卷 27, 编号 14 (2024)

Chemistry

Antiviral Activity of Natural Herbs and their Isolated Bioactive Compounds: A Review

Singh S., Murti Y., Semwal B.

摘要

Viruses are the cause of many human pathogenesis-related conditions. A serious hazard to public health has been created because of the increase in worldwide travel, fast urbanization, and infectious epidemics. At the same time, no preventative vaccines or antiviral treatments are currently available. Resources for developing new antiviral medications can be found in enhanced natural products and herbal medicines. These natural substances have aided the research on developing preventive vaccines and antiviral treatments. Based primarily on in vitro and in vivo searches, this review aims to explore the antiviral properties of plant extracts and some isolated plant natural products. Only a few antiviral medications have been given clinical approval, while numerous viruses continue to elude adequate immunization. Therefore, developing novel antiviral medicines is crucial, and natural substances make excellent sources for these new drugs. This review highlights various natural herbal drugs possessing antiviral properties.

Combinatorial Chemistry & High Throughput Screening. 2024;27(14):2013-2042
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Potential Role of Oxidative Stress in the Pathophysiology of Neurodegenerative Disorders

Singh S., Ahuja A., Pathak S.

摘要

Neurodegeneration causes premature death in the peripheral and central nervous system. Neurodegeneration leads to the accumulation of oxidative stress, inflammatory responses, and the generation of free radicals responsible for nervous disorders like amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disorders. Therefore, focus must be diverted towards treating and managing these disorders, as it is very challenging. Furthermore, effective therapies are also lacking, so the growing interest of the global market must be inclined towards developing newer therapeutic approaches that can intercept the progression of neurodegeneration. Emerging evidences of research findings suggest that antioxidant therapy has significant potential in modulating disease phenotypes. This makes them promising candidates for further investigation. This review focuses on the role of oxidative stress and reactive oxygen species in the pathological mechanisms of various neurodegenerative diseases, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disorders and their neuroprotection. Additionally, it highlights the potential of antioxidant-based therapeutics in mitigating disease severity in humans and improving patient compliance. Ongoing extensive global research further sheds light on exploring new therapeutic targets for a deeper understanding of disease mechanisms in the field of medicine and biology targeting neurogenerative disorders.

Combinatorial Chemistry & High Throughput Screening. 2024;27(14):2043-2061
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Nuclear Factor Kappa B: A Nobel Therapeutic Target of Flavonoids Against Parkinson's Disease

Singh N., Singh A., Mayank .

摘要

Parkinson's disease (PD), the most common brain-related neurodegenerative disorder, is comprised of several pathophysiological mechanisms, such as mitochondrial dysfunction, neuroinflammation, aggregation of misfolded alpha-synuclein, and synaptic loss in the substantia nigra pars compacta region of the midbrain. Misfolded alpha-synuclein, originating from damaged neurons, triggers a series of signaling pathways in both glial and neuronal cells. Activation of such events results in the production and expression of several proinflammatory cytokines via the activation of the nuclear factor κB (NF-κB) signaling pathway. Consequently, this cascade of events worsens the neurodegenerative processes, particularly in conditions, such as PD and synucleinopathies. Microglia, astrocytes, and neurons are just a few of the many cells and tissues that express the NF-κB family of inducible types of transcription factors. The dual role of NF-κB activation can be crucial for neuronal survival, although the classical NF-κB pathway is important for controlling the generation of inflammatory mediators during neuroinflammation. Modulating NF-κB-associated pathways through the selective action of several agents holds promise for mitigating dopaminergic neuronal degeneration and PD. Several naturally occurring compounds in medicinal plants can be an effective treatment option in attenuating PD-associated dopaminergic neuronal loss via selectively modifying the NF-κB-mediated signaling pathways. Recently, flavonoids have gained notable attention from researchers because of their remarkable anti-neuroinflammatory activity and significant antioxidant properties in numerous neurodegenerative disorders, including PD. Several subclasses of flavonoids, including flavones, flavonols, isoflavones, and anthocyanins, have been evaluated for neuroprotective effects against in vitro and in vivo models of PD. In this aspect, the present review highlights the pathological role of NF-κB in the progression of PD and investigates the therapeutic potential of natural flavonoids targeting the NF-κB signaling pathway for the prevention and management of PD-like manifestations with a comprehensive list for further reference. Available facts strongly support that bioactive flavonoids could be considered in food and/or as lead pharmacophores for the treatment of neuroinflammation-mediated PD. Furthermore, natural flavonoids having potent pharmacological properties could be helpful in enhancing the economy of countries that cultivate medicinal plants yielding bioactive flavonoids on a large scale.

Combinatorial Chemistry & High Throughput Screening. 2024;27(14):2062-2077
pages 2062-2077 views

Effect and Mechanisms of Huangqi-Shanzhuyu in the Treatment of Diabetic Nephropathy based on Network Pharmacology and In Vitro Experiments

Han Y., Wei S., Liu C., Nie Y., Yuan S., Ma Y., Zhao Y., Zhang G.

摘要

Background::Huangqi-Shanzhuyu (HS), a classic combination of Chinese herbal formulae, has been widely used for the treatment of diabetic nephropathy (DN). However, its pharmacological mechanism of action is still unclear.

Methods::The active ingredients of HS and their potential targets were identified through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the DN-related targets were determined from GeneCards, Online Mendelian Inheritance in Man (OMIM), PharmGkb, and Therapeutic Target Database (TTD). The Cytoscape software was used to construct a herb-disease-target network and screen core genes. STRING was employed to generate a protein-protein interaction (PPI) network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict the mechanism of action of HS in DN. Animal experiments and molecular docking were used to verify the potential mechanism.

Results::In total, 40 active ingredients and 180 effective targets of HS in DN were identified and 1115 DN-related targets were retrieved. From the PPI network, VEGFA, AKT1, IL6, IL1B, TP53, MMP9, PTGS2, CASP3, EGF and EGFR were identified as core genes. The anti-DN mechanism mainly involved multiple signaling pathways such as AGEs-RAGE. Animal experiments and molecular docking analysis confirmed that HS downregulated the expression of IL-1 and IL-6 via kaempferol-mediated inhibition of JNK1 phosphorylation.

Conclusions::HS exhibits a therapeutic effect in DN through its multiple ingredients that act on several targets and multiple signaling pathways, including AGEs-RAGE.

Combinatorial Chemistry & High Throughput Screening. 2024;27(14):2078-2089
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Effect of Fibroblast Growth Factor-21 Molecule on Coronary Collateral Development

Fedai H., Tascanov M.

摘要

Background:Collateral arteries provide an alternative source to the myocardium resulting from ischemia due to occlusive coronary artery disease and may help preserve myocardial function in the case of coronary artery disease (CAD). Although collateral development is so important, its pathophysiology has not been fully elucidated. Till now, no study has investigated the relationship between Fibroblast growth factor-21(FGF-21) and coronary collateral.

Objective:This study aims to investigate the pathophysiology of coronary collateral development.

Methods:In our study, which we planned as a case-control, 60 consecutive patients with ≥90 stenosis in at least one large coronary artery as a result of coronary angiography (CAG) and 30 patients with normal coronary angiography were included in the study cross-sectional. Demographic, echocardiographic and laboratory data were recorded. Coronary collateral circulation was evaluated using the Rentrop-Cohen method. FGF-21 levels were measured in all individuals.

Results:In the analysis, no significant difference was observed between the two groups in basic biochemical parameters other than HDL (p>0.05 for all). FGF-21 level was statistically significantly higher in the patient group compared to the control group (p: 0.003). Also, the FGF-21 level was found to be statistically significantly higher in the good collateral circulation group than the poor (p:0.006). Univariate and multivariate logistic regression analysis was performed to predict the presence of collateral. We found that FGF-21(p=0.006), and C-reactive protein (p=0.020) predicted the presence of collateral independently.

Conclusion:Collateral formation and cardiac prognosis are closely related. Our study is the first to investigate the relationship between collateral formation and FGF-21. Our study showed that the FGF-21 level is an independent predictor of collateral formation. In addition, there was a significant difference between bad and good collateral formation regarding FGF-21 levels.

Combinatorial Chemistry & High Throughput Screening. 2024;27(14):2090-2095
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Relationship Between Vitamin D Level and Index of Cardio Electrophysiological Balance in Children

Guzelcicek A., Kilinc E., Fedai H., Dedeoglu N., Toprak K., Tascanov M., Ocak M., Gungorer B., Kose D.

摘要

Background:Vitamin D deficiency has been found to be associated with various cardiovascular disorders, including hypertension, coronary artery disease, heart failure, peripheral vascular diseases, and sudden cardiac death. In the literature, it has been reported that many electrocardiographic parameters have been developed to predict ventricular arrhythmias. In recent studies, it is noteworthy that the index of cardio-electrophysiological balance (iCEB) and correct cardioelectrophysiological balance (iCEBc), which are electrocardiographic parameters, can be used as new, easy, cheap and non-invasive parameters to predict ventricular arrhythmias.

Objective:This study aimed to investigate the relationship between vitamin D deficiency and iCEB and iCEBc values in children.

Methods:A total of 186 patients were included in this study. Group 1 included 114 patients with vitamin D levels below 20 ng/ml; 50 patients with vitamin D levels of 21-29 ng/ml were included in Group 2; Group 3 consisted of 36 patients with a vitamin D level above 30 ng/ml. iCEB and iCEBc values were calculated by taking 12-lead ECG from all individuals and comparing them between groups.

Results:A total of 186 children, 114 subjects in Group 1, 36 subjects in Group 2, and 36 subjects in Group 3, were included in the study. Demographic characteristics and height-weight values of the groups were similar. Significant differences were found between the groups in terms of QT, QTc, QT/QRS, and QTc/QRS levels (p: 0.003, 0.028, 0.001, and 0.001, respectively). In the correlation analysis, a negative correlation was found between QTc/QRS and vitamin D level (r=-0.320, p=(<0.001) and between QT/QRS and vitamin D level (r=-0.268, p=(<0.001). Moreover, vitamin D level (β=0.389, p(<0.001) was determined as an independent predictor of QTc/QRS in multivariate logistic regression analysis.

Conclusion:iCEB and iCEBc parameters increase significantly in children with low vitamin D levels. These parameters are also evaluated during the follow-up of children with vitamin D deficiency in terms of the risk of ventricular arrhythmia. iCEBc can be used as an easy, inexpensive, non-invasive, and reproducible parameter.

Combinatorial Chemistry & High Throughput Screening. 2024;27(14):2096-2100
pages 2096-2100 views

Curcumin Reduces Hypoxia/Reperfusion Injury of Cardiomyocytes by Stimulating Vascular Endothelial Cells to Secrete FGF2

Cui J., Fan M., Wang Q.

摘要

Objective::Endothelial cells (ECs) can provide cell protection for cardiomyocytes (CMs) under hypoxia-reoxygenation (HR) conditions by secreting derived factors. This study aimed to explore the role of curcumin (CUR) in ECs for protecting CMs from HR injury.

Methods::A co-culture system for ECs and CMs was set up, and subjected to HR. The transcription, expression, and secretion of FGF2 were detected by RT-qPCR, western blot, and ELISA, respectively. siRNAs specifically targeting FGF2 were transfected into ECs. FGF2 receptor- specific inhibitors (AZD4547) were used to treat CMs.

Results::The co-culture with ECs did not affect the proliferation of CMs, while CUR and ECs co-culture had a synergistic effect on promoting the proliferation of CMs in HR. Furthermore, the co-culture with ECs did not affect the apoptosis and autophagy of CMs in HR. However, the co-culture of ECs after CUR treatment inhibited the apoptosis and autophagy of CMs in HR. CUR treatment significantly enhanced FGF2 mRNA, protein, and secretion levels of ECs in HR. In addition, CUR treatment increased FGF2 levels in the CMs medium in the ECs and CMs co-culture system. The reduction of FGF2 levels in the medium and the inhibition of FGF2 receptors significantly inhibited the proliferation of CMs and significantly promoted the apoptosis and autophagy of CMs in HR.

Conclusion::Focusing on the protective effects of CUR and ECs on cardiomyocytes is of great significance for the treatment of clinical myocardial HR injury.

Combinatorial Chemistry & High Throughput Screening. 2024;27(14):2101-2109
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Exploration of Key Genes Combining with Immune Infiltration Level and Tumor Mutational Burden in Hepatocellular Carcinoma

Chen J., Zhang L., Lu C., Xu C.

摘要

Background:Hepatocellular carcinoma (HCC) is a lethal malignancy due to its heterogeneity and aggressive behavior. Recently, somatic mutations and tumor cell interactions with the surrounding tumor immune microenvironment (TIME) have been reported to participate in HCC carcinogenesis and predict HCC progression. In this study, we aimed to investigate the association between tumor mutational burden (TMB) and TIME in HCC. Additionally, we sought to identify differentially expressed genes (DEGs) associated with HCC prognosis and progression.

Methods:The expression, clinical, and mutational data were downloaded from the cancer genome atlas (TCGA) database. The immune infiltration levels and TMB levels of the HCC samples were estimated and the samples were divided into immune cluster (ICR)-1 and 2 based on immune infiltration score and high and low TMB groups based on TMB score. Thereafter, differential gene expression analysis was conducted to identify the DEGs in the ICR1/2 and high/low TMB groups, and the intersecting DEGs were selected. Thereafter, Cox regression analysis was performed on 89 significant DEGs, among which 19 were associated with prognosis. These 19 DEGs were then used to construct a prognostic model based on their expression levels and regression coefficients. Thereafter, we analyzed the DEGs in mutant and wildtype TP53 HCC samples and identified high BCL10 and TRAF3 expression in the mutant TP53 samples. BCL10 and TRAF3 expression was detected by real-time quantitative reverse transcription PCR and immunohistochemistry, and their clinical correlation, biological function, and immune infiltration levels were analyzed by chi-square analyses, Gene Set Enrichment Analysis (GSEA), and "ssGSEA", respectively.

Results:The results of our study revealed that immune infiltration level was correlated with TMB and that they synergistically predicted poor prognosis of HCC patients. DEGs enriched in immune-related pathways could serve as indicators of immunotherapy response in HCC. Among these DEGs, BCL10 and TRAF3 were highly expressed in HCC tissues, especially in the mutant TP53 group, and they co-operatively exhibited immunological function, thereby affecting HCC progression and prognosis.

Conclusion:In this study, we identified BCL10 and TRAF3 as potential prognostic indicators in HCC patients. Additionally, we found that BCL10 and TRAF3 influence TMB and TIME in HCC patients and can be used for the development of immune-based therapies for improving the long-term survival of HCC patients.

Combinatorial Chemistry & High Throughput Screening. 2024;27(14):2110-2124
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Identification of Molecular Correlations of GSDMD with Pyroptosis in Alzheimer's Disease

Song T., Chen Y., Li C., Yao Y., Ma S., Shang Y., Cheng J.

摘要

Aim:An analysis of bioinformatics and cell experiments was performed to verify the relationship between gasdermin D (GSDMD), an executive protein of pyroptosis, and Alzheimer's disease (AD).

Methods:The training set GSE33000 was utilized to identify differentially expressed genes (DEGs) in both the AD group and control group, as well as in the GSDMD protein high/low expression group. Subsequently, the weighted gene co-expression network analysis (WGCNA) and the least absolute shrinkage and selection operator (LASSO) regression analysis were conducted, followed by the selection of the key genes for the subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The association between GSDMD and AD was assessed and confirmed in the training set GSE33000, as well as in the validation sets GSE5281 and GSE48350. Immunofluorescence (IF) was employed to detect the myelin basic protein (MBP), a distinctive protein found in the rat oligodendrocytes (OLN-93 cells). A range of concentrations (1-15 µmol/L) of β-amyloid 1-42 (Aβ1-42) were exposed to the cells, and the subsequent observations were made regarding cell morphology. Additionally, the assessments were conducted to evaluate the cell viability, the lactate dehydrogenase (LDH) release, the cell membrane permeability, and the GSDMD protein expression.

Results:A total of 7,492 DEGs were screened using GSE33000. Subsequently, WGCNA analysis identified 19 genes that exhibited the strongest correlation with clinical traits in AD. Additionally, LASSO regression analysis identified 13 key genes, including GSDMD, AFF1, and ATOH8. Furthermore, the investigation revealed that the key genes were associated with cellular inflammation based on GO and KEGG analyses. Moreover, the area under the curve (AUC) values for the key genes in the training and validation sets were determined to be 0.95 and 0.70, respectively. Significantly, GSDMD demonstrated elevated levels of expression in AD across both datasets. The positivity of MBP expression in cells exceeded 95%. As the concentration of Aβ1-42 action gradually escalated, the detrimental effects on cells progressively intensified, resulting in a gradual decline in cell survival rate, accompanied by an increase in lactate dehydrogenase release, cell membrane permeability, and GSDMD protein expression.

Conclusion:The association between GSDMD and AD has been observed, and it has been found that Aβ1-42 can induce a significant upregulation of GSDMD in OLN-93 cells. This suggests that Aβ1-42 has the potential to induce cellular pyroptosis and can serve as a valuable cellular pyroptosis model for the study of AD.

Combinatorial Chemistry & High Throughput Screening. 2024;27(14):2125-2139
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Long Non-coding RNAs Influence Aging Process of Sciatic Nerves in SD Rats

Kuang R., Zhang Y., Wu G., Zhu Z., Xu S., Liu X., Xu Y., Luo Y.

摘要

Objectives:To investigate the long non-coding RNAs (lncRNAs) changes in the sciatic nerve (SN) in Sprague Dawley (SD) rats during aging.

Methods:Eighteen healthy SD rats were selected at the age of 1 month (1M) and 24 months (24M) and SNs were collected. High-throughput transcriptome sequencing and bioinformatics analysis were performed. Protein-protein interaction (PPI) networks and competing endogenous RNA (ceRNA) networks were established according to differentially expressed genes (DEGs).

Result:As the length of lncRNAs increased, its proportion to the total number of lncRNAs decreased. A total of 4079 DElncRNAs were identified in Con vs. 24M. GO analysis was primarily clustered in nerve and lipid metabolism, extracellular matrix, and vascularization-related fields. There were 17 nodes in the PPI network of the target genes of up-regulating genes including Itgb2, Lox, Col11a1, Wnt5a, Kras, etc. Using quantitative RT-PCR, microarray sequencing accuracy was validated. There were 169 nodes constructing the PPI network of down-regulated target genes, mainly including Col1a1, Hmgcs1, Hmgcr. CeRNA interaction networks were constructed.

Conclusion:Lipid metabolism, angiogenesis, and ECM fields might play an important role in the senescence process in SNs. Col3a1, Serpinh1, Hmgcr, and Fdps could be candidates for nerve aging research.

Combinatorial Chemistry & High Throughput Screening. 2024;27(14):2140-2150
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Vernodalin Triggers ROS-Mediated Apoptosis in TPC-1 Human Papillary Thyroid Cancer Cells via Suppression of the MAPKs Signaling Pathway

Yang X., Wei M., An Y., Liang Q., Nan J., Vijayalakshmi A., Wang Z.

摘要

Background:Thyroid Cancer (TC) is an endocrine organ malignancy that has become more common in recent decades. Vernodalin (VN), a cytotoxic sesquiterpene, has been reported to exhibit anticancer properties against human breast and liver cancer cells. However, no study has explored the efficacy of VN with respect to its antiproliferative and apoptotic action on human Papillary Thyroid Cancer cells (PTC).

Objective:The study intended to examine the antitumor and antiproliferative effects of VN and the apoptosis mechanisms underlying its action on TPC-1 human PTC cells.

Methods:In this study, we examined the VN cell viability by MTT assay; performed ROS measurement by DCFH staining method, MMP identification by Rh-123 staining method, and apoptotic morphological assay by employing AO/EB and DAPI stain method, and further, p38 MAPK/ERK/JNK cell proliferation markers were determined by western blotting technique.

Results:The findings showed that VN could inhibit the growth of PTC cells by increasing intracellular ROS, damaging MMP, and stimulating apoptosis in a concentration-dependent manner. The study demonstrated how VN inhibited TPC-1 cell viability by causing ROS-induced cell death via the MAPK signaling pathway.

Conclusion:VN may serve as an agonist to impact apoptosis in PTC cells. In human PTC, VN could play an effective role in chemotherapy. More studies pertaining to animal tumor models are needed to prove its anti-cancer effectiveness in vivo.

Combinatorial Chemistry & High Throughput Screening. 2024;27(14):2151-2158
pages 2151-2158 views