Inhibitor of the non-structural protein 2 protease shows promising efficacy in mouse models of chikungunya.

Chikungunya virus (CHIKV) is responsible for the most endemic alphavirus infections called Chikungunya. The endemicity of Chikungunya has increased over the past two decades, and it is a pathogen with pandemic potential. There is currently no approved direct-acting antiviral to treat the disease. As part of our antiviral drug discovery program focused on alphaviruses and the non-structural protein 2 protease, we discovered that J12 and J13 can inhibit CHIKV nsP2 protease and block the replication of CHIKV in cell cultures. Both compounds are metabolically stable to human liver microsomal and S9 enzymes. J13 has excellent oral bioavailability in pharmacokinetics studies in mice and ameliorated Chikungunya symptoms in preliminary efficacy studies in mice. J13 exhibited an excellent safety profile in in vitro safety pharmacology and off-target screening assays, making J13 and its analogs good candidates for drug development against Chikungunya.

Nrf2-Mediated Antioxidant Response and Drug Efflux Transporters Upregulation as Possible Mechanisms of Resistance in Photodynamic Therapy of Cancers.

Photodynamic therapy (PDT) is a groundbreaking approach involving the induction of cytotoxic reactive oxygen species (ROS) within tumors through visible light activation of photosensitizers (PS) in the presence of molecular oxygen. This innovative therapy has demonstrated success in treating various cancers. While PDT proves highly effective in most solid tumors, there are indications that certain cancers exhibit resistance, and some initially responsive cancers may develop intrinsic or acquired resistance to PDT. The molecular mechanisms underlying this resistance are not fully understood. Recent evidence suggests that, akin to other traditional cancer treatments, the activation of survival pathways, such as the KEAP1/Nrf2 signaling pathway, is emerging as an important mechanism of post-PDT resistance in many cancers. This article explores the dual role of Nrf2, highlighting evidence linking aberrant Nrf2 expression to treatment resistance across a range of cancers. Additionally, it delves into the specific role of Nrf2 in the context of photodynamic therapy for cancers, emphasizing evidence that suggests Nrf2-mediated upregulation of antioxidant responses and induction of drug efflux transporters are potential mechanisms of resistance to PDT in diverse cancer types. Therefore, understanding the specific role(s) of Nrf2 in PDT resistance may pave the way for the development of more effective cancer treatments using PDT.

Inhibitors of the Structural and Nonstructural Proteins of Alphaviruses.

The Alphavirus genus includes viruses that cause encephalitis due to neuroinvasion and viruses that cause arthritis due to acute and chronic inflammation. There is no approved therapeutic for alphavirus infections, but significant efforts are ongoing, more so in recent years, to develop vaccines and therapeutics for alphavirus infections. This review article highlights some of the major advances made so far to identify small molecules that can selectively target the structural and the nonstructural proteins in alphaviruses with the expectation that persistent investigation of an increasingly expanding chemical space through a variety of structure-based design and high-throughput screening strategies will yield candidate drugs for clinical studies. While most of the works discussed are still in the early discovery to lead optimization stages, promising avenues remain for drug development against this family of viruses.

Isolation, characterization and modulatory potentials of ß-stigmasterol, ergosterol and xylopic acid from Anchomanes difformis on mitochondrial permeability transition pore in vitro.

Objective: Secondary metabolites and polyphenolic compounds from medicinal plants have been demonstrated to have multiple biological functions with promising research and development prospects. This study examined the effect of ß-stigmasterol (with ergosterol) and xylopic acid isolated from Anchomanes difformis on liver mitochondrial permeability transition pore (mPTP). Methods: The compounds were isolated by vacuum liquid chromatography. Mitochondrial swelling was assessed as changes in absorbance under succinate-energized conditions. Results: 1H and 13C NMR spectroscopic elucidation of the isolates affirmed the presence of ß-stigmasterol with ergosterol (1:0.3) and xylopic acid. The isolates reversed the increase in lipid peroxidation and inhibited the opening of mitochondrial permeability transition pores caused by calcium and glucose. Pharmacological inhibition of mPTP offers a promising therapeutic target for the treatment of mitochondrial-associated disorders. Conclusion: Reduction in the activity of calcium ATPase and the expression of Caspase-3 and -9 were observed, suggesting that they could play a role in protecting physicochemical properties of membrane bilayers from free radical-induced severe cellular damage and be useful in the management of diseases where much apoptosis occurs.

Justicia carnea extracts ameliorated hepatocellular damage in streptozotocin-induced type 1 diabetic male rats via decrease in oxidative stress, inflammation and increasing other risk markers.

IntroductionDiabetes mellitus is still a raging disease not fully subdued globally, especially in Africa. Our study aims to evaluate the anti-diabetic potentials of Justicia carnea extracts [crude (JCC), free (JFP) and bound phenol (JBP) fractions], in streptozotocin (STZ)-induced type-1 diabetes in male albino rats.Materials and MethodsAbout thirty (30) animals were induced for type 1 diabetes with STZ; thereafter, treatment began for 14 days, after which the animals were euthanized, blood/serum was collected, the liver was removed and divided into two portions, for biochemical and histopathological analyses. Standard procedures were used to evaluate the liver biomarkers, like alanine transaminase (ALT), fructose-1,6-bisphosphatase, glucose-6- phosphatase, hexokinase activities, albumin, bilirubin, hepatic glucose concentrations; antioxidant status and pro- and anti-inflammatory cytokines were similarly assessed.ResultsThese results revealed that the extracts ameliorated the harmful effects of STZ-induced diabetes in the liver by enhancing the activities of liver-based biomarkers, reducing the concentrations of pro-inflammatory cytokines and increasing the anti-inflammatory cytokine.DiscussionThe results agreed with previous research, and the free phenol fraction showed excellent results compared to othersConclusionThese suggested that J. carnea could serve as an alternative remedy in ameliorating liver complications linked to oxidative damage and inflammation in STZ-induced type-1 diabetes.

Modulatory Potential of Citrus sinensis and Moringa oleifera Extracts and Epiphytes on Rat Liver Mitochondrial Permeability Transition Pore.

BACKGROUND: Bioactive agents from medicinal and dietary plants have been reported to modulate the mitochondrial membrane permeability transition pores. OBJECTIVE: This study investigated the in vitro effects of C. sinensis (CSE) and M. oleifera (MOE) methanol leaf extracts and their epiphytes (CEP and MEP) on mitochondria permeability transition pores. METHODS: In vitro antioxidant activities of the extracts were determined using standard procedures and quantification of polyphenolic compounds in the extract was done using HPLC-DAD. Opening of the mitochondrial permeability transition pores was assessed as mitochondrial swelling and observed spectrophotometrically as changes in absorbance under succinate-energized conditions. Cytochrome c release was also assessed spectrophotometrically. RESULTS: From the results, CSE, MOE, CEP, and MEP inhibited lipid peroxidation and scavenged nitric oxide and DPPH radicals in a concentration-dependent manner. All extracts exhibited greater ferric reducing antioxidant potential. More so, the results showed that CSE, MOE, CEP, and MEP possess the substantive amount of total flavonoids and total phenolics. CSE and MOE had higher total flavonoids and total phenolic content when compared with the epiphytes. HPLC-DAD results revealed Tangeretin as the most abundant in CSE; Eriocitrin in citrus epiphytes; Moringine in MOE and Flavones in moringa epiphytes. All extracts inhibited calcium-induced opening of the pores in a concentration- dependent manner, with C. sinensis leaf extract (CSE) and moringa epiphyte (MEP) being the most potent in this regard with no significant release of cytochrome c at all concentrations. CONCLUSION: The results suggest that CSE and MEP have bioactive agents, which could be useful in the management of diseases where too much apoptosis occurs characterized by excessive tissue wastage, such as neurodegenerative conditions.

Kigelia africana (Lam.) Benth leaf extract inhibits rat brain and liver mitochondrial membrane permeability transition pore opening.

The effect of Kigelia africana on mitochondrial membrane permeability transition has not been explored. In this study, the effect of a solvent fraction of Kigelia africana leaf extract on mitochondrial membrane permeability transition of rat brain and liver was evaluated. A methanol extract of K. africana leaves was fractionated into different solvents by vacuum liquid chromatography and following preliminary screening, the dichloromethane:ethylacetate (1:1) fraction was selected for further assays. Constituent phytochemicals in the fraction were revealed by thin-layer chromatography and further purification was carried out to characterize the compounds. Brain and liver mitochondria were isolated and used for mitochondrial membrane permeability transition and adenosine triphosphatase assays. Exogenous Ca2+ and Al3+ were used to trigger the mitochondrial membrane permeability transition opening. Physicochemical properties revealed by thin-layer chromatography showed that the isolated compounds were flavonoids. The extract inhibited mitochondrial membrane permeability transition opening in the presence and absence of triggering agents in brain and liver mitochondria. It also inhibited mitochondrial lipid peroxidation and adenosine triphosphatase activity. These results suggest that the extract can limit the rate of apoptosis via inhibition of mitochondrial membrane permeability transition which is pivotal to the mitochondrial apoptotic pathway and is an important therapeutic target in some pathological conditions.