Oxalate Levels Research Articles

Lumasiran for primary hyperoxaluria type 1: What we have learned?

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive genetic disorder caused by mutations in the AGXT gene. The hepatic peroxisomal enzyme alanine glyoxylate aminotransferase (AGT) defects encoded by the AGXT gene increase oxalate production, resulting in nephrocalcinosis, nephrolithiasis, chronic kidney disease, and kidney failure. Traditional pharmacological treatments for PH1 are limited. At present, the treatment direction of PH1 is mainly targeted therapy which refer to a method that targeting the liver to block the pathway of the production of oxalate. Lumasiran (OxlumoTM, developed by Alnylam Pharmaceuticals), an investigational RNA interference (RNAi) therapeutic agent, is the first drug approved for the treatment of PH1, which was officially approved by the US Food and Drug Administration and the European Union in November 2020. It is also the only drug that has been shown to decrease harmful oxalate. Currently, there are 5 keys completed and ongoing clinical trials of lumasiran in PH1. Through the three phase III trials that completed the primary analysis period, lumasiran has been shown to be effective in reducing oxalate levels in urine and plasma in different age groups, such as children, adults, and patients with advanced kidney disease, including those on hemodialysis. In addition to clinical trials, cases of lumasiran treatment for PH1 have been reported in small infants, twin infants, and children diagnosed with PH1 after kidney transplantation. These reports confirm the effectiveness and safety of lumasiran. All adverse events were of mild to moderate severity, with the most common being mild, transient injection-site reactions. No deaths or severe adverse events were reported. This article reviews PH1 and lumasiran which is the only approved therapeutic drug, and provide new options and hope for the treatment of PH1.

The effect of Myrtus communis L. extract on nephrolithiasis model in rats.

Nephrolithiasis is a common urological disease that can lead to renal failure. Oxidative stress has been shown to be a contributing factor for nephrolithiasis and many agents have been studied to prevent and treat oxidative stress-related nephrolithiasis and renal damage. Myrtus communis (MC) extract has been shown to be an important antioxidant in different animal models. In this study, MC extract was administered preventively or therapeutically to rats with kidney stones, and its effectiveness was investigated. Wistar albino rats were divided into four groups (n=8); control (C), ethylene glycol (EG), EG+preventive MC, and EG+curative MC groups. The nephrolithiasis model was created by adding 0.75% EG to drinking water for 8 weeks. Ultimately, 24-hour urine was collected to measure calcium, citrate, and creatinine levels. After decapitation, kidney tissues were harvested for histological analyses, measurement of osteopontin and 8-hydroxydeoxyguanosine (8-OHdG) levels, and N-acetyl-β-glucosaminidase (NAG), myeloperoxidase (MPO) and caspase-3 activities. In 24-hour urine samples, calcium, citrate and creatinine levels were decreased in the EG group, while oxalate levels were increased and in treatment groups these parameters returned to control levels. MPO, 8-OHdG, caspase-3 and NAG activity were significantly increased in tissue and these changes were reversed in both MC groups. Histological findings also supported the biochemical parameters. MC can reduce oxidative stress and histopathological changes in kidney tissues in rat nephrolithiasis model when used as either a preventive or therapeutic agent. If supported with further clinical trials, MC might have clinical implications in preventing oxidative renal cell injury and ultimately kidney stone formation.

Effect of Soaking and Salt-Water Blanching on the Proximate, Antinutrients and Amino Acid Profile Composition of Cream Coloured Pigeon Pea Flours

The study was on the effect of processing: soaking and salt-water blanching and cooking on the proximate, anti-nutrient and amino-acid composition of cream coloured pigeon pea seeds’ flours. The proximate composition analysis showed significant (p>0.05) differences between the values obtained for crude protein, ash, fat, crude fibre, carbohydrates and moisture, in the raw/untreated and the processed pigeon pea. Healthy cleaned pigeon pea seeds (2.5kg) were divided into five portions of 500 g each. They were subjected to five different processing methods and coded AOP, BXY, CZK, DRN and EVT respectively. AOP represented the untreated flour; BXY represented salted and 1h boiled pigeon pea flour; CZK represented salted and 2h boiled pigeon pea flour; DRN represented 24h soaked and 1h boiled pigeon pea flour while EVT represented 2h boiled pigeon pea flour sample. The flours’ crude protein contents ranged from 19.54 to 21.68%, crude fat ranged from 2.40 to 3.96%; ash ranged from 3.48 to 5.20 %; fibre ranged from 9.45 to 10.19%, moisture ranged from 4.70 to 6.46 % while carbohydrates ranged from 50.48 to 57.49%. In the anti-nutrients’ assays, processing significantly reduced the levels of oxalate, saponins, alkaloids, tannins, cyanide and phytate. In addition to the significant differences, straight cooking without salt blanching or soaking yielded the highest levels of leucine, lysine, phenylaline, tryptophan, valine, methionine and histidine, 7 out of the 8 essential amino acids. The result of essential amino acid indices of the sample flours revealed that the flours are of good protein quality. This result also showed that straight-cooking yielded highest crude protein and highest levels of the essential amino acids. Also, processing generally lowered the levels of anti-nutrients in the pigeon pea seeds’ flours, thus making them safer for consumption. Salt-blanching yielded more softening and pastry product.

Potential Role of Lactobacillus and Bifidobacterium for Preventing Kidney Stones.

A probiotic is a living microorganism that promotes host health when grown under appropriate conditions. Kidney stones are one of the universal agonizing diseases that have increased dramatically in recent years. One of the causes of this disease is hyperoxaluria (HOU), which is known to be an important factor in the formation of oxalate stones and is manifested by high levels of oxalate in the urine. In addition, about 80% of kidney stones contain oxalate, and decomposition of this material by microbes is one way to dispose of it. Therefore, we examined a bacterial mixture containing Lactobacillus plantarum, Lactobacillus casei, Lactobacillus acidophilus, and Bifidobacterium longum to prevent of oxalate production in Wistar rats with kidney stones. We divided the rats into 6 groups defined in the method. The results of this study clearly show a decrease in urinary oxalate levels by exogenous means by L. plantarum, L. casei, L. acidophilus, and B. longum at the beginning of the experiment. Therefore, these bacteria can be used to control and prevent the formation of kidney stones. However, further studies should be conducted on the effects of these bacteria, and it is recommended to identify the gene responsible for the degradation of oxalate in order to develop a new probiotic.

Multiplex gene editing reduces oxalate production in primary hyperoxaluria type 1.

Targeting key enzymes that generate oxalate precursors or substrates is an alternative strategy to eliminate primary hyperoxaluria type I (PH1), the most common and life-threatening type of primary hyperoxaluria. The compact Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) from the Prevotella and Francisella 1 (Cpf1) protein simplifies multiplex gene editing and allows for all-in-one adeno-associated virus (AAV) delivery. We hypothesized that the multiplex capabilities of the Cpf1 system could help minimize oxalate formation in PH1 by simultaneously targeting the hepatic hydroxyacid oxidase 1 ( Hao1) and lactate dehydrogenase A ( Ldha) genes. Study cohorts included treated PH1 rats ( Agxt Q84X rats injected with AAV-AsCpf1 at 7 days of age), phosphate-buffered saline (PBS)-injected PH1 rats, untreated PH1 rats, and age-matched wild-type (WT) rats. The most efficient and specific CRISPR RNA (crRNA) pairs targeting the rat Hao1 and Ldha genes were initially screened ex vivo. In vivo experiments demonstrated efficient genome editing of the Hao1 and Ldha genes, primarily resulting in small deletions. This resulted in decreased transcription and translational expression of Hao1 and Ldha. Treatment significantly reduced urine oxalate levels, reduced kidney damage, and alleviated nephrocalcinosis in rats with PH1. No liver toxicity, ex-liver genome editing, or obvious off-target effects were detected. We demonstrated the AAV-AsCpf1 system can target multiple genes and rescue the pathogenic phenotype in PH1, serving as a proof-of-concept for the development of multiplex genome editing-based gene therapy.

Studies on Nutritional Profile and Mineral Bioavailability of some Solanum Species Consumed as Fruits in Ekiti State, Nigeria

African eggplants are highly valued constituents of the Nigerian food. However, their nutritional potentials have not been fully tapped due to inadequate information on their nutritional and anti-nutritional qualities. This present study investigated the proximate, minerals, anti-nutrient contents as well as the estimation of mineral ratios and Mineral Safety Index of four selected edible solanum species namely, Solanum anguivi, S. gilo, S. menalogena and S. aethiopicum. The proximate contents (%) ranged from 4.19-5.46 (moisture content), 1.71-2.49 (crude fat), 4.57-5.45 (crude ash), 3.76-4.93 (crude protein), 5.20-6.30 (crude fiber) and 77.14-78.58 (carbohydrate). The solanum species were good sources of energy with total metabolizable energy of 1.458MJ-1.484MJ. The four solanum species contained high K, Ca, Mg, low Fe, Mn, Zn and Cu, while amount of Cd, Ni and Pb were very low. The mineral ratios of K/Na, Ca/Mg, Ca/K, Zn/Cu and [K/(Ca+Mg)] were below the minimum good ratios levels of 1.0, 4.17, 4.0, 8.0 and 2.2 respectively which are good for man. The anti-nutrient contents revealed low phytate, oxalate and cyanide levels. The calculated Phytate/Zn, Phytate/Ca and Oxalate/Ca were lower than the threshold levels and would support absorption and bioavailability of Zn and Ca in the samples while that of Phytate/Fe was above the critical value and this indicates unavailability of iron in these eggplant fruits. The mineral differences observed showed that S. menalogena and S. aethiopicum had greater minerals while the Mineral Safety Index results revealed that the body could not be overloaded with any of the minerals investigated. The eggplants are rich in fiber, ash, carbohydrate and minerals with moderate protein. The low level of the anti-nutrient is good and poses no deleterious effect when consumed. The eggplants have nutritional health benefits; hence, their consumption should be encouraged to address food insecurity in Nigeria

Reduksi Kadar Oksalat dalam Umbi Porang Menggunakan Variasi Konsentrasi, Suhu dan Lama Perendaman dalam Larutan NaCl dan Akuades

Porang tubers contain compounds that have been widely used in health and industry, namely glucomannan. In addition, porang tubers also contain oxalate compounds that cause itching and burning when consumed directly. Porang tubers that have been cut with a size of 2x2 cm and a thickness of 0.5 cm are soaked using a solution of NaCl and distilled water. Immersion is used to reduce oxalate levels with variations in concentration, temperature and immersion time. Soaking porang tubers in either NaCl or distilled water can reduce oxalate levels. NaCl solution with a concentration of 7% has the highest % decrease in oxalate levels, which is 69.83%. NaCl solution has a better ability to reduce oxalate levels compared to distilled water. The immersion time of porang tubers with NaCl solution for 45 minutes had lower levels of oxalate than using distilled water for 60 minutes, namely 1.0809% (w/w). Porang tubers soaked in NaCl solution at a temperature of 60°C obtained a higher % decrease in oxalate levels compared to distilled water at the same temperature, which was 55.58%.

Gut microbe‐modulated metabolites are longitudinally associated with higher neurodegeneration biomarkers in cerebrospinal fluid (CSF)

AbstractBackgroundGut bacterial metabolites in circulation and postmortem brain tissue differ in abundance between cognitively unimpaired (CU) and Alzheimer’s disease (AD) individuals. Furthermore, in mice chronic injection of bacterial components exacerbates AD pathology. In CSF, we found the microbially‐produced trimethylamine‐N‐oxide was linked to AD and neurodegeneration biomarkers. However, the broader extent to which microbe‐modulated metabolites relate to AD and neurodegeneration is unknown. We tested the hypothesis that in CSF of non‐demented adults, elevated metabolites would longitudinally associate with higher biomarkers.MethodCSF was collected biannually in the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention studies. Biomarkers of pTau181, Aβ42, tTau, axonal (NfL) and synaptic (neurogranin, α‐synuclein) degeneration were quantified using Elecsys assays (NeuroToolKit robust prototype, Roche Diagnostics). Metabolite relative abundances were quantified via untargeted metabolomics analysis (ultrahigh performance liquid chromatography‐tandem mass spectrometry, Metabolon). A priori literature and database review identified 76 detected microbe‐modulated metabolites. 200 CU participants with two or more analyzed CSF samples were included in statistical analysis (Table 1). For each metabolite‐biomarker pair, multilevel linear growth modeling tested person‐level mean metabolite effects on biomarker slope and intercept, and time‐varying metabolite effects on biomarker intercept (Figure 1). Covariates included age, sex, and APOE risk score; Benjamini‐Hochberg corrections adjusted for Type I error inflation.ResultSeven metabolites were positively associated with biomarker slope or intercept (Table 2). Mean gluconate, glycerate, and oxalate levels were correlated with increased tTau slope, and N‐acetylaspartate, N‐acetylglutamate and cholesterol were correlated with higher a‐synuclein or neurogranin intercepts. Phenol sulfate was linked to tTau and α‐synuclein trajectories. To our knowledge, this is the first study detecting phenol sulfate in human CSF. No metabolites significantly associated with NfL or pTau181/Aβ42.ConclusionIn CSF, participants with higher mean levels of bacteria‐utilized metabolites exhibited accelerated neurodegeneration (tTau). Gluconate is metabolized by Bifidobacterium and Lactobacillus, two genera reduced in AD. Furthermore, the microbially‐produced phenol sulfate predicted greater tTau development and synaptic degeneration. Uremic toxins related to phenol sulfate dysregulate endothelial barriers in the central nervous system and vascular tissues. Additional studies should evaluate microbial metabolites as mediators of gut microbiome‐neurodegeneration relationships, and should determine if they represent modifiable pathways.

The SLC6A19 gene mutation in a young man with hyperglycinuria and nephrolithiasis: a case report and literature review

BackgroundHyperglycinuria is a rare disorder, with few reported cases, caused by either a defect in glycine metabolism or a disturbance in renal glycine reabsorption. Genetic findings of hyperglycinuria are rare and have not previously been reported in Chinese young men.Case presentationA 24-year-old man presented with a compliant of bilateral lumbago for 1 month. Abdominal computed tomography revealed bilateral kidney stones and right upper ureteral dilatation. The 24-h urine analysis showed high urine oxalate levels of 63 mg/day. Analysis of amino acids in urine revealed that his urinary glycine levels were abnormally high (2.38 µmol/mg creatinine). Whole-exome sequencing detected the SLC6A19 variant c.1278 C > T p. (Cys426). Flexible ureteroscopy with holmium laser lithotripsy was conducted twice to remove his bilateral nephrolithiasis. Postoperative stone biochemical composition analysis revealed that the stones were composed of approximately 70% calcium oxalate monohydrate and 30% calcium oxalate dihydrate. The patient was subsequently diagnosed with hyperglycinuria. Three months after the stone surgery, ultrasonography revealed one nodule under the right thyroid lobe during a health checkup. His serum parathyroid hormone (PTH) levels increased to 392.3 pg/mL. Resection of the right parathyroid nodule was performed, and the histopathological examination confirmed right parathyroid adenoma. During the 2-year follow-up period, nephrolithiasis did not relapse, and serum PTH, calcium, and phosphorus levels were normal.ConclusionThe SLC6A19 gene may have been significant in the development of hyperglycinuria in a Chinese young man. Further evaluation for the possibility of a glycine excretion disorder could be considered when encountering nephrolithiasis.

Unraveling correlations between calcium deficiency and spongy tissue in mango fruit flesh

Spongy tissue, as one of internal flesh breakdown in mango fruits, is correlated with calcium (Ca) deficiency, and adversely affects fruit quality and yield worldwide. However, the underlying mechanism causing spongy tissue remains unknown. Here, we explored the effects of Ca deficiency on spongy tissue in a susceptible cultivar, ‘Keitt’, at the physiological and molecular levels. Nutrient analysis showed that flesh with spongy tissue had lower Ca content and higher N/Ca, K/Ca and Mg/Ca rations than healthy fruit flesh. Ca accumulation in the cell wall, especially in chelator-soluble pectin, was elevated due to increased pectin content, lower levels of pectin methylesterification, and increased pectin methylesterase (PME) activity. During spongy tissue development, levels of Ca oxalate (CaOx) and oxalic acid both increased, whereas soluble Ca content decreased in the flesh. Transcriptomic analysis of healthy flesh and flesh with spongy tissue revealed 2054 up-regulated and 996 down-regulated genes. Gene ontology term analysis showed that the up-regulated genes were mainly enriched in functions related to the transmembrane transporter activity, calcium ion binding, and the cell wall. Importantly, up-regulated genes in spongy tissue included five glucuronate 4-epimerase (GAE) genes and two galactosyltransferase (GALT) genes, which involved in pectin synthesis; four PME genes which control pectin demethylesterification; and eight autoinhibited calcium-transporting ATPase (ACA) genes and two vacuole H+/Ca2+ exchanger (CAX) genes which contribute to Ca influx in the vacuole. Our findings illustrate a mechanism by which Ca deficiency leads to spongy tissue, which will contribute to efforts to control this physiological disorder.

Oxalic acid degradation in wood-rotting fungi. Searching for a new source of oxalate oxidase

Oxalate oxidase (EC 1.2.3.4) is an oxalate-decomposing enzyme predominantly found in plants but also described in basidiomycete fungi. In this study, we investigated 23 fungi to determine their capability of oxalic acid degradation. After analyzing their secretomes for the products of the oxalic acid-degrading enzyme activity, three groups were distinguished among the fungi studied. The first group comprised nine fungi classified as oxalate oxidase producers, as their secretome pattern revealed an increase in the hydrogen peroxide concentration, no formic acid, and a reduction in the oxalic acid content. The second group of fungi comprised eight fungi described as oxalate decarboxylase producers characterized by an increase in the formic acid level associated with a decrease in the oxalate content in their secretomes. In the secretomes of the third group of six fungi, no increase in formic acid or hydrogen peroxide contents was observed but a decline in the oxalate level was found. The intracellular activity of OXO in the mycelia of Schizophyllum commune, Trametes hirsuta, Gloeophyllum trabeum, Abortiporus biennis, Cerrena unicolor, Ceriosporopsis mediosetigera, Trametes sanguinea, Ceriporiopsis subvermispora, and Laetiporus sulphureus was confirmed by a spectrophotometric assay.

Antiurolithiatic Activity of Aqueous Extract of Ziziphus lotus on Ethylene Glycol-Induced Lithiasis in Rats

In Morocco, Ziziphus lotus is commonly used as an urolithiatic agent in the traditional medicine. To confirm this effect, an aqueous extract of Ziziphus lotus (AEZL) has been studied in ethylene glycolinduced urolithiasis model of rats. 30 male rats were randomly divided into five groups of six animals each. Group I served as a vehicle control and received distilled water (0.5 ml/100 g p.o.). All remaining groups received calculi inducing treatment for 28 days, comprised of 0.75% v/v ethylene glycol with 1% w/v ammonium chloride in drinking water ad libitum for 3 days followed by only 0.75% v/v ethylene glycol for 25 days. Group II served as lithiatic control and received distilled water (0.5 ml/100 g p.o.). Group III served as curative treatment group and received AEZL at doses of 150 mg/kg from 14th day to 28th day. Group VI served as preventive treatment group and received AEZL at doses of 150 mg/kg from 1st day to 28th day. Group V served as therapeutic and received a drug “Cystone” at dose of 750 mg/kg from 14th day to 28th day. The extract treatment decreased the levels of oxalate and calcium in urine. Crystalluria analysis showed that untreated rats excreted large CaOx monohydrate and few dihydrate crystals while treated animals excreted mostly small CaOx dihydrate crystals. Significant similarity was observed between preventive and therapeutic anti-urolithiatic effect of AEZL and anti-urolithiatic effect of cystone (P<0.001). These results demonstrated that AEZL have an anti-urolithiatic effect with preventive and therapeutic treatments in this experimental condition.

The retinal phenotype in primary hyperoxaluria type 2 and 3

BackgroundThe primary hyperoxalurias (PH1-3) are rare inherited disorders of the glyoxylate metabolism characterized by endogenous overproduction of oxalate. As oxalate cannot be metabolized by humans, oxalate deposits may affect various organs, primarily the kidneys, bones, heart, and eyes. Vision loss induced by severe retinal deposits is commonly seen in infantile PH1; less frequently and milder retinal alterations are found in non-infantile PH1. Retinal disease has not systematically been investigated in patients with PH2 and PH3.MethodsA comprehensive ophthalmic examination was performed in 19 genetically confirmed PH2 (n = 7) and PH3 (n = 12) patients (median age 11 years, range 3–59).ResultsMedian best corrected visual acuity was 20/20. In 18 patients, no retinal oxalate deposits were found. A 30-year-old male with PH2 on maintenance hemodialysis with plasma oxalate (Pox) elevation (> 100 µmol/l; normal < 7.4) demonstrated bilateral drusen-like, hyperreflective deposits which were interpreted as crystallized oxalate. Two siblings of consanguineous parents with PH2 presented with retinal degeneration and vision loss; exome-wide analysis identified a second monogenic disease, NR2E3-associated retinal dystrophy.ConclusionsRetinal disease manifestation in PH2 and PH3 is rare but mild changes can occur at least in PH2-associated kidney failure. Decline in kidney function associated with elevated plasma oxalate levels could increase the risk of systemic oxalosis. Deep phenotyping combined with genomic profiling is vital to differentiate extrarenal disease in multisystem disorders such as PH from independent inherited (retinal) disease.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Nutritional composition of some selected, unprocessed amaranth grain (Amaranthus spp) varieties in Nigeria

The Amaranth grain is highly nutritious, yet it is hardly utilized in Nigeria. This study seeks to evaluate the nutritional composition of the various Amaranth grains available locally within the country. Five identified varieties were obtained from a research institute in Nigeria and a variety from the market in Ondo State, Nigeria. The six varieties were sorted separately and cleaned manually prior to grinding into flour and then subjected to chemical analysis which included proximate content, minerals, and anti-nutritional composition. An investigation of the constituting proximate, minerals and anti-nutritional compositions of the grain flours was conducted, using standard procedures. Proximate composition was determined using the Association of Official Analytical Chemists (AOAC) methods, carbohydrates were determined by difference, energy content was determined using bomb calorimetry model, mineral analysis were done using atomic absorption spectrophotometer and flame photometer while the anti-nutrients were determined using potassium permanganate titration method and spectrophotometrically. The results were analyzed using ANOVA (p ˂ 0.05) which showed significant difference between the moisture content of the market sample and other types (9.50 – 12.13%). Also, the fat and crude fibre contents of Amaranth grain flour ranged from 5.84 to 21.06 % and 0.61 to 2.07 %, respectively. Though the protein contents of the flour samples were not significantly different (14.36 – 16.03%) from each other, the mineral composition (calcium 193.34 – 247.91 mg/100g, magnesium, 65.59 – 73.48 mg/100g, manganese 6.13 – 13.24 mg/100g, sodium 360 – 435 mg/100g) was relatively high. The anti–nutrient composition showed that the varieties were low in phytate and the values ranged from 0.21 –1.74 mg/100g, the oxalate level of the varieties averaged 15.02 mg/100g for the six samples, the tannin level ranged from 9954.6 to 13565 mg/100g. The study showed that Amaranth grain flour is potentially a food commodity item for value addition either by its lone use or in composite flour formulation. Key words: Amaranth grain flour, Proximate analysis, Protein content, Minerals, Anti–nutrients, Nigeria

Anti-urolithiatic Activity of Daidzin in Ethylene Glycol-Induced Urolithiasis in Rats.

Urolithiasis is a common urological disorder, which causes considerable morbidity in both genders at all age groups worldwide. Though treatment options such as diuretics and non-invasive techniques to disintegrate the deposits are available, but often they are found less effective in the clinics. In this work, we planned to investigate the ameliorative effects of daidzin against the ethylene glycol (EG)-induced urolithiasis in rats. The male albino rats were distributed into four groups (n = 6) as control (group I), urolithiasis induced by the administration of 0.75% EG (group II), urolithiasis induced rats treated with 50mg/kg of daidzin (group III), and urolithiasis rats treated with standard drug 750mg/kg of cystone (group IV). The urine volume, pH, and total protein in the urine were assessed. The activities of marker enzymes in both plasma and kidney tissues were analyzed using assay kits. The levels of kidney function markers such as calcium, oxalate, urea, creatinine, uric acid, magnesium, BUN, and phosphorous were estimated using assay kits. The status of antioxidants and inflammatory cytokines were also examined using kits. The renal tissues were examined by histopathological analysis. Our results revealed that the daidzin treatment effectively decreased the urine pH and protein level and increased the urine volume in the urolithiasis rats. Daidzin decreased the calcium, oxalate, uric acid, and urea, creatinine, and BUN levels and also improved the magnesium and phosphorus in the urolithiasis rats. The activities of AST, ALT, ALP, GGT, and LDH were effectively reduced by the daidzin in both serum and renal tissue. Daidzin also reduced the inflammatory marker and increased the antioxidant levels. Histopathology results also proved the therapeutic effects of daidzin. Together, our results displayed that daidzin is effective in the amelioration of EG-induced urolithiasis in rats.

Effects of Donepezil Treatment on Brain Metabolites, Gut Microbiota, and Gut Metabolites in an Amyloid Beta-Induced Cognitive Impairment Mouse Pilot Model.

Accumulated clinical and biomedical evidence indicates that the gut microbiota and their metabolites affect brain function and behavior in various central nervous system disorders. This study was performed to investigate the changes in brain metabolites and composition of the fecal microbial community following injection of amyloid β (Aβ) and donepezil treatment of Aβ-injected mice using metataxonomics and metabolomics. Aβ treatment caused cognitive dysfunction, while donepezil resulted in the successful recovery of memory impairment. The Aβ + donepezil group showed a significantly higher relative abundance of Verrucomicrobia than the Aβ group. The relative abundance of 12 taxa, including Blautia and Akkermansia, differed significantly between the groups. The Aβ + donepezil group had higher levels of oxalate, glycerol, xylose, and palmitoleate in feces and oxalate, pyroglutamic acid, hypoxanthine, and inosine in brain tissues than the Aβ group. The levels of pyroglutamic acid, glutamic acid, and phenylalanine showed similar changes in vivo and in vitro using HT-22 cells. The major metabolic pathways in the brain tissues and gut microbiota affected by Aβ or donepezil treatment of Aβ-injected mice were related to amino acid pathways and sugar metabolism, respectively. These findings suggest that alterations in the gut microbiota might influence the induction and amelioration of Aβ-induced cognitive dysfunction via the gut–brain axis. This study could provide basic data on the effects of Aβ and donepezil on gut microbiota and metabolites in an Aβ-induced cognitive impairment mouse model.

In vivo investigation of the inhibitory effect of Peganum harmala L. and its major alkaloids on ethylene glycol-induced urolithiasis in rats

Ethnopharmacological relevancePeganum harmala L. is a traditional medicinal plant used for centuries in folk medicine. It has a wide array of therapeutic attributes, which include hypoglycemic, sedative, anti-inflammatory, and antioxidant properties. The fruit decoction of this plant was claimed by Avicenna as traditional therapy for urolithiasis. Also, P. harmala seed showed a clinical reduction in kidney stone number and size in patients with urolithiasis. Aim of the studyIn light of the above-mentioned data, the anti-urolithiatic activities of the seed extracts and the major β-carboline alkaloids of P. harmala were investigated. Materials and methodsExtraction, isolation, and characterization of the major alkaloids were performed using different chromatographic and spectral techniques. The in vivo anti-urolithiatic action was evaluated using ethylene glycol (EG)-induced urolithiasis in rats by studying their mitigating effects on the antioxidant machinery, serum toxicity markers (i.e. nitrogenous waste, such as blood urea nitrogen, uric acid, urea, and creatinine), minerals (such as Ca, Mg, P, and oxalate), kidney injury marker 1 (KIM-1), and urinary markers (i.e. urine pH and urine output). ResultsTwo major alkaloids, harmine (P1) and harmalacidine HCl (P2), were isolated and in vivo evaluated alongside the different extracts. The results showed that P. harmala and its constituents/fractions significantly reduced oxidative stress at 50 mg/kg body weight, p.o., as demonstrated by increased levels of glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), and catalase (CAT) in kidney homogenate as compared to the EG-treated group. Likewise, the total extract, pet. ether fraction, n-butanol fraction, and P1, P2 alleviated malondialdehyde (MDA) as compared to the EG-treated group. Serum toxicity markers like blood urea nitrogen (BUN), creatinine, uric acid, urea, kidney injury molecule-1 (Kim-1), calcium, magnesium, phosphate, and oxalate levels were decreased by total extract, pet. ether fraction, n-butanol fraction, P1, and P2 as compared to the EG-treated group. Inflammatory markers like NFκ-B and TNF-α were also downregulated in the kidney homogenate of treatment groups as compared to the EG-treated group. Moreover, urine output and urine pH were significantly increased in treatment groups as compared to the EG-treated group deciphering anti-urolithiatic property of P. harmala. Histopathological assessment by different staining patterns also supported the previous findings and indicated that treatment with P. harmala caused a gradual recovery in damaged glomeruli, medulla, interstitial spaces and tubules, and brown calculi materials as compared to the EG-treated group. ConclusionThe current research represents scientific evidence on the use of P. harmala and its major alkaloids as an effective therapy in the prevention and management of urolithiasis.

Факторы риска нефролитиаза после радикальной цистэктомии с кишечной пластикой мочевого пузыря.

Introduction. Some studies have shown that urolithiasis is much more common in the group of patients who underwent radical cystectomy (RC) with intestinal plastic bladder than the average for the population. The aim of this study included the search of the frequency of urinary stones formation in patients after RC, depending on the type of intestinal plasty of the bladder and the type of urinary diversion, the analysis of risk factors for lithogenesis, the search for metabolic lithogenic disorders in this category of patients, and the assessment of the severity of the identified changes. Materials and methods. The work analyzed the data of 214 patients (169 men and 45 women) who were operated from 2008 to 2021 with a diagnosis of bladder cancer. Patients underwent RC with the formation of a hetero- or orthotopic ileoconduit. We analyzed the indicators of general urine analysis, biochemical blood test, bacteriological analysis of urine for flora, performed both before RC and in the late postoperative period. Also The results of ultrasound of the kidneys, bladder (reservoir), MSCT of the kidneys performed before RC and in the late postoperative period were studied. We selected 37 patients from the general group in random order, who prospectively underwent a biochemical blood test, a biochemical analysis of daily urine, and an assessment of the acid-base composition of venous blood. Statistical analysis was performed by calculating the relative risk, as well as calculating the t-test for independent groups using the computer program Statistica 10.0 (StatSoft USA). Results. Urinary stones of the upper urinary tract after RC, ortho- and heterotopic intestinal plastics of the bladder in the late postoperative period (more than 1 year) were diagnosed in 27 out of 214 patients (12.6%). The relative risk of urolithiasis in patients with pyelectasis before surgery is 3.87 times higher than in patients without changes in pelvicalyceal system at the preoperative stage (p=0.0004). In patients after RC with impaired renal function in stages III-V (GFR 60 ml/min (p=0.005). RC patients with a BMI &gt;30 had a 2.431-fold higher risk of urinary stone formation than those with a BMI 7.0, diagnosed after surgical treatment (p=0.003). The relative risk of developing urolithiasis in patients with urine pH &gt;7.0 detected before surgery is 4.85 (p&lt;0.0001). There was a trend towards an increase in the number of urolithiasis cases in patients who underwent RC with bacteriuria diagnosed after surgery according to urine culture (in patients with identified Enterococcus spp., Enterobacter cloacae, Providencia rettgeri (p&lt;0.05)) compared with patients in of which sterile urine was detected. In patients suffering from urolithiasis after undergoing RC, compared with the control group of patients in the biochemical analysis of blood, there is a statistically significant difference between the level of creatinine (p=0.033), a decrease in the level of GFR from 79.9 to 68.7 (p=0.046). There was a statistically significant increase in the pH level of the urine (p=0.0025), an increase in the level of oxalates in the daily urine (p=0.0035), a decrease in the concentration of uric acid (p= 0.039), calcium (p=0.024) in urolithiasis patients after RCE compared with patients in the control group in biochemical analysis of daily urine. Conclusion. The presence of an expansion of the pelvicalyceal system before surgery, the patient's BMI&gt; 30, urine pH&gt; 7.0 both before and after the operation, a decrease in the patient's GFR &lt;60 ml / min and the presence of bacteriuria in the general analysis of urine after RC are the risk factors for the urolithiasis after RC, intestinal plasty of the bladder.

Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies.

Due to the lack of treatment options for the genetic disease primary hyperoxaluria (PH), including three subtypes PH1, PH2, and PH3, caused by accumulation of oxalate forming kidney stones, there is an urgent need for the development of a drug therapy aside from siRNA drug lumasiran for patients with PH1. After the recent success of drug therapies based on small interfering RNA (siRNA), nedosiran is currently being developed for the treatment of three types of PH as a siRNA-based modality. Through specific inhibition of lactate dehydrogenase enzyme, the key enzyme in biosynthesis of oxalate in liver, phase 1, 2, and 3 clinical trials of nedosiran have achieved the desired primary end point of reduction of urinary oxalate levels in patients with PH1. More PH2 and PH3 patients need to be tested for efficacy. It has also produced a favorable secondary end point on safety and toxicity in PH patients. In addition to common injection site reactions that resolved spontaneously, no severe nedosiran treatment-associated adverse events were reported. Based on the positive results in the clinical studies, nedosiran is a candidate siRNA drug to treat PH patients.

Evaluation of Anti Urolithiatic Activity of Dolichos biflorus Seed Extract by Using Ethylene Glycol Induced Model

In the phytochemical screening, it was found that Dolichos Biflorus seed extract contained the presence of tannins steroids, protein, flavonoids, terpenoids, mucilage, saponin, and carbohydrate, but no alkaloids fixed oil. So, this plant has highly diuretic activity. Which can use for the treatment of urolithiasis.&#x0D; Objective: The Present study aims to investigate the anti-Urolithiatic activity of Dolichos Biflorus methanolic seed extract in a rat model.&#x0D; Methods: Dolichos Biflorus Seeds Extract were evaluated for anti-Urolithiatic activity. Urolithiasis has been induced in Wistar rats through Ethylene glycol (0.75%v/v, p.o). Upon completion of the experiment, animals in all groups have been sacrificed and biochemical parameters such as; calcium, creatinine, Phosphorus, Uric acid, Alkaline Phosphatase BUN (Blood Urea Nitrogen), and histology of Kidney have been observed. Furthermore, Potassium, Oxalate levels, and Alanine Amino Transferases were measured.&#x0D; Results: The extract of Dolichos Biflorus was proven to be safe in the toxicity findings.&#x0D; It has been shown that in-vivo significant effect of plant extract was able to manage the urolithiatic markers such as calcium, creatinine, phosphorus, uric acid, alkaline phosphatase, BUN (Blood Urea Nitrogen), and potassium. In the urolithiatic rats it has been observed that abundant crystal depositions, renal epithelial cells had more tubular dilatation and damage shown by large spaces in the tissue, renal stone deposition damages the renal tissue and detoriate the renal function. Urolithiatic markers such as calcium, creatinine, phosphorus, uric acid, alkaline phosphatase, BUN (Blood Urea Nitrogen), and potassium were normal in animals receiving plant extract and prevent renal cell injury.&#x0D; Conclusion: All its findings and phytoconstituents existing inside the extract must stay the viable chemical materials involved in the prevention of Urolithiatic.