity (c-MYC, hTERT, CDK1, CDK4, and CDK6) was significantly decreased following treatment of cancer cells with Ch-J-NPs. Conversely, the expression of caspase-3, and caspase-9 significantly increased. BAX (pro-apoptotic) to BCL2 (anti-apoptotic) expression ratio, also increased significantly after treatment of cells with Ch-J-NPs.

Conclusion and implications:

 Ch-J-NPs showed significant anti-cell cyclic and apoptotic effects on OVCAR-3 cells.

Sepsis induces brain dysfunction and there is still a requirement for an unemployed viable restorative approach. This study aimed to investigate the role of dasatinib in the modulation of proinflammatory mediators, attenuating neuroinflammatory response, and it's signaling pathway during endotoxemia.

Experimental approach: 

Twenty-four adult male Swiss-albino mice were randomized into four groups: sham (undergo laparotomy without cecal ligation and puncture, sepsis (laparotomy with cecal ligation and puncture), vehicle-dimethyl sulfoxide, dasatinib (20 mg/kg/day) intraperitoneally. Brain tissue used for assessment of interleukin (IL)-6, IL-1β, tumor necrosis factor-alpha (TNF-α), IL-10, Toll-like receptor 4 (TLR4), protein kinase B (AKT), phosphoinositide 3-kinases (PI3K), signal transducer and activator of transcription 3 (STAT3), and histopathological examination.

Brain tissue levels of TNF-α, IL-6, and IL1 β were higher in the sepsis group than in the sham and vehicle groups. The dasatinib group had considerably lower tissue levels of these markers and significantly higher tissue values of IL-10 than the sepsis and vehicle groups. The sham group had much lower tissue values of TLR4, AKT, STAT3, and PI3k than in sepsis and vehicle groups. Furthermore, tissue levels of these markers in the dasatinib group were considerably lower than those in the sepsis and vehicle groups. Histopathology demonstrated that dasatinib might considerably reduce brain damage and the intensity of neuroinflammation when compared to sepsis and vehicle groups that showed extensive brain inflammation and damage.

Conclusion and implication: 

Dasatinib attenuated endotoxemia-induced acute brain damage in mice via modulating effects on TLR4, PI3K, AKT, and STAT3 downstream signaling pathways.

Treatment of malignancies with chemotherapy and surgery is often associated with disease recurrence and metastasis. Immunotherapy improves cancer treatment by creating an active response against tumor antigens. Various cancer cells express a large amount of glucose-regulated protein 78 (GRP78) protein on their surface. Stimulating the immune system against this antigen can expose cancer cells to the immune system. Herein, we investigated the effectiveness of a cGRP78-based vaccine against different cancer cells.

Experimental approach: 

BALB/c mice were immunized with the cGRP78. The humoral immune response against different cancer cells was assessed by Cell-ELISA. The cellular immunity response was determined by splenocyte proliferation assay with different cancer antigens. The effect of vaccination on metastasis was investigated in vaccinated mice by injecting melanoma cancer cells into the tail of mice.

These results indicated that the cGRP78 has acceptable antigenicity and stimulates the immune system to produce antibodies. After three injections, the amount of produced antibody was significantly different from the control group. Compared to the other three cell types, Hela and HepG2 showed the highest reaction to the serum of vaccinated mice. Cellular immunity against the B16F10 cell line had the best results compared to other cells. The metastasis results showed that after 30 days, the growth of B16F10 melanoma cancer cells was not noticeable in the lung tissue of vaccinated mice.

Conclusion and implications: 

Considering the resistance of vaccinated mice to metastasis, this vaccine offers a promising prospect for cancer treatment by inhibiting the spread of cancer cells.

Acetaminophen (APAP) is a commonly used antipyretic and pain reliever that its overdose causes acute liver toxicity. Umbelliferone (UMB) has many pharmacological effects. In this study, the hepatoprotective effect of UMB on acute hepatotoxicity induced by APAP was investigated.

Experimental approach: 

Forty-nine male mice were separated into seven groups. The control received vehicle (i.p.), UMB group received UMB (120 mg/kg, i.p.), APAP group was treated with a single dose of APAP (350 mg/kg, i.p.), and pretreated groups received N-acetylcysteine (NAC, 200 mg/kg, i.p.) or different doses of UMB (30, 60, and 120 mg/kg, i.p.), respectively before APAP. Twenty-four hours after APAP injection, mice were sacrificed and blood and liver samples were collected. Then, serum and tissue samples were investigated for biochemical and histological studies.

A single dose of APAP caused elevation in the serum liver enzymes, including alanine aminotransferase, aspartate transaminase, and alkaline phosphatase. The amounts of thiobarbituric acid reactive substances, tumor necrosis factor-alpha, and nitric oxide increased in the mice’s liver tissue. Moreover, the amount of total thiol and the activity of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) significantly diminished in the APAP group. Histological results confirmed the hepatotoxicity induced by APAP. However, UMB (more effective at 60 and 120 mg/kg) lessened APAP-induced hepatic injuries, which is comparable with NAC effects.

Conclusion and implications: 

The findings of this study provided evidence that UMB ameliorates liver injury induced by APAP through its antioxidant and anti-inflammatory effects.

Background and

DNA fragmentation factor 40 (DFF40) as an apoptotic molecule can represent a novel approach to cancer treatment. Lycosin-I (LYC-I), a peptide derived from spider venom, was considered for the targeted delivery of DFF40 to cancer cells. This study attempted to produce soluble DFF40-LYC-I and evaluate its selective lethal effects on HeLa cells.

Experimental approach: pTWIN1 vector was used to produce LYC-I and DFF40-LYC-I in E. coli BL21 (DE3) fused to inteins 1 and 2. IPTG concentration and incubation temperature were optimized to achieve the highest level of soluble product. To remove inteins 1 and 2 from the recombinant peptide or protein, pH shift and dithiothreitol were used for a 24-h incubation period at room temperature, respectively. MTT assay was performed to assess the biological effects of these bio-molecules on HeLa and HUVEC cell lines.

LYC-I and DFF40-LYC-I were detected in SDS-PAGE with bands of approximately 57 and 97 kDa, respectively. Furthermore, the 3 and 43 kDa bands showed the purified molecules. The IC50 value of DFF40-LYC-I and DFF40 was determined as 6.6 and 17.03 μg/mL for HeLa, respectively. LYC-I had no cytotoxic effects on both cell lines, even at high concentrations.

Conclusion and implications: 

A new fusion protein with targeted cancer treatment potential was produced for the first time by LYC-I with a safe profile on normal cells. This fusion protein exhibited higher cytotoxic effects in cancer cells compared to normal cells. However, additional investigations are required to determine the apoptosis induction and evaluate selective toxicity against other cancer and normal cell lines.

Oxidative stress plays an important role in Alzheimer’s disease (AD) pathogenesis. Moringa oleifera leaf (MOL) extract has been shown to have antioxidant activities. Here, we studied the antioxidative and anti-apoptotic effects of water-soluble MOL extract in an amyloid beta (Aβ)-induced oxidative stress model of AD.

Experimental approach: 

The effect of amyloid beta (Aβ)1-42 and MOL extract on differentiated SH-SY5Y cell viability was assessed by MTT assay. Cells were treated with Aβ1-42, MOL extract, or MOL extract followed by Aβ1-42. The mitochondrial membrane potential (ΔΨm) and the reactive oxygen species (ROS) were evaluated by flow cytometry and dihydroethidium (DHE) assay, respectively. Western blotting was used to assess the expression of mitochondrial proteins TIMM23 and NDUFS3, apoptosis-related proteins Bax, Bcl-2, and cleaved caspase-3 along with fluorescence analysis of caspase-3/7, and Akt phosphorylation.

MOL extract pretreatment at 25, 50, and 100 μg/mL prevented ΔΨm reduction. At 100-μg/mL, MOL extract decreased TIMM23 and NDUFS3 proteins and DHE signals in Aβ1-42-treated cells. MOL extract pretreatment (25, 50, and 100 μg/mL) also alleviated the apoptosis indicators, including Bax, caspase-3/7 intensity, and cleaved caspase-3, and increased Bcl-2 levels in Aβ1-42-treated cells, consistent with a reduction in the number of apoptotic cells. The protective effects of MOL extract were possibly mediated through Akt activation, evidenced by increased Akt phosphorylation.

Conclusion and implications: 

The neuroprotective effect of MOL extract could be mediated via the activation of Akt, leading to the suppression of oxidative stress and apoptosis in an Aβ1-42 model of AD.