Inhibition Of Key Enzymes Research Articles

Anti-diabetic, anti-bacterial and anti-oxidant potential of new biologically active thiazole-derivatives: Experimental and molecular docking studies

In this study, we synthesised and characterised a series of thiazole derivatives (compounds 3a–j) and assessed their potential for anti-diabetic, anti-bacterial and anti-oxidant activities. The anti-diabetic potential of the compounds was assessed by measuring their inhibition of key enzymes involved in blood glucose regulation. Compound 3i demonstrated the highest α-Amylase inhibition activity (IC50 value: 18.68 µg/mL), while compounds 3i and 3c exhibited significant α-Glucosidase inhibition (IC50 values: 20.25 and 22.63 µg/mL respectively), even surpassing the control drug, Acarbose (IC50 value: 33.77 µg/mL). Interestingly, most of the compounds displayed favourable dipeptidyl peptidase IV (DPP IV) inhibition and DPPH scavenging ability, with compound 3i showing the highest DPP IV inhibition ability (IC50 value: 23.81 µg/mL) and most robust anti-oxidant potential (IC50 value: 2.50 µg/mL). Additionally, anti-bacterial studies against Staphylococcus aureus and Escherichia coli revealed compounds 3i and 3c as effective inhibitors of bacterial growth. The MICs (4, 16, 16, and 32 µg/mL) and MBCs (4, 32, 32, and 16 µg/mL) respectively of the compounds supported their potential application in controlling and preventing bacterial growth. These results provide valuable insights into the multifunctional properties of the new thiazole derivatives and their potential in managing diabetes, combating bacterial infections, and serving as anti-oxidants.

Protective efficacy of nafronyl in diabetic retinopathy through targeted inhibition of key enzymes.

Diabetic retinopathy is governed by abnormal apoptosis, increased capillary pressure, and other linked pathology that needs an efficient treatment by multitargeted approaches. Thus, the current study aimed to explore the potential of inhibition of targeted enzymes (DPP4, ACE-2, and aldose reductase) and free radical scavenging capabilities of selected compounds (nafronyl or naftidrofuryl) through in silico and in vivo investigations. Significant binding energies were observed in complexes of aldolase reductase, angiotensin type 1 receptor, and DPP4 against the nafronyl and sitagliptin more than -7.5kcal/mol. Further validation of free energy was confirmed by calculations of molecular mechanics Poisson-Boltzmann surface area (MMPBSA), and configurational stabilities examined by PCA (principal component analysis). Additionally, drug-likeness was examined by the Swiss ADME web tool, which showed significant findings. Consequently, in vivo experimentations showed significant inflammation and alterations in retinal layers of inner plexiform (inner limiting membrane, nerve fibers, and ganglionic cells), inner nuclear layer (bipolar cells and horizontal cells), and photoreceptors cells. Whereas the treatments (nafronyl and sitagliptin) caused significant improvements in the histoarchitecture of the retina. Additionally, the HOMA indices (IR-insulin resistance, sensitivity, and β cells functioning) and levels of free radicals were significantly altered in the diabetic control group in comparison to intact control. Nafronyl administration showed significant ameliorations in HOMA indices as well as antioxidant levels. Based on the results, it can be concluded that nafronyl efficiently interacts with target enzymes, which may result in potent inhibition and ameliorations in retinal histology as well as glucose homeostasis and antioxidants.

Bacteriostatic Activity of Janthinobacterium lividum and Purified Violacein Fraction against Clavibacter michiganensis

Clavibacter michiganensis causes plant diseases and is included in the list of microorganisms subject to export control. Janthinobacterium lividum is capable of synthesizing a pigment with antagonistic potential. The purpose of the study was to evaluate the activity of J. lividum VKM B-3705D and the pigment fraction against C. michiganensis VKM Ac-1402. The results of spectrophotometric and nuclear magnetic resonance analysis showed that the pigment synthesized by the J. lividum VKM B-3705D corresponds to violacein. The J. lividum strain demonstrated potential bacteriostatic activity against C. michiganensis VKM Ac-1402 when both strains were co-cultured. Compared to the control (DMSO), the violacein solution suppressed the specific growth of Clavibacter by 57.7%. The mechanism of suppression of the growth of Clavibacter is discussed. One of the ways to suppress the growth of C. michiganensis may be the inhibition of key enzymes. Violacein inhibited the activity of adenosine triphosphatase (ATPase, EC 3.6.1.3) compared to the control (DMSO) by 23.2%. Thus, the current study of the bacteriostatic effect may be a decisive step towards the development of a plant protection product.

Fomentariol, a Fomes fomentarius Compound, Exhibits Anti-Diabetic Effects in Fungal Material: An In Vitro Analysis

The present study screened various fungal species for inhibitors of alpha-glucosidase, alpha-amylase, and DPP-4, enzymes that are crucial in carbohydrate metabolism. Ethanolic extracts exhibited superior inhibitory activity compared to water extracts, suggesting their potential as sources of anti-diabetic agents. Further fractionation revealed fomentariol from Fomes fomentarius as a potent inhibitor of alpha-glucosidase and DPP-4, with higher activity against alpha-glucosidase than acarbose. Fomentariol presents a novel avenue for diabetes management, demonstrating the simultaneous inhibition of key enzymes in glucose metabolism. However, comprehensive clinical studies are needed to evaluate its safety and efficacy in humans.

Synergistic antifungal mechanism of cinnamaldehyde and nonanal against Aspergillus flavus and its application in food preservation

Aspergillus flavus colonization on agricultural products during preharvest and postharvest results in tremendous economic losses. Inspired by the synergistic antifungal effects of essential oils, the aims of this study were to explore the mechanism of combined cinnamaldehyde and nonanal (SCAN) against A. flavus and to evaluate the antifungal activity of SCAN loading into diatomite (DM). Shriveled mycelia were observed by scanning electron microscopy, especially in the SCAN treatment group. Calcofluor white staining, transmission electron microscopy, dichloro-dihydro-fluorescein diacetate staining and the inhibition of key enzymes in tricarboxylic acid cycle indicated that the antifungal mechanism of SCAN against A. flavus was related to the cell wall damage, reactive oxygen species accumulation and energy metabolism interruption. RNA sequencing revealed that some genes involved in antioxidation were upregulated, whereas genes responsible for cell wall biosynthesis, oxidative stress, cell cycle and spore development were significantly downregulated, supporting the occurrence of cellular apoptosis. In addition, compared with the control group, conidia production in 1.5 mg/mL DM/cinnamaldehyde, DM/nonanal and DM/SCAN groups were decreased by 27.16%, 48.22% and 76.66%, respectively, and the aflatoxin B1 (AFB1) contents decreased by 2.00%, 73.02% and 84.15%, respectively. These finding suggest that DM/SCAN complex has potential uses in food preservation.

In Vitro Evaluation of α‐Glucosidase and α‐Amylase Inhibition in Thai Culinary Vegetables

Diabetes management through dietary intervention has gained significant interest, particularly in the use of natural plant‐based inhibitors of key enzymes involved in carbohydrate digestion. The objective of this study was to assess the inhibitory effects of ten Thai culinary vegetables on α‐glucosidase and α‐amylase, including Chinese chive (Allium tuberosum), holy basil (Ocimum tenuiflorum), star gooseberry (Phyllanthus acidus), galangal (Alpinia galanga), bamboo grass (Tiliacora triandra), Turkey berry (Solanum torvum), cassod tree (Senna siamea), dill (Anethum graveolens L.), noni (Morinda citrifolia), and pearl wattle (Leucaena leucocephala). All vegetables were extracted using deionized water at a 1 : 10 ratio in an ultrasonic bath operating at 350 W and a frequency of 50 Hz for 30 minutes. The α‐glucosidase inhibitory activities of the vegetable extracts ranged from 13.42 ± 0.23% to 79.84 ± 0.47%, while the inhibitory activities against α‐amylase were relatively modest, ranging from 4.82 ± 3.32% to 27.49 ± 1.67%. Cassod tree exhibited the highest α‐glucosidase inhibition with the lowest IC50 at 126.38 ± 0.98 μg/mL, followed by galangal (203.17 ± 1.05 μg/mL) and holy basil (1,240 ± 20.31 μg/mL), respectively. These results may hold promise for encouraging the consumption of vegetables as a strategy for diabetes management through the targeting of key enzyme inhibition.

Recent Advances in Enteric Methane Mitigation and the Long Road to Sustainable Ruminant Production.

Mitigation of methane emission, a potent greenhouse gas, is a worldwide priority to limit global warming. A substantial part of anthropogenic methane is emitted by the livestock sector, as methane is a normal product of ruminant digestion. We present the latest developments and challenges ahead of the main efficient mitigation strategies of enteric methane production in ruminants. Numerous mitigation strategies have been developed in the last decades, from dietary manipulation and breeding to targeting of methanogens, the microbes that produce methane. The most recent advances focus on specific inhibition of key enzymes involved in methanogenesis. But these inhibitors, although efficient, are not affordable and not adapted to the extensive farming systems prevalent in low- and middle-income countries. Effective global mitigation of methane emissions from livestock should be based not only on scientific progress but also on the feasibility and accessibility of mitigation strategies.

Wnt10b protects cardiomyocytes against doxorubicin-induced cell death via MAPK modulation.

Doxorubicin, an anthracycline chemotherapeutic known to incur heart damage, decreases heart function in up to 11% of patients. Recent investigations have implicated the Wnt signaling cascade as a key modulator of cardiac tissue repair after myocardial infarction. Wnt upregulation in murine models resulted in stimulation of angiogenesis and suppression of fibrosis after ischemic insult. However, the molecular mechanisms of Wnt in mitigating doxorubicin-induced cardiac insult require further investigation. Identifying cardioprotective mechanisms of Wnt is imperative to reducing debilitating cardiovascular adverse events in oncologic patients undergoing treatment. Exposing human cardiomyocyte AC16 cells to varying concentrations of Wnt10b and DOX, we observed key metrics of cell viability. To assess the viability and apoptotic rates, we utilized MTT and TUNEL assays. We quantified cell and mitochondrial membrane stability via LDH release and JC-1 staining. To investigate how Wnt10b mitigates doxorubicin-induced apoptosis, we introduced pharmacologic inhibitors of key enzymes involved in apoptosis: FR180204 and SB203580, ERK1/2 and p38 inhibitors. Further, we quantified apoptotic executor enzymes, caspase 3/7, via immunofluorescence. AC16 cells exposed solely to doxorubicin were shrunken with distorted morphology. Cardioprotective effects of Wnt10b were demonstrated via a reduction in apoptosis, from 70.1% to 50.1%. LDH release was also reduced between doxorubicin and combination groups from 2.27-fold to 1.56-fold relative to the healthy AC16 control group. Mitochondrial membrane stability was increased from 0.67-fold in the doxorubicin group to 5.73 in co-treated groups relative to control. Apoptotic protein expression was stifled by Wnt10b, with caspase3/7 expression reduced from 2.4- to 1.3-fold, and both a 20% decrease in p38 and 40% increase in ERK1/2 activity. Our data with the AC16 cell model demonstrates that Wnt10b provides defense mechanisms against doxorubicin-induced cardiotoxicity and apoptosis. Further, we explain a mechanism of this beneficial effect involving the mitochondria through simultaneous suppression of pro-apoptotic p38 and anti-apoptotic ERK1/2 activities.

Multitargeted inhibition of key enzymes associated with diabetes and Alzheimer's disease by 1,3,4-oxadiazole derivatives: Synthesis, in vitro screening, and computational studies.

A library of 22 derivatives of 1,3,4-oxadiazole-2-thiol was synthesized, structurally characterized, and assessed for its potential to inhibit α-amylase, α-glucosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and antioxidant activities. Most of the tested compounds demonstrated good to moderate inhibition potential; however, their activity was lower than that of the standard acarbose. Significantly, compound 3f exhibited the highest inhibition potential against α-glucosidase and α-amylase enzymes, with IC50 values of 18.52 ± 0.09 and 20.25 ± 1.05 µM, respectively, in comparison to the standard acarbose (12.29 ± 0.26; 15.98 ± 0.14 µM). Compounds also demonstrated varying degrees of inhibitory potential against AChE (IC50 = 9.25 ± 0.19 to 36.15 ± 0.12 µM) and BChE (IC50 = 10.06 ± 0.43 to 35.13 ± 0.12 µM) enzymes compared to the standard donepezil (IC50 = 2.01 ± 0.12; 3.12 ± 0.06 µM), as well as DPPH (IC50 = 20.98 ± 0.06 to 52.83 ± 0.12 µM) and ABTS radical scavenging activities (IC50 = 22.29 ± 0.18 to 47.98 ± 0.03 µM) in comparison to the standard ascorbic acid (IC50 = 18.12 ± 0.15; 19.19 ± 0.72). The kinetic investigations have demonstrated that the compounds exhibit competitive-type inhibition for α-amylase, noncompetitive-type inhibition for α-glucosidase and AChE, and mixed-type inhibition for BChE. Additionally, a molecular docking study was performed on all synthetic oxadiazoles to explore the interaction details of these compounds with the active sites of the enzymes.

Pistacia lentiscus L. Fatty Oil and its Unsaponifiable Matter: Antidiabetic and Neuroprotective Activities

Background: The inhibition of key enzymes involved in type II diabetes and Alzheimer’s disease is an effective therapeutic approach for managing these health disorders. This study aimed to assess the antidiabetic and neuroprotective effects of Pistacia lentiscus L.
 Methods: The potential of Pistacia lentiscus L. fatty oil (PLFO) was investigated against the activities of α-amylase, α-glucosidase, acetylcholinesterase, and butyrylcholinesterase. Additionally, the unsaponifiable matter (USM) of this oil was isolated and screened for the same activities. Furthermore, the antioxidant power of both extracts was evaluated using DPPH, ABTS, and CUPRAC assays.
 Results: The results revealed that PLFO exhibited a low antioxidant effect primarily due to its USM. The potent antidiabetic effect of PLFO was also attributed to its USM, while the whole oil was responsible for the neuroprotective effect.
 Conclusion: These findings suggest that PLFO and its USM could serve as natural sources of compounds for managing type II diabetes and Alzheimer’s disease.

Hypoxia-induced reprogramming of glucose-dependent metabolic pathways maintains the stemness of human bone marrow-derived endothelial progenitor cells

The benefits of hypoxia for maintaining the stemness of cultured human bone marrow-derived endothelial progenitor cells (BM EPCs) have previously been demonstrated but the mechanisms responsible remain unclear. Growing evidences suggest that cellular metabolism plays an important role in regulating stem cell fate and self-renewal. Here we aimed to detect the changes of glucose metabolism and to explore its role on maintaining the stemness of BM EPCs under hypoxia. We identified the metabolic status of BM EPCs by using extracellular flux analysis, LC–MS/MS, and 13C tracing HPLC-QE-MS, and found that hypoxia induced glucose metabolic reprogramming, which manifested as increased glycolysis and pentose phosphate pathway (PPP), decreased tricarboxylic acid (TCA) and mitochondrial respiration. We further pharmacologically altered the metabolic status of cells by employing various of inhibitors of key enzymes of glycolysis, PPP, TCA cycle and mitochondria electron transport chain (ETC). We found that inhibiting glycolysis or PPP impaired cell proliferation either under normoxia or hypoxia. On the contrary, inhibiting pyruvate oxidation, TCA or ETC promoted cell proliferation under normoxia mimicking hypoxic conditions. Moreover, promoting pyruvate oxidation reverses the maintenance effect of hypoxia on cell stemness. Taken together, our data suggest that hypoxia induced glucose metabolic reprogramming maintains the stemness of BM EPCs, and artificial manipulation of cell metabolism can be an effective way for regulating the stemness of BM EPCs, thereby improving the efficiency of cell expansion in vitro.

Comparison of Physicochemical Characteristics and Bioactivity of Olive Oil Mill Wastewaters from Traditional and Water-Saving ARA-Controlled Three-Phase Decanter

Olive mill wastewater (OMW) is one of the most environmentally concerning food processing effluents due to its phytotoxicity. Recently, several bioactive compounds with potential applications in food, pharmaceutical, and agricultural industries have been identified in OMW. This study aimed to compare, for the first time, the physico-chemical characteristics and biological activity of OMW obtained by two different types of three-phase decanters: a traditional one and a water-saving ARA decanter. DPPH, ABTS, FRAP, and β-carotene bleaching tests were used to investigate the antioxidant effects. The inhibition of key enzymes involved in hyperglycemia and hypolipidemia were also assessed. A high concentration of phenolic compounds was found in OMW obtained by the ARA-controlled system. Hydroxytyrosol resulted as the dominant compound, with a content of 502.3 mg/kg. OMW extract obtained by ARA decanter resulted as the most active in the FRAP test, with value of 67.23 µMFe (II)/g. A moderate inhibitory activity was found against α-amylase, α-glucosidase, and lipase enzymes. Data obtained by this study evidenced that the use of the ARA decanter allows for obtaining OMW extract characterized by a higher content of phytochemicals in comparison to those obtained by the traditional phase decanter, and a consequent higher biological activity. At the same time, the use of this equipment allows for the reduction of environment impact.

Nutrients, Phytochemicals and In Vitro Disease Prevention of Nephelium hypoleucum Kurz Fruit

Nephelium hypoleucum Kurz is an evergreen tree in the Sapindaceae family, mostly found in the forests of some Southeast Asia countries, especially Thailand. The lack of biological information regarding this tree has led to inappropriate agricultural management, conservation and utilization. Thus, this study aims to examine the nutritional composition, organic acid and phenolic profiles and in vitro health properties through several key enzyme inhibitions against some civilization diseases including Alzheimer's disease (β-secretase (BACE-1), butyrylcholinesterase (BChE) and acetylcholinesterase (AChE)), obesity (lipase), hypertension (angiotensin-converting enzyme (ACE)) and diabetes (dipeptidyl peptidase-IV (DPP-IV), α-amylase and α-glucosidase) on the aril (flesh) part of N. hypoleucum Kurz fruit. The remaining fruit parts including the pericarp (peel) and seed were also assessed as sources of potential phenolics as well as key enzyme inhibitors. As results, carbohydrate (17.18 g) was found to be a major source of energy (74.80 kcal) in the aril (100 g fresh weight), with trace amounts of protein (0.78 g) and fat (0.32 g). The fruit aril also contained high insoluble dietary fiber (5.02 g) and vitamin C (11.56 mg), while potassium (215.82 mg) was detected as the major mineral. Organic acid profile indicated that the aril was rich in citric acid, while the phenolic profile suggested predominant quercetin and kaempferol. Interestingly, high gallic acid contents were detected in both pericarp and seed, with the latter 3.2-fold higher than the former. The seed also possessed the highest total phenolic content (TPC, 149.45 mg gallic acid equivalent/g dry weight), while total anthocyanin content (TAC, 0.21 mg cyanidin-3-O-glucoside equivalent/g dry weight) was only detected in pericarp. High TPC also led to high enzyme inhibitory activities in seed including BACE-1, AChE, BChE, ACE, DPP-IV and α-glucosidase. Interestingly, aril with the highest α-amylase inhibition suggested strong inhibitory distribution, predominantly from quercetin and kaempferol. Lipase inhibitory activities were only detected in the aril and pericarp, suggesting the biological function of these two phenolics and possibly anthocyanins.

Strong Feedback Inhibition of Key Enzymes in the Morphine Biosynthetic Pathway from Opium Poppy Detectable in Engineered Yeast.

Systematic screening of morphine pathway intermediates in engineered yeast revealed key biosynthetic enzymes displaying potent feedback inhibition: 3'-hydroxy-N-methylcoclaurine 4'-methyltransferase (4'OMT), which yields (S)-reticuline, and the coupled salutaridinol-7-O-acetyltransferase (SalAT) and thebaine synthase (THS2) enzyme system that produces thebaine. The addition of deuterated reticuline-d1 to a yeast strain able to convert (S)-norcoclaurine to (S)-reticuline showed reduced product accumulation in response to the feeding of all four successive pathway intermediates. Similarly, the addition of deuterated thebaine-d3 to a yeast strain able to convert salutaridine to thebaine showed reduced product accumulation from exogenous salutaridine or salutaridinol. In vitro analysis showed that reticuline is a noncompetitive inhibitor of 4'OMT, whereas thebaine exerts mixed inhibition on SalAT/THS2. In a yeast strain capable of de novo morphine biosynthesis, the addition of reticuline and thebaine resulted in the accumulation of several pathway intermediates. In contrast, morphine had no effect, suggesting that circumventing the interaction of reticuline and thebaine with 4'OMT and SalAT/THS2, respectively, could substantially increase opiate alkaloid titers in engineered yeast.

Iridoid- and flavonoid-enriched fractions of Cornus sanguinea and Cornus mas exert antioxidant and anti-inflammatory effects and inhibit key enzymes in the treatment of metabolic disorders.

Background: Berry fruits are recognized as a "superfood" due to their high content of bioactive compounds and health benefits. Scope and approach: Herein, extracts of Cornus sanguinea and Cornus mas fresh and dried fruits obtained by different extraction procedures (ethanolic and hydroalcoholic maceration, ultrasound-assisted extraction, and Soxhlet apparatus) were analysed using liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry (LC-ESI-QTOF-MS) and compared to identify the main healthy compounds and their impact on the inhibition of key enzymes (pancreatic lipase, α-glucosidase, and α-amylase) associated with metabolic disorders. The antioxidant activity and inhibition of nitric oxide (NO) and NF-κB pathway were also investigated. Key findings and conclusions: Flavonoids, iridoids, and phenolic acids were the main classes of identified compounds. Herein, kaempferol 3-O-galactoside, kaempferol 3-O-glucoside, quercetin, quercetin 3-O-xyloside, and myricetin 3-O-galactoside were detected for the first time in C. sanguinea. Remarkable antioxidant effects and promising α-glucosidase and lipase inhibitory activity were observed with extracts obtained by hydroalcoholic maceration of both Cornus dried fruits. Consequently, these extracts were subjected to fractionation using Amberlite XAD-16 resin. The most promising biological activities, which are attributed to the presence of some flavonoids and iridoids, were detected with the C. sanguinea fractions, in particular SD2(II). The results of this study offer new insights into the potential development of functional foods, nutraceuticals, and food supplements using the Cornus species.

UHPLC-MS/MS identification, quantification of flavonoid compounds from Areca catechu L. extracts and in vitro evaluation of antioxidant and key enzyme inhibition properties involved in hyperglycemia and hypertension

Arecanut (Areca catechu L.) is an important commercial crop extensively used in traditional and modern medicine. The studies on bioactive compounds and bioactivities of arecanut extracts are a fundamental requirement for future pharmacological research. This study focused on the flavonoid compounds of arecanut and their in vitro bioactivities, including antioxidant activities and inhibitory potential towards enzymes involved in the treatment of hyperglycemia and hypertension. Furthermore, ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC–MS/MS) was utilized to characterize the flavonoid compositions in extracts of arecanut. The results showed that all extracts from different parts of arecanut (flower, husk, seed) had high contents of polyphenols, flavonoids and proanthocyanins. In total, seventy-two flavonoid compounds were identified and among them twenty-eight flavonoid compounds were quantitated. The dominated flavonoid compounds in three extracts were significantly different. The major flavonoids recognized in flower extract were cynaroside, luteolin and diosmetin, while the flavonoid compositions were dominated by schaftoside and diosmetin in husk extract. The flavonoids with higher contents in seed extract were catechin, procyanidin B1, procyanidin B2 and L-epicatechin. The results of scavenging activities towards DPPH·, ABTS·+, OH·−and O2·− demonstrated that all extracts from arecanut displayed good free radical scavenging abilities. All extracts also exhibited strong reducing power, especially arecanut seed extract. Additionally, arecanut seed extract were characterized by the strongest α-amylase and α-glucosidase inhibitory capacities, which were significantly superior to acarbose. Arecanut seed extract were also found to possess the highest angiotensin-converting enzyme (ACE) inhibitory properties compared to flower and husk extracts. In conclusion, arecanut is enriched in natural bioactive compounds with potent antioxidant activities and inhibitory effects on the enzyme related to hypertension and hyperglycemia. It can be a potential source for application in the relevant medicinal aspects.

Targeting Wnt/β-catenin signaling pathway in triple-negative breast cancer by benzylic organotrisulfides: Contribution of the released hydrogen sulfide towards potent anti-cancer activity.

The potent anti-cancer activity of naturally occurring organopolysulfides has attracted wide research attention over the last two decades. Sustained donation of hydrogen sulfide (H2S) from organopolysulfides is found to be beneficial for the treatment of several organ-specific cancers. In the present study, for the first time, the mechanism of action for the potent anti-cancer activity of bis(3,5-dimethoxybenzyl) trisulfide 4 against highly aggressive triple-negative breast cancer cells (MDA-MB-231) is described. Preliminary in vitro studies revealed potent anti-proliferative activity of the trisulfide 4 against triple-negative breast cancer cells with an IC50 value of 1.0μM. Mechanistic studies reveal that the compound exhibited anti-cancer activity, primarily by targeting and suppressing the Wnt/β-catenin signaling pathway. The inactivation of the β-catenin level was associated with the cell cycle arrest in the G2/M phase and the significant down-regulation of downstream signaling genes such as Cyclin D1 and c-Myc expression. Several control experiments with analogous organosulfur compounds and the key enzyme inhibitors reveal that the presence of a trisulfide unit in the compound is crucial for the desired inactivation of β-catenin expression, which is promoted by GSK-3β-induced phosphorylation of β-catenin and its proteasomal degradation. Moreover, the trisulfide unit or the released H2S induced down-regulation of the p53 expression with the possible S-sulfhydration process led to p53-independent up-regulation of p21 expression. Therefore, the key results of this study highlighting the potency of synthetic benzylic organotrisulfide and the released H2S towards the growth inhibition of triple-negative breast cancer via Wnt/β-catenin signaling pathway would certainly be helpful for further studies and developing small-molecule anti-cancer therapeutics in future.

Personalized quantitative models of NAD metabolism in hepatocellular carcinoma identify a subgroup with poor prognosis.

Cancer cells are known to undergo metabolic adaptation to cater to their enhanced energy demand. Nicotinamide adenine dinucleotide (NAD) is an essential metabolite regulating many cellular processes within the cell. The enzymes required for NAD synthesis, starting from the base precursor - tryptophan, are expressed in the liver and the kidney, while all other tissues convert NAD from intermediate precursors. The liver, being an active metabolic organ, is a primary contributor to NAD biosynthesis. Inhibition of key enzymes in the NAD biosynthetic pathways is proposed as a strategy for designing anti-cancer drugs. On the other hand, NAD supplementation has also been reported to be beneficial in cancer in some cases. As metabolic adaptation that occurs in cancer cells can lead to perturbations to the pathways, it is important to understand the exact nature of the perturbation in each individual patient. To investigate this, we use a mathematical modelling approach integrated with transcriptomes of patient samples from the TCGA-LIHC cohort. Quantitative profiling of the NAD biosynthesis pathway helps us understand the NAD biosynthetic status and changes in the controlling steps of the pathway. Our results indicate that NAD biosynthesis is heterogeneous among liver cancer patients, and that Nicotinate phosphoribosyl transferase (NAPRT) levels are indicative of the NAD biosynthetic status. Further, we find that reduced NAPRT levels combined with reduced Nicotinamide phosphoribosyl transferase (NAMPT) levels contribute to poor prognosis. Identification of the precise subgroup who may benefit from NAD supplementation in subgroup with low levels of NAPRT and NAMPT could be explored to improve patient outcome.

In Silico Screening of Active Compounds in Garri for the Inhibition of Key Enzymes Linked to Diabetes Mellitus

Through in silico screening, this study seeks to demonstrate a connection between ethnopharmacological claims and the bioactive components found in Garri against potential targets for diabetes. The process of molecular docking involving different bonding modes of compounds in Garri with active cavities of target receptors for proteins human pancreatic alpha-amylase (HPA) and human lysosomal acid-alpha-glucosidase (GAA) was carried out in autodock vina. Density functional theory was used for quantum chemical analysis, while ADME/T properties of the top binding compounds were predicted using the Admetsar and Swissadme database. From the results, (20E)-6-hydroxycholesta-9(11),20(22)-diene-3,23-dione, 25-dedhydrotigogenin, cochlioquinone B, and psi-diosgenin, showed the best docking results (> −8.1 to −9.8 kcal/mol), when compared with the standard control drugs acarbose (−7.9 kcal/mol) and 1-deoxynojirimycin (< −5.1 kcal/mol). The results from the ADME/T prediction also revealed that the compounds had good pharmacokinetic properties. The study provided insights into the development of better inhibitors to treat diabetes from garri.

Plant based polyphenol associations with protein: A prospective review

This review discusses the classes of plant polyphenols along with their binding mechanisms with protein molecules. Generally, polyphenols bind in covalent and non-covalent orientations with protein molecules. Their addition to the protein usually results in undesirable flavors and tastes inside the proteins. They also affect the color of the food. Plant polyphenols are found to act in a protective way against cardiovascular disease, neurodegenerative diseases, diabetes, and cancer. In addition to redox activity, their modes of action include the inhibition of key enzymes, modulation of transcription factors or cell receptors, and finally, perturbation of protein aggregates. Dietary polyphenols usually play a key role in protein digestion by forming covalent and non-covalent bonds with proteins. In addition, polyphenols and plant phenolics possess the scavenging ability of reactive oxygen species (ROS), including radical/non-radical oxygen species including HOC•, H2O2, HOCl, 1O2 (singlet oxygen), and oxidatively generated radicals derived from LDL biomolecules such as ROOC• and oligonucleic acids.