Apicoplast-Resident Processes: Exploiting the Chink in the Armour of Plasmodium falciparum Parasites.

The discovery of a relict plastid, also known as an apicoplast (apicomplexan plastid), that houses housekeeping processes and metabolic pathways critical to Plasmodium parasites' survival has prompted increased research on identifying potent inhibitors that can impinge on apicoplast-localised processes. The apicoplast is absent in humans, yet it is proposed to originate from the eukaryote's secondary endosymbiosis of a primary symbiont. This symbiotic relationship provides a favourable microenvironment for metabolic processes such as haem biosynthesis, Fe-S cluster synthesis, isoprenoid biosynthesis, fatty acid synthesis, and housekeeping processes such as DNA replication, transcription, and translation, distinct from analogous mammalian processes. Recent advancements in comprehending the biology of the apicoplast reveal it as a vulnerable organelle for malaria parasites, offering numerous potential targets for effective antimalarial therapies. We provide an overview of the metabolic processes occurring in the apicoplast and discuss the organelle as a viable antimalarial target in light of current advances in drug discovery. We further highlighted the relevance of these metabolic processes to Plasmodium falciparum during the different stages of the lifecycle.

Antioxidative and anti-diabetic effects of Tapinanthus cordifolius leaf extract on high-fat diet and streptozotocin-induced type 2 diabetic rats.

Type 2 diabetes mellitus (T2DM) remains a global health concern despite current treatment options. This study investigated the potential of Tapinanthus cordifolius (TC) leaf extract as a therapeutic agent for T2DM. T2DM was induced in rats using a high-fat diet and streptozotocin. Diabetic rats received daily oral administration of TC extract (200, 400, or 800 mg/kg) and metformin (400 mg/kg) or remained untreated for 21 days. Blood glucose levels, body weight, diabetic symptoms, oxidative stress markers, and gene expression of metabolic regulators were assessed. TC treatment significantly reduced blood glucose levels and restored body weight in diabetic rats, comparable to the effects of metformin. TC also increased antioxidant enzyme activities (SOD, GST, and CAT) and decreased lipid peroxidation in various tissues. Furthermore, TC upregulated gene expression of glucose transporter type 4 (GLUT-4) and adiponectin receptor 2 (ADIPOR-2) while downregulating pro-inflammatory cytokines TNF-α and IL-6. This study provides the first in vivo evidence supporting TC leaf extract's anti-diabetic and antioxidant efficacy. The findings suggest that TC holds promise as a natural therapeutic agent for managing T2DM through multiple mechanisms, including improved glycemic control, enhanced insulin sensitivity, and protection against oxidative stress and tissue damage. In conclusion, this study validates the ethnobotanical use of TC as an anti-diabetic agent. Further research is warranted to isolate the bioactive compounds responsible for these effects.

Corrigendum to "Toxicopathological, proinflammatory and stress response evaluation of Terminalia catappa extract in male Wistar rats" [Toxicol. Rep. 8 (2021) 1769-1776].

[This corrects the article DOI: 10.1016/j.toxrep.2021.10.005.].

In vitro and in silico inhibitory validation of Tapinanthus cordifolius leaf extract on alpha-glucosidase in the management of type 2 diabetes.

The anti-diabetic properties of medicinal plants are becoming more widely recognized. To identify potential anti-diabetic agents for diabetes drug discovery, the current study used in vitro and in silico approaches to assess the alpha glucosidase inhibitory activities of Tapinanthus cordifolius (TC) leaf extracts and its bioactive components respectively. In vitro alpha glucosidase inhibitory assay was carried out on TC extract and fractions at various concentrations (50-1600 µg/mL), and the compounds with alpha glucosidase inhibitory potentials were identified using molecular docking, pharmacophore modelling, and molecular dynamics simulation. The crude extract exhibited the highest activity with an IC50 value of 248 µg/mL. Out of the 42 phytocompounds of the extract, α-Tocopherol-ß-d-mannoside gave the lowest binding energy of -6.20 Kcal/mol followed by, 5-Ergosterol (-5.46 kcal/mol), Acetosyringone (-4.76 kcal/mol), and Benzaldehyde, 4-(Ethylthio)-2,5-Dimethoxy-(-4.67 kcal/mol). The selected compounds interacted with critical active site amino acid residues of alpha-glucosidase, just like the reference ligand. Molecular dynamics simulation revealed the formation of a stable complex between α-glucosidase and α-Tocopherol-ß-d-mannoside, with ASP 564 sustaining two hydrogen bond connections for 99.9 and 75.0% of the simulation duration, respectively. Therefore, the selected TC compounds, especially α-Tocopherol-ß-d-mannoside might be explored for future research and development as diabetic medicines.Communicated by Ramaswamy H. Sarma.

Counteractive role of Terminalia catappa leaf extract on hematological and coagulation disturbance in Type 2 diabetic rats.

Background and Aim: Diabetes mellitus is a leading cause of mortality worldwide associated with hyperglycemia-induced hematological aberrations and thromboembolic complications. This study aimed to explore the modulatory effect of Terminalia catappa leaf aqueous crude extract (TCLE) on hematological and coagulation disturbances in a Type 2 diabetic rat model. Materials and Methods: High-fat diet streptozotocin-induced diabetic rats were treated orally with 400 and 800 mg/kg body weight TCLE daily for 28 days. Full blood count, coagulation parameters, plasma calcium (Ca), and erythrocyte glycogen (GLYC) levels were assessed using standard procedures. Results: Terminalia catappa leaf aqueous crude extract treatment had a significant (p < 0.05) prolonging effect on clotting and bleeding times while increasing Ca, GLYC and mean corpuscular volume in diabetic rats. On the other hand, lymphocytes (LYM), platelet (PLT) count, mean PLT volume, neutrophil-LYM ratio (NLR), and PLT-LYM ratio (PLR) of TCLE-treated diabetic animals were significantly reduced (p < 0.05) compared with untreated diabetic animals. Lymphocyte, PLT count, NLR, and PLR correlated positively (p < 0.05) with plasma glucose, while a significant positive association was observed between Ca and GLYC. On the other hand, a strong negative association (p < 0.05) was observed between clotting time and fasting plasma glucose. Conclusion: These findings suggest that T. catappa leaf extract may be useful in reversing diabetic-mediated hematological anomalies due to its anticoagulant and anti-anemic activities.

Ficus exasperata Attenuates Acetaminophen-Induced Hepatic Damage via NF-κB Signaling Mechanism in Experimental Rat Model.

Ficus exasperata has been used to treat ulcer, diabetes, fever, and a variety of stress-related disorders. Acetaminophen (APAP) overdose is the most common cause of drug-induced acute liver injury. In this study, we evaluated the hepatoprotective effect and antioxidant capacity of ethanolic extract of F. exasperata (EFE) on acetaminophen-induced hepatotoxicity in albino rats. Rats were pretreated with EFE (150, 250, 500 mg/kg) and thereafter received 250 mg/kg APA intraperitoneally (i.p.). The normal control group received distilled water, while the negative control group received 250 mg/kg APAP, respectively. Hepatotoxicity and oxidative stress-antioxidant parameters were then assessed. Flavonoids, saponins, steroids, and glycosides, but not phenolics were detected by EFE phytochemical analysis. No mortality was recorded on acute exposure of rats to varying concentrations of APAP after 24 h; however, a dose-dependent increase in severity of convulsion, urination, and hyperactivity was observed. APAP overdose induced high AST, ALT, ALP, and total bilirubin levels in the serum, invoked lipid peroxidation, depleted GSH, decreased CAT, SOD, and GST levels, respectively. Nitric oxide (NO) level, myeloperoxidase activity, TNF-α, IL-1ß, NF-κB, COX-2, MCP-1, and IL-6 were also increased. Importantly, pretreatment of rats with EFE before acetaminophen ameliorated and restored cellular antioxidant status to levels comparable to the control group. Our results show and suggest the hepatoprotective effect of F. exasperata and its ability to modulate cellular antioxidant status supports its use in traditional medicine and renders it safe in treating an oxidative stress-induced hepatic injury.

Terminalia catappa aqueous leaf extract reverses insulin resistance, improves glucose transport and activates PI3K/AKT signalling in high fat/streptozotocin-induced diabetic rats.

Rising prevalence of type 2 diabetes mellitus (T2DM) in sub-Saharan Africa has necessitated surveys of antidiabetic medicinal plants. This study assessed the antidiabetic mechanism of Terminalia catappa aqueous leaf extract (TCA) in high fat/low dose streptozotocin-induced type 2 diabetic rats. T2DM was induced by a combination of high-fat diet and low dose STZ (30 mg/kg bw) and the animals were administered with TCA (400 and 800 mg/kg bw) orally daily for 28 days. Biochemical parameters and indices for diabetes including renal function tests and pancreatic histology were evaluated. Relative expression of hepatic insulin resistance, signalling and glucose transport genes were also assessed. Induction of T2DM resulted in significant (p < 0.05) weight loss, dysregulated glucose level and clearance, electrolyte imbalance and disrupted diabetic biochemical parameters. Diabetes onset also perturbed ß-cell function and insulin resistance indices, damaged pancreas microanatomy, while disrupting the expression of insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and glucose transporter isoform 4 (GLUT-4) mRNA. Oral treatment of diabetic animals with TCA significantly (p < 0.05) ameliorated alterations due to T2DM induction in a manner comparable with glibenclamide. These results suggest TCA exerts its antidiabetic action by reversing insulin resistance, improving glucose transport and activating PI3K/AKT signalling.

Terminalia catappa Extract Palliates Redox Imbalance and Inflammation in Diabetic Rats by Upregulating Nrf-2 Gene.

This study aims at evaluating the ameliorative role of Terminalia catappa aqueous leaf extract (TCA) on hyperglycaemia-induced oxidative stress and inflammation in a high-fat, low dose streptozotocin-induced type 2 diabetic rat model. Experimental rats were treated orally with 400 and 800 mg/kg bw TCA daily for four weeks. Antioxidant enzyme activities, plasma glucose concentration, protein concentration, oxidative stress, and inflammation biomarkers were assayed using standard methods. Hepatic relative expressions of tumour necrosis factor-alpha (TNF-α), interleukin-six (IL-6), and nuclear factor-erythroid 2 related factor 2 (Nrf-2) were also assessed. Molecular docking and prediction of major TCA phytoconstituents' biological activity related to T2DM-induced oxidative stress were evaluated in silico. Induction of diabetes significantly (p < 0.05) reduced superoxide dismutase, glutathione-S-transferase, and peroxidase activities. Glutathione and protein stores were significantly (p < 0.05) depleted, while glucose, MDA, interleukin-six (IL-6), and tumour necrosis factor-α (TNF-α) concentrations were significantly (p < 0.05) increased. A significant (p < 0.05) upregulation of hepatic TNF-α and IL-6 expression and downregulation (p < 0.05) of Nrf-2 expression were observed during diabetes onset. TCA treatment significantly (p < 0.05) modulated systemic diabetic-induced oxidative stress and inflammation, mRNA expression dysregulation, and dysregulated macromolecule metabolism. However, only 800 mg/kg TCA treatment significantly (p < 0.05) downregulated hepatic TNF-α expression. 9-Oxabicyclo[3.3.1]nonane-2,6-diol and 1,2,3-Benzenetriol bound comparably to glibenclamide in Nrf-2, IL-6, and TNF-α binding pockets. They were predicted to be GST A and M substrate, JAK2 expression, ribulose-phosphate 3-epimerase, NADPH peroxidase, and glucose oxidase inhibitors. These results suggest that TCA ameliorates hyperglycaemia-induced oxidative stress and inflammation by activating Nrf-2 gene.

Type 2 Diabetes Mellitus Mediation by the Disruptive Activity of Environmental Toxicants on Sex Hormone Receptors: In Silico Evaluation.

This study investigates the disruptive activity of environmental toxicants on sex hormone receptors mediating type 2 diabetes mellitus (T2DM). Toxicokinetics, gene target prediction, molecular docking, molecular dynamics, and gene network analysis were applied in silico techniques. From the results, permethrin, perfluorooctanoic acid, dichlorodiphenyltrichloroethane, O-phenylphenol, bisphenol A, and diethylstilbestrol were the active toxic compounds that could modulate androgen (AR) and estrogen-α and -ß receptors (ER) to induce T2DM. Early growth response 1 (EGR1), estrogen receptor 1 (ESR1), and tumour protein 63 (TP63) were the major transcription factors, while mitogen-activated protein kinases (MAPK) and cyclin-dependent kinases (CDK) were the major kinases upregulated by these toxicants via interactions with intermediary proteins such as PTEN, AKT1, NfKß1, SMAD3 and others in the gene network analysis to mediate T2DM. These toxicants pose a major challenge to public health; hence, monitoring their manufacture, use, and disposal should be enforced. This would ensure reduced interaction between people and these toxic chemicals, thereby reducing the incidence and prevalence of T2DM.

Toxicopathological, proinflammatory and stress response evaluation of Terminalia catappa extract in male Wistar rats.

The present study was carried out to assess the oral safety, proinflammatory and stress response effect of Terminalia catappa aqueous leaf extract (TCA) in male Wistar rats. The acute and sub-acute oral toxicity of TCA was assessed using guidelines 423 and 407 of the Organisation for Economic Co-operation and Development (OECD), respectively. Signs of clinical toxicity, morbidity and mortality were observed. The biochemical, haematological, proinflammatory, stress response and histopathological indices were assessed. In the acute toxicity study, no sign of clinical toxicity, morbidity, and mortality was observed for TCA treatment, up to 5000 mg/kg bwt. However, in the sub-acute toxicity study, repeated daily TCA treatment significantly (p<0.05) altered the body weight gain, plasma alkaline phosphatase activity and albumin concentration. There were no obvious morphological and macroscopic alterations in the organs investigated. TCA appear not to elicit any proinflammatory, stress, systemic and organ toxic effect when utilised at the reported dose and time frame.

Anopheles metabolic proteins in malaria transmission, prevention and control: a review.

The increasing resistance to currently available insecticides in the malaria vector, Anopheles mosquitoes, hampers their use as an effective vector control strategy for the prevention of malaria transmission. Therefore, there is need for new insecticides and/or alternative vector control strategies, the development of which relies on the identification of possible targets in Anopheles. Some known and promising targets for the prevention or control of malaria transmission exist among Anopheles metabolic proteins. This review aims to elucidate the current and potential contribution of Anopheles metabolic proteins to malaria transmission and control. Highlighted are the roles of metabolic proteins as insecticide targets, in blood digestion and immune response as well as their contribution to insecticide resistance and Plasmodium parasite development. Furthermore, strategies by which these metabolic proteins can be utilized for vector control are described. Inhibitors of Anopheles metabolic proteins that are designed based on target specificity can yield insecticides with no significant toxicity to non-target species. These metabolic modulators combined with each other or with synergists, sterilants, and transmission-blocking agents in a single product, can yield potent malaria intervention strategies. These combinations can provide multiple means of controlling the vector. Also, they can help to slow down the development of insecticide resistance. Moreover, some metabolic proteins can be modulated for mosquito population replacement or suppression strategies, which will significantly help to curb malaria transmission.

Ganoderma Lucidum from Red Mushroom Attenuates Formaldehyde-Induced Liver Damage in Experimental Male Rat Model.

The majority of liver-related illnesses are caused by occupational and domestic exposure to toxic chemicals like formaldehyde (FA), which is widely common in Africa and the world at large. Hence, measures should be taken to protect humans from its hazardous effects. This study, therefore, examines the protective potential of Ganoderma lucidum (100 mg/kg body weight) on formaldehyde-induced (40%) liver oxido-inflammation in male rats. Male Wistar rats, 150-200 g, were allotted into four groups of 10 animals as follows: Group 1 was orally treated with 1 mg/mL distilled water, Group 2 was exposed to a 40% formaldehyde vapor environment for 30 min per day, Group 3 was orally treated with 100 mg/kg ethanol extract of Ganoderma lucidum, and Group 4 was co-administered formaldehyde and 100 mg/kg ethanol extract of Ganoderma lucidum. Rats were then sacrificed 24 h after administering the last dose of treatment, and the livers were excised. Ganoderma lucidum significantly reversed the formaldehyde-mediated reduction in body and organ weight. Ganoderma lucidum administration significantly prevented oxido-inflammation by reducing the levels of hydrogen peroxide and malondialdehyde and increasing the activity of antioxidant enzymes and glutathione contents, as well as the normal level of nitrite and myeloperoxidase production in FA-treated rats. Additionally, Ganoderma lucidum reversed a large decline in proinflammatory markers in formaldehyde. Furthermore, Ganoderma lucidum restores formaldehyde-induced histological alterations in the liver. Collectively, our results provide valuable information on the protective potential of Ganoderma lucidum in protecting formaldehyde-induced liver oxido-inflammation in male rats.

Nauclea latifolia Sm. Leaf Extracts Extenuates Free Radicals, Inflammation, and Diabetes-Linked Enzymes.

This study was carried out to assess the in vitro antioxidant, anti-inflammatory and antidiabetic effects of Nauclea latifolia (Sm.) leaf extracts. Ethanolic (NLE) and aqueous (NLA) extract of N. latifolia leaves were prepared and assessed for their anti-inflammatory activity, antioxidant potential, α-amylase and α-glucosidase inhibitory activities, and the mechanism of enzyme inhibition in vitro using standard established methods. From the results, phytochemicals such as flavonoids, phenolics, glycosides, and tannins were detected in both extracts of N. latifolia with NLE having a significantly (p < 0.05) higher phytochemical content. NLE displayed significantly (p < 0.05) better total antioxidant capacity, reducing power, 2,2-diphenyl-2-picrylhydrazyl, and hydrogen peroxide radical scavenging activities. For anti-inflammatory activities, 70.54 ± 2.45% albumin denaturation inhibition was observed for NLE while 68.05 ± 1.03% was recorded for NLA. Likewise, 16.07 ± 1.60 and 14.08 ± 1.76% were obtained against hypotonic solution and heat-induced erythrocyte haemolysis, respectively, for NLE while 20.59 ± 4.60 and 24.07 ± 1.60% were respective NLA values. NLE (IC50: 4.20 ± 0.18 and 1.19 ± 0.11 mg/mL) and NLA (IC50: 11.21 ± 0.35 and 2.64 ± 0.48 mg/mL) α-glucosidase and α-amylase inhibitory activities were dose-dependent with uncompetitive and competitive inhibition elicited, respectively, by the extracts. A significant positive association (p < 0.01 and 0.05) was identified between antioxidant activity and carbohydrate-metabolising enzyme inhibitory activity. The obtained result suggests N. latifolia leaf could serve as an alternative candidate for managing diabetes mellitus due to its antioxidant and anti-inflammatory association with diabetes-linked enzymes.

Model Optimization and In Silico Analysis of Potential Dipeptidyl Peptidase IV Antagonists from GC-MS Identified Compounds in Nauclea latifolia Leaf Extracts.

Dipeptidyl peptidase IV (DPP-IV) is a pharmacotherapeutic target in type 2 diabetes. Inhibitors of this enzyme constitute a new class of drugs used in the treatment and management of type 2 diabetes. In this study, phytocompounds in Nauclea latifolia (NL) leaf extracts, identified using gas chromatography-mass spectroscopy (GC-MS), were tested for potential antagonists of DPP-IV via in silico techniques. Phytocompounds present in N. latifolia aqueous (NLA) and ethanol (NLE) leaf extracts were identified using GC-MS. DPP-IV model optimization and molecular docking of the identified compounds/standard inhibitors in the binding pocket was simulated. Drug-likeness, pharmacokinetic and pharmacodynamic properties of promising docked leads were also predicted. Results showed the presence of 50 phytocompounds in NL extracts of which only 2-O-p-methylphenyl-1-thio-ß-d-glucoside, 3-tosylsedoheptulose, 4-benzyloxy-6-hydroxymethyl-tetrahydropyran-2,3,5-triol and vitamin E exhibited comparable or better binding iGEMDOCK and AutoDock Vina scores than the clinically prescribed standards. These four compounds exhibited promising drug-likeness as well as absorption, distribution, metabolism, excretion and toxicity (ADMET) properties suggesting their candidature as novel leads for developing DPP-IV inhibitors.

GC-MS Analysis and Inhibitory Evaluation of Terminalia catappa Leaf Extracts on Major Enzymes Linked to Diabetes.

Terminalia catappa leaves are used in managing both diabetes mellitus and its complications in Southwest Nigeria. However, its inhibitory activity on enzymes implicated in diabetes is not very clear. This study investigated the in vitro inhibitory properties and mode of inhibition of T. catappa leaf extracts on enzymes associated with diabetes. The study also identified some bioactive compounds as well as their molecular interaction in the binding pocket of these enzymes. Standard enzyme inhibition and kinetics assays were performed to determine the inhibitory effects of aqueous extract (TCA) and ethanol extract (TCE) of T. catappa leaves on α-glucosidase and α-amylase activities. The phytoconstituents of TCA and TCE were determined using GC-MS. Molecular docking of the phytocompounds was performed using Autodock Vina. TCA and TCE were the most potent inhibitors of α-glucosidase (IC50 = 3.28 ± 0.47 mg/mL) and α-amylase (IC50 = 0.24 ± 0.08 mg/mL), respectively. Both extracts displayed a mixed mode of inhibition on α-amylase activity, while mixed and noncompetitive modes of inhibition were demonstrated by TCA and TCE, respectively, on α-glucosidase activity. The GC-MS analytic chromatogram revealed the presence of 24 and 22 compounds in TCE and TCA, respectively, which were identified mainly as phenolic compounds, terpenes/terpenoids, fatty acids, and other phytochemicals. The selected compounds exhibited favourable interactions with the enzymes compared with acarbose. Overall, the inhibitory effect of T. catappa on α-amylase and α-glucosidase may be ascribed to the synergistic action of its rich phenolic and terpene composition giving credence to the hypoglycaemic nature of T. catappa leaves.

Potential Anti-Cancer Flavonoids Isolated From Caesalpinia bonduc Young Twigs and Leaves: Molecular Docking and In Silico Studies.

Tyrosine kinase (TK), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are important cancer therapeutic target proteins. Based on reported anti-cancer and cytotoxic activities of Caesalpinia bonduc, this study isolated phytochemicals from young twigs and leaves of C bonduc and identified the interaction between them and cancer target proteins (TK, VEGF, and MMP) in silico. AutoDock Vina, iGEMDOCK, and analysis of pharmacokinetic and pharmacodynamic properties of the isolated bioactives as therapeutic molecules were performed. Seven phytochemicals (7-hydroxy-4'-methoxy-3,11-dehydrohomoisoflavanone, 4,4'-dihydroxy-2'-methoxy-chalcone, 7,4'-dihydroxy-3,11-dehydrohomoisoflavanone, luteolin, quercetin-3-methyl, kaempferol-3-O-ß-d-xylopyranoside and kaempferol-3-O-α-l-rhamnopyranosyl-(1 → 2)-ß-D-xylopyranoside) were isolated. Molecular docking analysis showed that the phytochemicals displayed strong interactions with the proteins compared with their respective drug inhibitors. Pharmacokinetic and pharmacodynamic properties of the compounds were promising suggesting that they can be developed as putative lead compounds for developing new anti-cancer drugs.

The interplay of post-translational modification and gene therapy.

Several proteins interact either to activate or repress the expression of other genes during transcription. Based on the impact of these activities, the proteins can be classified into readers, modifier writers, and modifier erasers depending on whether histone marks are read, added, or removed, respectively, from a specific amino acid. Transcription is controlled by dynamic epigenetic marks with serious health implications in certain complex diseases, whose understanding may be useful in gene therapy. This work highlights traditional and current advances in post-translational modifications with relevance to gene therapy delivery. We report that enhanced understanding of epigenetic machinery provides clues to functional implication of certain genes/gene products and may facilitate transition toward revision of our clinical treatment procedure with effective fortification of gene therapy delivery.

Report: Cytotoxic flavonoids from the young twigs and leaves of Caesalpinia bonduc (Linn) Roxb.

The extraction, fractionation and recognition of flavonoids from the ethanolic extract of young twigs and leaves of C. bonduc were carried out. In addition, cytotoxic study of the flavonoids on two cancer cell lines, BGC-823 and HeLa was carried our using sulphorhodamine B assay. Seven flavonoids, six of which are being reported for the first time in this plant, were isolated. Their structures were identified by MS and NMR spectroscopic methods. Petroleum ether, ethyl acetate and water fractions exhibited moderate cytotoxic activity against HeLa cells. Five compounds showed cytotoxic activity against HeLa cell in comparison with Paclitaxel, while only one compound showed a good degree of cytotoxic activity against BGC-823 cell in comparison to Paclitaxel. The results obtained showed a structure - activity relationship.