The significance of persisters in tuberculosis drug discovery: Exploring the potential of targeting the glyoxylate shunt pathway.

The significant challenge in confronting TB eradication is the discursive treatment that results in the disease reactivation, patient non compliance and drug resistance. The presently available drug regimen for TB largely targets the active bacilli and thus remains inadequate against the dormant or persistent subpopulation of Mtb that results in latent TB affecting a quarter of the global population. The crucial pathways that are particularly essential for the survival of dormant Mtb demand better apprehension. Novel drugs are needed to specifically address these persisters in order to enhance treatment effectiveness. Among such pathways, the glyoxylate bypass plays a critical role in the persistence and latent infection of Mtb, making it a promising target for drug development in recent years. In this review, we have compiled the attributes of bacterial subpopulations liable for latent TB and the pathways indispensable for their survival. Specifically, we delve into the glyoxylate shunt pathway and its key enzymes as potential drug targets.

Hydroxycitric acid prevents hyperoxaluric-induced nephrolithiasis and oxidative stress via activation of the Nrf2/Keap1 signaling pathway.

Nephrolithiasis is a common and frequently-occurring disease in the urinary system with high recurrence. The present study aimed to explore the protective effect and underlying mechanism of hydroxycitric acid (HCA) in hyperoxaluria-induced nephrolithiasis in vitro and in vivo. Crystal deposition and pathophysiological injury in rat models of glyoxylate-induced nephrolithiasis were examined using H&E staining. Cell models of nephrolithiasis were established by oxalate-treated renal tubular epithelial cells. The levels of oxidative stress indexes were determined by ELISA kits. Cell proliferation in vivo and in vitro was evaluated using a cell counting kit-8 (CCK-8) assay and Ki-67 cell proliferation detection kit. Cell apoptosis was measured by flow cytometry and TUNEL staining. The protein levels were examined by western blotting. Our results showed that HCA administration significantly reduced crystal deposition and kidney injury induced by glyoxylate. HCA also alleviated oxidative stress via upregulating the antioxidant enzyme activities of superoxide dismutase (SOD) and catalase (CAT) and reducing the malondialdehyde (MDA) content. Moreover, HCA treatment promoted cell proliferation and inhibited apoptosis of renal tubular epithelial cells exposed to hyperoxaluria. Of note, Nrf2 activator dimethyl fumarate (DMF) exerted the same beneficial effects as HCA in nephrolithiasis. Mechanistically, HCA prevented crystal deposition and oxidative stress induced by hyperoxaluria through targeting the Nrf2/Keap1 antioxidant defense pathway, while knockdown of Nrf2 significantly abrogated these effects. Taken together, HCA exhibited antioxidation and anti-apoptosis activities in nephrolithiasis induced by hyperoxaluria via activating Nrf2/Keap1 pathway, suggesting that it may be an effective therapeutic agent for the prevention and treatment of nephrolithiasis.

Intramuscular administration of glyoxylate rescues swine from lethal cyanide poisoning and ameliorates the biochemical sequalae of cyanide intoxication.

Cyanide-a fast-acting poison-is easy to obtain given its widespread use in manufacturing industries. It is a high-threat chemical agent that poses a risk of occupational exposure in addition to being a terrorist agent. FDA-approved cyanide antidotes must be given intravenously, which is not practical in a mass casualty setting due to the time and skill required to obtain intravenous access. Glyoxylate is an endogenous metabolite that binds cyanide and reverses cyanide-induced redox imbalances independent of chelation. Efficacy and biochemical mechanistic studies in an FDA-approved preclinical animal model have not been reported. Therefore, in a swine model of cyanide poisoning, we evaluated the efficacy of intramuscular glyoxylate on clinical, metabolic, and biochemical endpoints. Animals were instrumented for continuous hemodynamic monitoring and infused with potassium cyanide. Following cyanide-induced apnea, saline control or glyoxylate was administered intramuscularly. Throughout the study, serial blood samples were collected for pharmacokinetic, metabolite, and biochemical studies, in addition, vital signs, hemodynamic parameters, and laboratory values were measured. Survival in glyoxylate-treated animals was 83% compared with 12% in saline-treated control animals (p < .01). Glyoxylate treatment improved physiological parameters including pulse oximetry, arterial oxygenation, respiration, and pH. In addition, levels of citric acid cycle metabolites returned to baseline levels by the end of the study. Moreover, glyoxylate exerted distinct effects on redox balance as compared with a cyanide-chelating countermeasure. In our preclinical swine model of lethal cyanide poisoning, intramuscular administration of the endogenous metabolite glyoxylate improved survival and clinical outcomes, and ameliorated the biochemical effects of cyanide.

Prophylaxis and therapeutic effects of raspberry (Rubus idaeus) on renal stone formation in Balb/c mice.

PURPOSE: To evaluate the prophylactic potential of herbal decoction from Rubus idaeus, a medicinal plant widely used in the Middle East to treat kidney stones, by assessing the effect of administration in experimentally induced calcium oxalate (CaOx) nephrolithiasis in mice. MATERIALS AND METHODS: This study was based on administration of glyoxylate and/or herbal treatments simultaneously for 12 days, followed by histological and biochemical tests. Group I was used as a negative control. Group II was only given daily intra-abdominal injection of glyoxylate (80 mg/Kg). Group III and IV were given 100 mg/kg/day and 200 mg/kg/day of aqueous extract of R. idaeus by gavage, respectively in addition to glyoxylate injection. To examine the effect of anti-oxidants on hyperoxaluria-induced changes in kidney, the enzymatic and non-enzymatic anti-oxidant levels were assessed. RESULTS: Significant reductions were obtained in the urinary oxalate, calcium and phosphorus values in the herbal-treated groups relative to untreated animals while creatinine excretion increased. Serum oxalate, calcium and creatinine were significantly reduced, while phosphorus was not significantly changed. Kidney content of calcium was higher in the untreated group. Mice in treated groups at 12 days had significantly more superoxide dismutase, catalase, glutathione reductase (GSH) and G6PD activities than the untreated group. Hyperoxaluria-induced generation of malondialdehyde (MDA) and protein carbonyls was significantly prevented in the treated groups. R. idaeus had a significantly high content of vitamin E in the herbal treated groups. The histology showed more CaOx deposition in the kidneys of untreated animals. CONCLUSION: Rubus idaeus has an impressive prophylactic effect on CaOx stones in nephrolithic mice. There is a possible role of lipid peroxidation in CaOx stone formation which may has a relationship with the major risk factors in urine including oxalate, calcium, phosphorus and MDA. Further experimental studies are required to elucidate the chemical constituents of the active ingredients of this interesting plant.

Prophylaxis and therapeutic effects of raspberry (Rubus idaeus) on renal stone formation in Balb/c mice

PURPOSE: To evaluate the prophylactic potential of herbal decoction from Rubus idaeus, a medicinal plant widely used in the Middle East to treat kidney stones, by assessing the effect of administration in experimentally induced calcium oxalate (CaOx) nephrolithiasis in mice. MATERIALS AND METHODS: This study was based on administration of glyoxylate and/or herbal treatments simultaneously for 12 days, followed by histological and biochemical tests. Group I was used as a negative control. Group II was only given daily intra-abdominal injection of glyoxylate (80 mg/Kg). Group III and IV were given 100 mg/kg/day and 200 mg/kg/day of aqueous extract of R. idaeus by gavage, respectively in addition to glyoxylate injection. To examine the effect of anti-oxidants on hyperoxaluria-induced changes in kidney, the enzymatic and non-enzymatic anti-oxidant levels were assessed. RESULTS: Significant reductions were obtained in the urinary oxalate, calcium and phosphorus values in the herbal-treated groups relative to untreated animals while creatinine excretion increased. Serum oxalate, calcium and creatinine were significantly reduced, while phosphorus was not significantly changed. Kidney content of calcium was higher in the untreated group. Mice in treated groups at 12 days had significantly more superoxide dismutase, catalase, glutathione reductase (GSH) and G6PD activities than the untreated group. Hyperoxaluria-induced generation of malondialdehyde (MDA) and protein carbonyls was significantly prevented in the treated groups. R. idaeus had a significantly high content of vitamin E in the herbal treated groups. The histology showed more CaOx deposition in the kidneys of untreated animals. CONCLUSION: Rubus idaeus has an impressive prophylactic effect on CaOx stones in nephrolithic mice. There is a possible role of lipid peroxidation in CaOx stone formation which may has a relationship with the major risk factors in urine including oxalate, calcium, phosphorus and MDA. Further experimental studies are required to elucidate the chemical constituents of the active ingredients of this interesting plant.

Piridoxilate-associated nephrocalcinosis: a new form of chronic oxalate nephropathy.

Piridoxilate is an association of glyoxylic acid and pyridoxine in which pyridoxine is supposed to facilitate in vivo transformation of glyoxylic acid to glycine rather than to oxalic acid. However, it has recently been shown that long-term treatment with piridoxilate may result in overproduction of oxalic acid and in calcium oxalate nephrolithiasis. We report a patient in whom piridoxilate induced both oxalate nephrolithiasis and chronic oxalate nephropathy with renal insufficiency, an association that has not been previously described. Therefore, piridoxilate should be added to the list of chemicals responsible for chronic oxalate nephropathy.

[Effect of antihypoxic agents on the blood supply and function of the intact and ischemic myocardium]. / O vliianii nekotorykh antigipoksantov na krovosnabzhenie i funktsional'noe sostoianie intaktnogo i ishemizirovannogo miokarda.

It was established in experiments on cats anesthesized with nembutal that the antihypoxic drugs sodium hydroxybutyrate, piracetam and glio-6 increased blood outflow from the coronary heart sinus. This was accompanied by a rise in the content of oxyhemoglobin in coronary venous blood. Sodium hydroxybutyrate was shown to exhibit the highest and most prolonged effect. On the contrary, the effect of glio-6 did not last long. All the antihypoxic drugs enhanced myocardial contractility without changing or slightly reducing the pulse rate. In experimental acute coronary circulation failure (temporary occlusion of the coronary artery with the recording of the epicardial electrogram), sodium hydroxybutyrate and, to a lesser degree, piracetam were discovered to improve the function of the focus of myocardial ischemia. A single administration of glio-6 did not affect the focus of acute myocardial ischemia.

Spontaneous and drug-induced remission of alcoholic organic brain syndrome: clinical, psychometric, and neurophysiological studies.

The spontaneous and drug-induced remission of alcoholic organic brain syndrome was studied in a double-blind, placebo-controlled trial. Forty patients with alcoholic organic brain syndrome (OBS) were randomly assigned to a 6-week treatment with either placebo or piridoxilate, a reciprocal salt between two stereoisomers of the glyoxylic acid-substituted piridoxine. Clinical, psychometric, and computer-assisted spectral analyses of the electroencephalogram (EEG) were carried out in weeks 0, 2, 4, and 6. Piridoxale-5-phosphate (PLP) blood level determination and laboratory investigations were performed before therapy and also in weeks 4 and 6. Both groups of patients demonstrated significant clinical improvement over 6 weeks of treatment, but the improvement in the piridoxilate-treated group was significantly greater than that in the placebo group. This conclusion was also confirmed by psychometric tests demonstrating a greater improvement in attention, concentration, attention variability, tapping, visual and numerical memory, and aftereffect (Archimedean spiral) in the piridoxilate than in the placebo group. Spectral analysis of the EEG showed an increase in alpha and a decrease in fast beta activities in both groups, while delta activity was attenuated only in the piridoxilate-treated group. The latter was found to be significantly correlated with the improvement in psychopathology. The present data confirm previous predictions about the encephalotropic and psychotropic properties of piridoxilate; these predictions were based on pharmaco-EEG trials in the elderly that suggested vigilance-improving qualities of piridoxilate. The reversible alcoholic OBS appears to be a suitable model for the assessment of therapeutic efficacy of nootropic drugs.

[Protective effect of pyridoxilate on the hypoxic myocardium. Experimental studies]. / Effet protecteur du piridoxilate sur le myocarde hypoxique. Etudes expérimentales.

The protective action of piridoxilate on hypoxic myocardium has been studied on rats in acute hypoxia (isolated heart, perfused with a non-oxygenated solution) and in prolonged hypoxia (3 days at high [3454 m] altitude). Piridoxilate maintained a higher ATP level with a much lower production of lactate. The mechanisms of action of piridoxilate are probably fairly similar to those of Na dichloracetate.