Compounds Berberine Research Articles

A Mendelian analysis of the causality between inflammatory cytokines and digestive tract cancers.

In this study, we performed a two-sample Mendelian randomization (MR) analysis to assess the causality between inflammatory cytokines and the risk of digestive tract cancers (DTCs). Furthermore, we conducted a molecular docking study to predict the therapeutic mechanisms of traditional Chinese medicine (TCM) compounds in the treatment of DTCs. In our MR analysis, genetic variations associated with eight types of DTCs were utilized, which were sourced from a large publicly available genome-wide association study dataset (7929 cases and 1 742 407 controls of European ancestry) and inflammatory cytokines data from a genome-wide association study summary of 8293 European participants. Inverse-variance weighted method, MR-Egger, and weighted median were performed to analyze and strengthen the final results. We investigated the effects of 41 inflammatory molecules on 8 types of DTCs. Subsequently, the effect of DTCs on positive inflammatory factors was analyzed by means of inverse MR. Molecular docking was exploited to predict therapeutic targets with TCM compounds. Interleukin-7, interleukin-16, macrophage colony-stimulating factor, monokine induced by interferon-gamma, and vascular endothelial growth factor may be significantly associated with various types of DTCs. Five TCM compounds (baicalin, berberine, curcumin, emodin, and salidroside) demonstrated better binding energies to both interleukin-7 and vascular endothelial growth factor than carboplatin. This study provides strong evidence to support the potential causality of some inflammatory cytokines on DTCs and indicates the potential molecular mechanism of TCM compounds in the treatment of DTCs. Key message What is already known on this topic The increasing evidence indicates that inflammatory cytokines are implicated in the pathogenesis of digestive tract cancers (DTCs). Nevertheless, the causal relationship between inflammatory cytokines and DTCs remains indistinct. Additionally, certain traditional Chinese medicine compounds have been demonstrated to treat DTCs by influencing inflammatory factors, yet their underlying potential mechanisms remain ambiguous. What this study adds In this study, Mendelian randomization analysis was performed for the first time regarding the causality between human inflammatory cytokines and eight types of DTCs, which revealed that inflammatory factors may play different roles in different types of DTCs. Moreover, molecular docking of key inflammatory factors was implemented, indicating the targets for drug actions. How this study might affect research, practice, or policy This research has the potential to reveal the causality between 41 inflammatory factors and 8 DTCs, offering novel perspectives for the prevention and management strategies of DTCs. Additionally, it indicates the targets for the actions of traditional Chinese medicine on the key inflammatory factors of these cancers.

Discovery of Small Molecule Glycolytic Stimulants for Enhanced ApoE Lipidation in Alzheimer's Disease Cell Model.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by pathophysiological deposits of extracellular amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles of tau. The central role of Aβ in AD pathology is well-established, with its increased deposition attributed mainly to its decreased cerebral clearance. Here, it is noteworthy that apolipoprotein E (ApoE), the most significant risk factor for AD, has been shown to play an isoform-specific role in clearing Aβ deposits (ApoE2 > ApoE3 > ApoE4), owing mainly to its lipidation status. In addition to the pathophysiological Aβ deposits, AD is also characterized by abnormal glucose metabolism, which is a distinct event preceding Aβ deposition. The present study established, for the first time, a possible link between these two major AD etiologies, with glucose metabolism directly influencing ApoE lipidation and its secretion by astrocytes expressing human ApoE4. Specifically, glucose dose-dependently activated liver X receptor (LXR), leading to elevated ABCA1 and ABCG1 protein levels and enhanced ApoE lipidation. Moreover, co-treatment with a glycolytic inhibitor significantly inhibited this LXR activation and subsequent ApoE lipidation, further supporting a central role of glucose metabolism in LXR activation leading to enhanced ApoE lipidation, which may help against AD through potential Aβ clearance. Therefore, we hypothesized that pharmacological agents that can target cellular energy metabolism, specifically aerobic glycolysis, may hold significant therapeutic potential against AD. In this context, the present study also led to the discovery of novel, small-molecule stimulants of astrocytic glucose metabolism, leading to significantly enhanced lipidation status of ApoE4 in astrocytic cells. Three such newly discovered compounds (lonidamine, phenformin, and berberine), owing to their promising cellular effect on the glycolysis-ApoE nexus, warrant further investigation in suitable in vivo models of AD.

Berberine and hesperidin prevent the memory consolidation impairment induced by pentylenetetrazole in zebrafish

This study verified the effects of the natural compounds berberine and hesperidin on seizure development and cognitive impairment triggered by pentylenetetrazole (PTZ) in zebrafish. Adult animals were submitted to a training session in the inhibitory avoidance test and, after 10 minutes, they received an intraperitoneal injection of 25, 50, or 100 mg/kg berberine or 100 or 200 mg/kg hesperidin. After 30 minutes, the animals were exposed to 7.5 mM PTZ for 10 minutes. Animals were submitted to the test session 24 h after the training session to verify their cognitive performance. Zebrafish larvae were exposed to 100 µM or 500 µM berberine or 10 µM or 50 µM hesperidin for 30 minutes. After, larvae were exposed to PTZ and had the seizure development evaluated by latency to reach the seizure stages I, II, and III. Adult zebrafish pretreated with 50 mg/kg berberine showed a longer latency to reach stage III. Zebrafish larvae pretreated with 500 µM berberine showed a longer latency to reach stages II and III. Hesperidin did not show any effect on seizure development both in larvae and adult zebrafish. Berberine and hesperidin pretreatments prevented the memory consolidation impairment provoked by PTZ-induced seizures. There were no changes in the distance traveled in adult zebrafish pretreated with berberine or hesperidin. In larval stage, berberine caused no changes in the distance traveled; however, hesperidin increased the locomotion. Our results reinforce the need for investigating new therapeutic alternatives for epilepsy and its comorbidities.

Development and validation of simultaneous HPLC-PDA analysis method for quality control of Hwang-ryeon-hae-dok-tang: An analytical quality by design approach

This study introduces an advanced analytical method for quality control of botanical drugs, focusing on Hwang-ryeon-hae-dok-tang (HRHDT), a traditional herbal prescription utilized for inflammation, gastritis, fever, and hypertension. Botanical drugs pose a challenge due to their complex composition, requiring reliable and robust analytical techniques. Our step-by-step procedure included defining the analytical target profile, risk assessment, screening and optimizing design of experiment, measuring the design space, and Monte Carlo simulation. The established HPLC-PDA method enables the simultaneous analysis of four major compounds (geniposide, baicalin, palmatine, and berberine) present in HRHDT. The optimized conditions involve a gradient elution with acetonitrile and water, both containing 0.1% trifluoroacetic acid, a 32 °C column temperature, 254 nm detection wavelength, and 1.0 mL/min flow rate. A successful validation demonstrated excellent linearity (R2: 0.9984–0.9989) and accuracy (recovery: 100.61%–102.44%), with precise repeatability and intermediate precision (%RSD: 0.39%–0.83%). These results further confirm the reliability and accuracy of the analytical method. Overall, our design-based approach not only facilitated the development of robust analytical methods but also allowed for flexible operation ranges. Therefore, this methodology holds significant potential for ensuring the quality of botanical drug products within the pharmaceutical industry.

SIRT1 inhibitors within Qing-Luo-Yin alleviated white adipose tissues-mediated inflammation in antigen-induced arthritis mice.

White adipose tissues (WAT) release large amounts of inflammatory mediators, which are responsible for the pathology of rheumatoid arthritis (RA). The current study investigated the involvement of WAT in the treatments of antigen-induced arthritis (AIA) mice with the herbal formula Qing-Luo-Yin (QLY). Cytokines and biochemical/metabolic indicators were determined by ELISA and colorimetry methods, respectively. Monocytes were analyzed by flow cytometry. Tissues were subjected to PCR, western-blot and histological analyses. Pre-adipocytes were cultured in the different mouse serum from the in vivo experiment, and some of them were treated by certain compounds or/and lipopolysaccharide. Afterwards, the catalytic activity and thermostability of SIRT1 were tested. Gene/protein expression and cytokine production were investigated too. NAMPT and SIRT1 were silenced in some cells by siRNA. AIA mice suffered from inflammatory adipokines-mediated metabolism and immune disorders. Besides joint protective effects, QLY therapies favored adipocyte differentiation and suppressed inflammatory adipokines release. The up-regulation of fatty acid oxidation and inflammatory monocyte polarization was therefore inhibited in peripheral tissues. PPARγ expression was generally promoted by QLY. Whereas, SIRT1 activity was always impaired, indicated by the declined NAD+ levels and the increased ace-p65 expression. QLY effectively inhibited eNAMPT release in AIA mouse serum-cultured pre-adipocytes. This effect was antagonized by resveratrol (a SIRT1 agonist) and overshadowed by NAMPT silencing. QLY-related compounds berberine, dioscin and sophocarpine showed high binding affinities to SIRT1, stabilized this protein, and inhibited its deacetylation activity in vitro. Their effects on ace-p65 expression were weakened when SIRT1 was silenced. SIRT1 inhibitors in QLY reduced eNAMPT production and up-regulated PPARγ in AIA mice, leading to inflammation remission. These clues show that except for the well-known anti-inflammatory functions, SIRT1 participates in inflammatory reactions too and could be a potential anti-rheumatic target.

Structure-yeast α-glucosidase inhibitory activity relationship of 9-O-berberrubine carboxylates.

Thirty-five 9-O-berberrubine carboxylate derivatives were synthesized and evaluated for yeast α-glucosidase inhibitory activity. All compounds demonstrated better inhibitory activities than the parent compounds berberine (BBR) and berberrubine (BBRB), and a positive control, acarbose. The structure-activity correlation study indicated that most of the substituents on the benzoate moiety such as methoxy, hydroxy, methylenedioxy, benzyloxy, halogen, trifluoromethyl, nitro and alkyl can contribute to the activities except multi-methoxy, fluoro and cyano. In addition, replacing benzoate with naphthoate, cinnamate, piperate or diphenylacetate also led to an increase in inhibitory activities except with phenyl acetate. 9, 26, 27, 28 and 33 exhibited the most potent α-glucosidase inhibitory activities with the IC50 values in the range of 1.61-2.67μM. Kinetic study revealed that 9, 26, 28 and 33 interacted with the enzyme via competitive mode. These four compounds were also proved to be not cytotoxic at their IC50 values. The competitive inhibition mechanism of these four compounds against yeast α-glucosidase was investigated using molecular docking and molecular dynamics simulations. The binding free energy calculations suggest that 26 exhibited the strongest binding affinity, and its binding stability is supported by hydrophobic interactions with D68, F157, F158 and F177. Therefore, 9, 26, 28 and 33 would be promising candidates for further studies of antidiabetic activity.

Protective Application of Chinese Herbal Compounds and Formulae in Intestinal Inflammation in Humans and Animals.

Intestinal inflammation is a chronic gastrointestinal disorder with uncertain pathophysiology and causation that has significantly impacted both the physical and mental health of both people and animals. An increasing body of research has demonstrated the critical role of cellular signaling pathways in initiating and managing intestinal inflammation. This review focuses on the interactions of three cellular signaling pathways (TLR4/NF-κB, PI3K-AKT, MAPKs) with immunity and gut microbiota to explain the possible pathogenesis of intestinal inflammation. Traditional medicinal drugs frequently have drawbacks and negative side effects. This paper also summarizes the pharmacological mechanism and application of Chinese herbal compounds (Berberine, Sanguinarine, Astragalus polysaccharide, Curcumin, and Cannabinoids) and formulae (Wumei Wan, Gegen-Qinlian decoction, Banxia xiexin decoction) against intestinal inflammation. We show that the herbal compounds and formulae may influence the interactions among cell signaling pathways, immune function, and gut microbiota in humans and animals, exerting their immunomodulatory capacity and anti-inflammatory and antimicrobial effects. This demonstrates their strong potential to improve gut inflammation. We aim to promote herbal medicine and apply it to multispecies animals to achieve better health.

The identification of material basis of Si Miao Formula effective for attenuating non-alcoholic fatty liver disease

Ethnopharmacological relevanceThe Si Miao Formula (SMF), a traditional Chinese medicine, originated from the "Cheng Fang Bian Du" during the Qing Dynasty and is commonly employed for the treatment of gout and hyperuricemia. We have demonstrated the anti-NAFLD effect of SMF by regulating hepatic lipid metabolism in high fat and high sucrose (HFHS) feeding mice in our previous report. However, the material basis of SMF for its anti-NAFLD effect remains unknown. Aim of the studyTo compare the effeciacy of different components of SMF and identify the material basis for its anti-NAFLD effect. Materials and methodsIn the present study, a “Leave-one out” strategy was adopted by removing one herb from SMF each time, and the anti-NAFLD effects of four decomposed recipes containing three herbs were evaluated in C57BL/6J mice fed with an HFHS diet for 16 weeks. The chemical components of SMF and the absorbed entities in serum were assayed using UHPLC-Q-Exactive-Orbitrap HRMS. Finally, a new chemical combination with four compounds (berberine, betaine, caffeic acid, p-coumaric acid, 2:2:1:1) were generated (SMF component composition, SMF_CC), and its anti-NAFLD effect was evaluated by comparing with the original SMF in the mouse model. ResultsVarified effects on NAFLD mice were observed among the decomposed recipes of SMF, while the original SMF showed advantages over its decomposed recipes. A total of 111 chemicals were identified from SMF, and 21 of them were detected in serum after oral administration of SMF. Comparing to SMF, SMF_CC showed comparable anti-NAFLD effect in HFHS-diet-fed mice, which was associated with the inhibition of hepatic fatty acid synthesis and transport, as well as inflammation. ConclusionOur current results suggested that the original SMF was better than its decomposed recipes in NAFLD management, and the derived SMF_CC was also effective in inhibiting NAFLD formation, highlighting its potential of being a novel natural agent for NAFLD therapy.

Ameliorative effects of the Coptis inflorescence extract against lung injury in diabetic mice by regulating AMPK/NEU1 signaling

BackgroundIn diabetic patients, complications are the leading cause of death and disability, while diabetic lung damage has received little research. The Coptis inflorescence extract (CE) has hypoglycemic properties, but the mechanism of its protective role on diabetic lung injury is understood. PurposeThis study aims to explore the protective actions and molecular mechanism of CE and its active ingredients in diabetic lung disease. MethodTwenty-nine metabolites were identified in the metabolomic profile of CE using HPLC-ESI/MS, and high-content substances of berberine (BBR) and linarin (LIN) were isolated from CE using column chromatography. The potential targets and molecular mechanisms of CE against diabetic lung damage were systematically investigated by network pharmacology and in vitro experimental validation. ResultsCE significantly improved lung function and pathology. CE (360 mg/kg) or metformin treatment significantly improved lipid metabolism disorders, including decreased HDL-C and elevated serum TG, TC, and LDL-C levels. Furthermore, CE's chemical composition was determined using the HPLC-QTOF-MS method. CE identified five compounds as candidate active compounds (Berberine, Linarin, Palmatine, Worenine, and Coptisine). Network pharmacology analysis predicted CE contained five active compounds and target proteins, that AMPK, TGFβ1, and Smad might be the key targets in treating diabetic lung injury. Then we investigated the therapeutic effect of bioactive compounds of CE on diabetic lung damage through in vivo and in vitro experiments. Intragastric administration with BBR (50 mg/kg) or LIN (20 mg/kg) suppressed weight loss, hyperglycemia, and dyslipidemia, significantly alleviating lung inflammation in diabetic mice. Further mechanism research revealed that LIN or BBR inhibited alveolar epithelial-mesenchymal transition induced by high glucose by regulating AMPK/NEU-mediated signaling pathway. ConclusionIn conclusion, the administration of CE can effectively alleviate diabetic lung damage, providing a scientific basis for lowering blood sugar to moisturize lung function. BBR and LIN, the main components of CE, can effectively alleviate diabetic lung damage by regulating AMPK/NEU1 Signaling and inhibiting the TGF-β1 level, which may be a critical mechanism of its effects.

Revealing anti-fungal potential of plant-derived bioactive therapeutics in targeting secreted aspartyl proteinase (SAP) of Candida albicans: a molecular dynamics approach

Candida species have established themselves as a major source of nosocomial infections. Increased expression of secreted aspartyl proteinases (SAP5) plays a crucial role in the pathogenesis of Candida species. Phytotherapeutics continue to serve as a viable resource for discovering novel antifungal agents. Hence the main aim of the present investigation is to explore the possible inhibitory role of the selected bioactive molecules against the SAP5 enzyme of C. albicans using in silico approach. Molecular docking and dynamic simulations were utilized to predict the binding affinity of the lead molecules using the AutoDock and Gromacs in-silico screening tools. Results of preliminary docking simulations show that the compounds hesperidin, vitexin, berberine, adhatodine, piperine, and chlorogenic acid exhibit significant interactions with the core catalytic residues of the target protein. The best binding ligands (hesperidin, vitexin, fluconazole) were subjected to molecular dynamics (MD) and essential dynamics of the trajectories. Results of the MD simulation confirm that the ligand-protein complexes became more stable from 20 ns until 100 ns. The calculated residue-level contributions to the interaction energy along a steady simulation trajectory of all three hits (hesperidin (−132.720 kJ/mol), vitexin (−83.963 kJ/mol) and fluconazole (−98.864 kJ/mol)) ensure greater stability of the leads near the catalytic region. Essential dynamics of PCA and DCCM analysis signifies that the binding of hesperidin and vitexin created a more structurally stable environment in the protein target. The overall outcomes of this study clearly emphasize that the bioactive therapeutics found in medicinal herbs may have remarkable scope in managing Candida infection.

RP-HPLC Method for Simultaneous Estimation of Rutin and Berberine in Bulk and Anti-Urolithiatic Formulation

Standardization of active phytochemicals is essential for the quality assessment of herbal formulations. In current study a new, simple, rapid and economical RP-HPLC technique was developed and validated for simultaneous estimation of marker compounds rutin and berberine. The mobile phase used was a mixture of acetonitrile, 0.1% orthophosphoric acid in the ratio of 50:50 v/v on a Shiseido Capcell pak C18 column (250 × 4.6 mm, 5 μ) with wavelength detection using UV detector at 265 nm. The time taken for elution of rutin and berberine were 2.27 and 3.31 min, respectively. The linearity range for both rutin and berberine was observed from 5 to 25 μg/mL with correlation co-efficient of 0.997 and 0.999, respectively. The developed method was precise with % relative standard deviation value < 2 for both intra- and inter-day precision. The accuracy of the developed method was accomplished at three concentration levels and the recovered percentage was 99-100.2%. The developed and validated technique was successfully used as standardization tool for the simultaneous determination of markers rutin and berberine in the marketed anti-urolithiatic homeopathic formulation.

Chemical profiling and quantification of Yihuang decoction by high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry and a diode array detector

Yihuang decoction (YHD) is one of the most famous formulas in tradition Chinese medicine (TCM) and has been clinically used for treatment of vaginitis, pelvic inflammation and other gynecological diseases for hundreds of years. However, its chemical composition remains unclear. In this study, high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS) was employed for its chemical profiling investigation. As a result, 90 components were chemically defined, including 23 alkaloids, 14 organic acids, 3 phenylethanoid glycosides, 4 iridoid glycosides, 5 terpenoid lactones, 10 flavonoids, 8 nucleobases and nucleosides, 12 amino acids, and 11 other compounds. In addition, 8 representative compounds (acteoside, allantoin, berberine, 4-O-feruloylquinic acid, 5-O-feruloylquinic acid, gallic acid, geniposidic acid, and phellodendrine) were simultaneously determined in 10 batches of YHD samples by HPLC with a diode array detector (HPLC-DAD). For all the analytes, their calibration curves showed good linearity (R2 >0.9990) within the test ranges. RSDs of precision, repeatability and stability test were all below 3.50%. The overall recoveries ranged from 93.63% to 105.02%, with RSDs less than 3.50%. This study is supposed to exhibit a comprehensive chemical profiling of YHD and to provide some strong basis for quality control and even for action mechanism of this ancient classical prescription.

Gene expression, molecular docking, and molecular dynamics studies to identify potential antifungal compounds targeting virulence proteins/genes VelB and THR as possible drug targets against Curvularia lunata.

Curvuluria lunata is a melanized fungus pathogenic to both plants and animals including humans, causing from mild, febrile to life-threatening illness if not well treated. In humans, it is an etiological agent of keratomycosis, sinusitis, and onychomycosis in immunocompromised and immunocompetent patients. The development of multiple-drug-resistant strains poses a critical treatment issue as well as public health problem. Natural products are attractive prototypes for drug discovery due to their broad-spectrum efficacy and lower side effects. The present study explores possible targets of natural antifungal compounds (α-pinene, eugenol, berberine, and curcumin) against C. lunata via gene expression analysis, molecular docking interaction, and molecular dynamics (MD) studies. Curcumin, berberine, eugenol, and α-pinene exhibited in vitro antifungal activity at 78μg/ml, 156μg/ml, 156μg/ml, and 1250μg/ml, respectively. In addition, treatment by these compounds led to the complete inhibition of conidial germination and hindered the adherence when observed on onion epidermis. Several pathogenic factors of fungi are crucial for their survival inside the host including those involved in melanin biosynthesis, hyphal growth, sporulation, and mitogen-activated protein kinase (MAPK) signalling. Relative gene expression of velB, brn1, clm1, and pks18 responsible for conidiation, melanin, and cell wall integrity was down-regulated significantly. Results of molecular docking possessed good binding affinity of compounds and have confirmed their potential targets as THR and VelB proteins. The docked structures, having good binding affinity among all, were further refined, and rescored from their docked poses through 100-ns long MD simulations. The MDS study revealed that curcumin formed a stable and energetically stabilized complex with the target protein. Therefore, the study concludes that the antifungal compounds possess significant efficacy to inhibit C. lunata growth targeting virulence proteins/genes involved in spore formation and melanin biosynthesis.

Network pharmacology, molecular docking, and experimental pharmacology explored Ermiao wan protected against periodontitis via the PI3K/AKT and NF-κB/MAPK signal pathways

Ethnopharmacological relevanceErmiao Wan (EMW), a classic and famous traditional Chinese medicine (TCM)-based herbal formula combined Phellodendron chinense C.K.Schneid. (Cortex Phellodendri Chinsis, CP) and Atractylodes lancea (Thunb.) DC. (Rhizoma Atractylodis, RA) with the weight composition of 1:1, has been used for the treatment of periodontitis in China for a long time. However, its efficacy and mechanism of action are still unclear now. Aim of the studyThis study explored the efficacy and pharmaceutical mechanism of action of EMW against periodontitis. Materials and methodsThe efficacy of EMW against periodontitis was evaluated using the ligature-induced periodontitis (LIP) mice, and inflammatory-related factors in gingiva and alveolar bone loss were determined using the qRT-PCR and micro-CT assays. The potential pharmacological mechanisms were predicted by bioinformatics analysis and further confirmed by the qRT-PCR and western blotting assays. ResultsEMW exhibited inhibitory effects on periodontitis in the LIP mice. Bio-informational analysis showed the core compounds (berberine and chlorogenic acid) targeted the key genes (AKT, MAPK1, MAPK14, NF-κB, TNF, IL-2, and IL1B) through regulating the PI3K/AKT and NF-κB/MAPK signal pathways, which were validated using the qRT-PCR and western blotting assays. ConclusionsEMW could eliminate alveolar bone loss and inhibit inflammation, thereby preventing the development of periodontitis. The mechanism of action may be achieved by regulating the PI3K/AKT and NF-κB/MAPK signal pathways. Therefore, EMW was a potential therapy for the treatment of periodontitis.

Identification of natural small molecule modulators of MurB from Salmonella enterica serovar Typhi Ty2 strain using computational and biophysical approaches.

The increase of antibiotic-resistant bacterial pathogens has created challenges in treatment and warranted the design of antibiotics against comparatively less exploited targets. The peptidoglycan (PG) biosynthesis delineates unique pathways for the design and development of a novel class of drugs. Mur ligases are an essential component of bacterial cell wall synthesis that play a pivotal role in PG biosynthesis to maintain internal osmotic pressure and cell shape. Inhibition of these enzymes can interrupt bacterial replication and hence, form attractive targets for drug discovery. In the present work, we focused on the PG biosynthesis pathway enzyme, UDP-N-acetylpyruvylglucosamine reductase, from Salmonella enterica serovar Typhi (stMurB). Biophysical characterization of purified StMurB was performed to gauge the molecular interactions and estimate thermodynamic stability for determination of attributes for possible therapeutic intervention. The thermal melting profile of MurB was monitored by circular dichroism and validated through differential scanning calorimetry experiment. Frequently used chemical denaturants, GdmCl and urea, were employed to study the chemical-induced denaturation of stMurB. In the search for natural compound-based inhibitors, against this important drug target, an in silico virtual screening based investigation was conducted with modeled stMurB structure. The three top hits (quercetin, berberine, and scopoletin) returned were validated for complex stability through molecular dynamics simulation. Further, fluorescence binding studies were undertaken for the selected natural compounds with stMurB alone and with NADPH bound form. The compounds scopoletin and berberine, displayed lesser binding to stMurB whereas quercetin exhibited stronger binding affinity than NADPH. This study suggests that quercetin can be evolved as an inhibitor of stMurB enzyme.

Screening of plant-based natural compounds as an inhibitor of FtsZ from Salmonella Typhi using the computational, biochemical and in vitro cell-based studies

Salmonella Typhi is emerging as a drug-resistant pathogen, particularly in developing countries. Hence, the progressive development of new antibiotics against novel drug targets is essential to prevent the spread of infections and mortality. The cell division protein FtsZ is an ideal drug target as the cell wall synthesis in bacteria is driven by the dynamic treadmilling nature of the FtsZ. The polymerization of the FtsZ provides the essential mechanical constricting force and flexibility to modulate the cell wall synthesis. Any alteration in FtsZ polymerization leads to the bactericidal or bacteriostatic effect. In this study, we have evaluated the secondary metabolites of natural compounds berberine chloride, cinnamaldehyde, scopoletin, quercetin and eugenol as potential inhibitors of FtsZ from Salmonella Typhi (stFtsZ) using computational, biochemical, and in vivo cell-based assays. Out of these five compounds, berberine chloride and cinnamaldehyde exhibited the best binding affinity of Kd = 7 μM and 10 μM, respectively and inhibit stFtsZ GTPase activity and polymerization by 70 %. The compound berberine chloride showed the best MIC of 500 μg/mL and 175 μg/mL against gram-negative and gram-positive bacterial strains. The findings support that these natural compounds can be used as a backbone structure to develop a broad spectrum of antibacterial agents.

Investigation of Molecular Mechanism of Banxia Xiexin Decoction in Colon Cancer via Network Pharmacology and In Vivo Studies.

Objective Banxia Xiexin decoction (BXD) is widely used in the treatment of gastrointestinal and other digestive diseases. This study is based on network pharmacology to explore the molecular mechanism of BXD in the treatment of colon cancer. Methods The bioactive components and potential targets of BXD were obtained from public database. The protein-protein interaction (PPI) network of the potential targets of BXD for colon cancer was constructed based on the STRING database, cytoscape software, gene ontology (GO), and kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis of the PPI network. Finally, we established a xenograft nude mouse model to verify the effect of BXD in colon cancer treatment. Results We have acquired a total of 55 bioactive components and 136 cross-targets of BXD. The results of enrichment analysis suggested that the oxidate stress and diet were the key factors of colon cancer occurrence, and AGE-RAGE signaling pathway plays an essential role in the treatment of colon cancer with BXD. Animal experiments revealed that BXD could suppress tumor growth and induce tumor cell apoptosis in the xenograft nude mouse model with HCT116 cells. Conclusion This study uncovered that BXD inhibits the malignant progression of colon cancer that may be related to multiple compounds (berberine, quercetin, baicalein, etc.), multiple targets (Bcl2, Bax, IL6, TNFα, CASP3, etc.), and multiple pathways (human cytomegalovirus infection, AGE-RAGE signaling pathway in diabetic complications, etc.).

In Silico Screening of Synthetic and Natural Compounds to Inhibit the Binding Capacity of Heavy Metal Compounds against EGFR Protein of Lung Cancer.

Inorganic pollutant, specifically heavy metals' contamination, is a significant matter of concern and is one of the key contributors in various health disorders including cancer. However, the interaction of heavy metals (HMs) with lung cancer has rarely been explored yet. Therefore, the present study was intended with the aim to identify the interactions of HMs with the target protein “epidermal growth factor receptor (EGFR)” of lung cancer and explore potential drug candidates, which could inhibit the active site of EGFR against HM exposure. The molecular operating environment (MOE) tool was used to study the interactions of HMs with EGFR protein. The drug-drug interaction (DDI) network approach was used to identify the potential drug candidates, which were further confirmed and compared with the commercial medicines/control group. Various compounds of twenty-three HMs were docked with EGFR protein. Out of which tinidazole, thallium bromodimethyl, and silver acetate (Sn, Ti, and Ag compounds) showed strong interactions with EGFR based on lowest-scoring values (-20.42, -7.86, and -7.74 kcal/mol, respectively). Among 1280 collected drug candidates, three synthetic compounds viz., ZINC00602803, ZINC00602685, and ZINC06718468 and three natural compounds (berberine chloride, transresveratrol, and ellagic acid) depicted strong binding capacity with EGFR. Specifically, the scoring value of ZINC00602803 (-30.99 kcal/mol) was even lowest than standard lung cancer drugs (afatinib, erlotinib, and gefitinib). Our findings revealed that both natural and synthetic compounds having strong associations with EGFR protein could be potential candidates to inhibit the interaction between HMs and lung cancer protein and can also be used as an alternative for the prevention and treatment of lung cancer. However, in vitro and in vivo studies should be conducted to validate the aforementioned natural and synthetic compounds.

Targeting Epigenetic Regulatory Enzymes for Cancer Therapeutics: Novel Small-Molecule Epidrug Development.

Dysregulation of the epigenetic enzyme-mediated transcription of oncogenes or tumor suppressor genes is closely associated with the occurrence, progression, and prognosis of tumors. Based on the reversibility of epigenetic mechanisms, small-molecule compounds that target epigenetic regulation have become promising therapeutics. These compounds target epigenetic regulatory enzymes, including DNA methylases, histone modifiers (methylation and acetylation), enzymes that specifically recognize post-translational modifications, chromatin-remodeling enzymes, and post-transcriptional regulators. Few compounds have been used in clinical trials and exhibit certain therapeutic effects. Herein, we summarize the classification and therapeutic roles of compounds that target epigenetic regulatory enzymes in cancer treatment. Finally, we highlight how the natural compounds berberine and ginsenosides can target epigenetic regulatory enzymes to treat cancer.

Identification and estimation of bioactive constituents Negundoside, Berberine chloride, and Marmelosin by HPLC and HPTLC for development of quality control protocols for Ayurvedic medicated oil formulation

BackgroundAnu Taila is an ancient medicated oil Ayurvedic preparation that is commonly used for nasya karma. It contains more than 25 herbs and goat milk as per the Ayurvedic Formulary of India (AFI). It strengthens the neck, shoulder, and chest muscles and improves the capacity of sense organs. It delays the aging process and reduces hair fall. Recent studies showed that it is also useful in COVID-19. In the current study, an attempt to develop quality control protocols and evaluate the standardization parameters like refractive index, iodine value, saponification value, peroxide value, acid value, rancidity, HPTLC fingerprint profile along with major bioactive compound and quantification of Berberine chloride, Negundoside, and Marmelosin by HPLC. Establishing quality protocol and standard parameters like physicochemical parameters and estimation of bioactive compounds of this preparation is significant for quality control.ResultsIn this study, HPTLC identifies bioactive chemical compounds like Berberine chloride, Marmelosin, Negundoside, glycyrrhizin, and para hydroxybenzoic acid (PHBA), Lupeol, Embelin, and Solasodine, which were present in the Anu Taila formulation. HPLC was used to estimate the bioactive marker compounds Negundoside, Berberine chloride, and Marmelosin were present in the Anu Taila formulation. The quantitative evaluation of Berberine chloride (0.0013%), Marmelosin (0.0366%), Negundoside (0.0086%) is present in Anu Taila formulation.ConclusionThe study reveals that sufficient quality control parameters were followed during the preparation of the formulation. Physicochemical analysis was carried out as per the guidelines of Ayurvedic Pharmacopeia of India. HPTLC and HPLC profiles generated in this particular study can be considered as a preliminary tool ascertaining the authenticity of Anu Taila.