In Silico Studies, Anti-oxidant Properties, Antisorbitol Dehydrogenase, Anti-alpha Amylase and Anti-gastrointestinal Cancer Potential of Violanthin as a Natural Compound.

In vitro studies have shown flavonoids to be effective antioxidants. Flavonoid C-glycosides have antioxidant properties, but there are very few data on their cellular antioxidant activity. The chemical activities of violanthin against alpha amylase and sorbitol dehydrogenase were investigated utilizing the molecular docking study. The anti-cancer activities of the compounds were evaluated against MKN45, AGS, and KATO III cell lines. The chemical activities of violanthin against some of the expressed surface receptor proteins (estrogen receptor, folate receptor, and CD44) in the mentioned cell lines were estimated using molecular docking calculations. 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) analyzes were performed to determine the effects of compound on cell viability levels. The results showed the possible interactions and their features at an atomic level. The docking scores indicated that violanthin has a significant binding affinity to the enzymes and proteins. IC50 values of violanthin for gastric cell lines (MKN45, AGS, KATO III) were 31.95±3.95, 53.06±6.02, 47.98±5.16 µM, respectively. For α-amylase and sorbitol dehydrogenase enzymes, IC50 values were 25.03 and 1.47 µM. Moreover, this compound formed strong contact with the enzymes and receptors. Therefore, violanthin could be a potential inhibitor for these enzymes and cancer cells. Several secondary problems of diabetes mellitus have been discovered to be prevented or treated with sorbitol dehydrogenase inhibitors.

Anti-lung Cancer, Anti-microbial, Anti-α-glucosidase, Anti-sorbitol Dehydrogenase, and in silico Studies of Wogonoside and Isoliquiritigenin as Natural Compounds.

Natural substances have long been used in cancer treatment, particularly in Chinese or Indian traditional medicine. Natural compounds are defined as chemical molecules that are found in fungus, marine animals, plants, or bacteria and have significant biological and pharmacological effects. Wogonoside and isoliquiritigenin are two well-known examples of plant-derived chemicals. Several modern anti-cancer medications also come from natural sources. The mic test was used to conduct tests on various natural substances' antimicrobial and antifungal properties. MTT assay was used on lung cancer, and normal (HUVEC) cell lines for analyzing of cytotoxicity and anti-lung cancer effects of Wogonoside and Isoliquiritigenin. These Wogonoside and Isoliquiritigenin had high cell death and anti-lung cancer effects against SPC-A-1, SK-LU-1, and 95D cell lines. Among the above cell lines, the best result of anti-cancer properties of Wogonoside and Isoliquiritigenin was gained in the cell line of KATO III. We examined the inhibition effects on two important enzymes using these two compounds and determined the results. PnPG and NADPH were used as substrates for enzymes. IC50 of Wogonoside and Isoliquiritigenin compounds were 18.25±4.18 and 112.64±16.02 nM for α-glucosidase and 54.72±8.61 and 47.12±11.56 nM for sorbitol dehydrogenase, respectively. For Wogonoside, gram-negative bacteria (K. pneumoniae and E. coli) had MIC values of 9.75±0.95 and 13.77±1.43 µg/mL, gram-positive bacteria (E. faecalis and S. aureus) of 37.02±4.52 and 24.85±3.64 µg/mL, respectively. Finally, molecular docking was done for enzyme results and anticancer results. Results of enzymes and antibacterial, antifungal were in level of micromolar that is good impacts. These natural compounds may be anti-diabetic, anticancer, antibacterial candidates for drug design.

A medical odyssey of a 72-year-old man with Charcot-Marie-Tooth disease type 2 newly diagnosed with biallelic variants in SORD gene causing sorbitol dehydrogenase deficiency.

A 72-year-old man was referred to the Undiagnosed Diseases Network (UDN) because of gradual progressive weakness in both lower extremities for the past 45 years. He was initially diagnosed as having Charcot-Marie-Tooth disease type 2 (CMT2) without a defined molecular genetic cause. Exome sequencing (ES) failed to detect deleterious neuromuscular variants. Very recently, biallelic variants in sorbitol dehydrogenase (SORD) were discovered to be a novel cause of inherited neuropathies including CMT2 or distal hereditary motor neuropathy (dHMN) referred to as Sorbitol Dehydrogenase Deficiency with Peripheral Neuropathy (SORDD, OMIM 618912). The most common variant identified was c.757delG; p.A253Qfs*27. Through the Vanderbilt UDN clinical site, this patient was formally diagnosed with SORDD after the identification of homozygosity for the above SORD frameshift through UDN Genome Sequencing (GS). His medical odyssey was solved by GS and detection of extremely high levels of sorbitol. The diagnosis provided him the opportunity to receive potential treatment with an investigational drug in a clinical trial for SORDD. We suggest that similar studies be considered in other individuals thought to possibly have CMT2 or dHMN.

Expanding the genetic and clinical spectrum of SORD-related peripheral neuropathy by reporting a novel variant c.210T>G and evidence of subclinical muscle involvement.

BACKGROUND AND AIMS: Biallelic variants in the sorbitol dehydrogenase (SORD) gene have been identified as the genetic cause of autosomal recessive (AR) peripheral neuropathy (PN) manifesting as Charcot-Marie-Tooth disease type 2 (CMT2) or distal hereditary motor neuropathy (dHMN). We aim to observe the genetic and clinical spectrum of a cohort of patients with SORD-related PN (SORD-PN). METHODS: A total of 107 patients with AR or sporadic CMT2/dHMN underwent molecular diagnosis by whole-exome sequencing and subsequent Sanger sequencing validation. Available phenotypic data for SORD-PN were collected and analyzed. RESULTS: Eleven (10.28%) of 107 patients were identified as SORD-PN, including four with CMT2 and seven with dHMN. The SORD variant c.210 T > G;p.His70Gln in F-d3 was firstly reported and subsequent analysis showed that it resulted in loss of SORD enzyme function. Evidence of subclinical muscle involvement was frequently detected in patients with SORD-PN, including mildly to moderately elevated serum creatine kinase (CK) levels in 10 patients, myogenic electrophysiological changes in one patient, and muscle edema in five patients undergoing lower extremity MRI. Fasting serum sorbitol level was 88-fold higher in SORD-PN patients (9.69 ± 1.07 mg/L) than in healthy heterozygous subjects (0.11 ± 0.01 mg/L) and 138-fold higher than in healthy controls (0.07 ± 0.02 mg/L). INTERPRETATION: The novel SORD variant c.210 T > G;p.His70Gln and evidence of subclinical muscle involvement were identified, which expanded the genetic and clinical spectrum of SORD-PN. Subclinical muscle involvement might be a common but easily overlooked clinical feature. The serum CK and fasting serum sorbitol levels were expected to be sensitive biomarkers confirmed by follow-up cohort study.

Sorbitol reduction via govorestat ameliorates synaptic dysfunction and neurodegeneration in sorbitol dehydrogenase deficiency.

Sorbitol dehydrogenase (SORD) deficiency has been identified as the most frequent autosomal recessive form of hereditary neuropathy. Loss of SORD causes high sorbitol levels in tissues due to the inability to convert sorbitol to fructose in the 2-step polyol pathway, leading to degenerative neuropathy. The underlying mechanisms of sorbitol-induced degeneration have not been fully elucidated, and no current FDA-approved therapeutic options are available to reduce sorbitol levels in the nervous system. Here, in a Drosophila model of SORD deficiency, we showed synaptic degeneration in the brain, neurotransmission defect, locomotor impairment, and structural abnormalities in the neuromuscular junctions. In addition, we found reduced ATP production in the brain and ROS accumulation in the CNS and muscle, indicating mitochondrial dysfunction. Applied Therapeutics has developed a CNS-penetrant next-generation aldose reductase inhibitor (ARI), AT-007 (govorestat), which inhibits the conversion of glucose to sorbitol. AT-007 significantly reduced sorbitol levels in patient-derived fibroblasts, induced pluripotent stem cell-derived (iPSC-derived) motor neurons, and Drosophila brains. AT-007 feeding in Sord-deficient Drosophila mitigated synaptic degeneration and significantly improved synaptic transduction, locomotor activity, and mitochondrial function. Moreover, AT-007 treatment significantly reduced ROS accumulation in Drosophila CNS, muscle, and patient-derived fibroblasts. These findings uncover the molecular and cellular pathophysiology of SORD neuropathy and provide a potential treatment strategy for patients with SORD deficiency.

An inducible Komagataella phaffii system for protein expression using sorbitol dehydrogenase promoter.

OBJECTIVES: The aim of the present work was to develop a methanol-independent Komagataella phaffii (K. phaffii) strain using a non-methanol promoter. RESULTS: In this study, the food grade enzyme xylanase from Aspergillus niger ATCC 1015 was used as the reporter protein, a recombinant K. phaffii containing a cascade gene circus was designed and constructed using sorbitol as inducer. Sorbitol induced PSDH leading to MIT1 expression firstly, and heterologous protein xylanase expression finally. This system showed 1.7 fold of xylanase activity at the condition of single copy number of extra MIT1, and 2.1 fold of xylanase activity at condition of multi-copy extra MIT1 gene. CONCLUSIONS: This sorbitol-induced expression system of K. phaffii avoided toxic and explosive methanol. It was a novel cascade gene expression and a food safety system.

Anticancer and Biological Effects of Some Natural Compounds and Theoretical Investigation of them Against RdRP of SARS-COV-2: In Silico and In Vitro Studies.

In this study, Skullcapflavone I and Skullcapflavone II molecules showed good inhibitory activities against α-glucosidase and sorbitol dehydrogenase enzymes with IC50 values of 102.66 ± 8.43 and 95.04 ± 11.52 nM for α-glucosidase and 38.42 ± 3.82 and 28.81 ± 3.26 µM for sorbitol dehydrogenase. The chemical activities of Skullcapflavone I and Skullcapflavone II against α-glucosidase and sorbitol dehydrogenase were assessed by conducting the molecular docking study. The anticancer activities of the compounds were examined against SW-626, SK-OV-3, OVCAR3, and Caov-3 cell lines. The chemical activities of Skullcapflavone I and Skullcapflavone II against some of the expressed surface receptor proteins (estrogen receptor, EGFR, androgen receptor, and GnRH receptor) in the mentioned cell lines were investigated using in silico calculations. Moreover, the activity of the compounds against RNA polymerase of SARS-COVE-2 was also assessed using the molecular modeling study. These compounds created strong contacts with the enzymes and receptors. The considerable binding affinity of the compounds to the enzymes and proteins showed their ability as inhibitors. Furthermore, even at modest dosages, these substances markedly reduced the viability of ovarian cancer cells. Additionally, the viability of ovarian cancer cells was significantly decreased by a 300 µM dosage of all compounds. Antiovarian cancer results of Skullcapflavone I on SK-OV-3, SW-626, OVCAR3, and Caov-3 were 63.14, 1.55, 19.42, and 52.04 µM, respectively. Also, cytotoxicity results of Skullcapflavone II on SK-OV-3, SW-626, OVCAR3, and Caov-3 were 5.18, 21.44, 33.87, and 72.66 µM, respectively.

Membrane-bound sorbitol dehydrogenase is responsible for the unique oxidation of D-galactitol to L-xylo-3-hexulose and D-tagatose in Gluconobacter oxydans.

BACKGROUND: Gluconobacter oxydans, is used in biotechnology because of its ability to oxidize a wide variety of carbohydrates, alcohols, and polyols in a stereo- and regio-selective manner by membrane-bound dehydrogenases located in periplasmic space. These reactions obey the well-known Bertrand-Hudson's rule. In our previous study (BBA-General Subjects, 2021, 1865:129740), we discovered that Gluconobacter species, including G. oxydans and G. cerinus strain can regio-selectively oxidize the C-3 and C-5 hydroxyl groups of D-galactitol to rare sugars D-tagatose and L-xylo-3-hexulose, which represents an exception to Bertrand Hudson's rule. The enzyme catalyzing this reaction is located in periplasmic space or membrane-bound and is PQQ (pyrroloquinoline quinine) and Ca2+-dependent; we were encouraged to determine which type of enzyme(s) catalyze this unique reaction. METHODS: Enzyme was identified by complementation of multi-deletion strain of Gluconobacter oxydans 621H with all putative membrane-bound dehydrogenase genes. RESULTS AND CONCLUSIONS: In this study, we identified this gene encoding the membrane-bound PQQ-dependent dehydrogenase that catalyzes the unique galactitol oxidation reaction in its 3'-OH and 5'-OH. Complement experiments in multi-deletion G. oxydans BP.9 strains established that the enzyme mSLDH (encoded by GOX0855-0854, sldB-sldA) is responsible for galactitol's unique oxidation reaction. Additionally, we demonstrated that the small subunit SldB of mSLDH was membrane-bound and served as an anchor protein by fusing it to a red fluorescent protein (mRubby), and heterologously expressed in E. coli and the yeast Yarrowia lipolytica. The SldB subunit was required to maintain the holo-enzymatic activity that catalyzes the conversion of D-galactitol to L-xylo-3-hexulose and D-tagatose. The large subunit SldA encoded by GOX0854 was also characterized, and it was discovered that its 24 amino acids signal peptide is required for the dehydrogenation activity of the mSLDH protein. GENERAL SIGNIFICANCE: In this study, the main membrane-bound polyol dehydrogenase mSLDH in G. oxydans 621H was proved to catalyze the unique galactitol oxidation, which represents an exception to the Bertrand Hudson's rule, and broadens its substrate ranges of mSLDH. Further deciphering the explicit enzymatic mechanism will prove this theory.

Skeletal muscle involvement in biallelic SORD mutations: case report and review of the literature.

Biallelic mutations in the sorbitol dehydrogenase (SORD) gene have been identified as a genetic cause of autosomal recessive axonal Charcot-Marie-Tooth disease 2 (CMT2) and distal hereditary motor neuropathy (dHMN). We herein review the main phenotypes associated with SORD mutations and report the case of a 16-year-old man who was referred to our outpatient clinic for a slowly worsening gait disorder with wasting and weakness of distal lower limbs musculature. Since creatine phosphokinase (CPK) values were persistently raised (1.5fold increased) and a Next-Generation Sequencing CMT-associated panel failed in identifying pathogenic variants, a muscle biopsy was performed with evidence of alterations suggestive of a protein surplus distal myopathy. Finally, Whole-Exome Sequencing (WES) identified two pathogenic SORD variants in the heterozygous state: c.458C > A (p.Ala153Asp) and c.757delG (p.Ala253Glnfs*27). This is an isolated report of compound heterozygosity for two SORD mutations associated with clinical and histological signs of skeletal muscle involvement, expanding the phenotypic expression of SORD mutations.

Phytochemical Composition and In Vitro Antioxidant, Anti-Inflammatory, Anticancer, and Enzyme-Inhibitory Activities of Artemisia nilagirica (C.B. Clarke) Pamp.

Plants have been employed in therapeutic applications against various infectious and chronic diseases from ancient times. Various traditional medicines and folk systems have utilized numerous plants and plant products, which act as sources of drug candidates for modern medicine. Artemisia is a genus of the Asteraceae family with more than 500 species; however, many of these species are less explored for their biological efficacy, and several others are lacking scientific explanations for their uses. Artemisia nilagirica is a plant that is widely found in the Western Ghats, Kerala, India and is a prominent member of the genus. In the current study, the phytochemical composition and the antioxidant, enzyme-inhibitory, anti-inflammatory, and anticancer activities were examined. The results indicated that the ethanol extract of A. nilagirica indicated in vitro DPPH scavenging (23.12 ± 1.28 µg/mL), ABTS scavenging (27.44 ± 1.88 µg/mL), H2O2 scavenging (12.92 ± 1.05 µg/mL), and FRAP (5.42 ± 0.19 µg/mL). The anti-inflammatory effect was also noticed in the Raw 264.7 macrophages, where pretreatment with the extract reduced the LPS-stimulated production of cytokines (p < 0.05). A. nilagirica was also efficient in inhibiting the activities of α-amylase (38.42 ± 2.71 µg/mL), α-glucosidase (55.31 ± 2.16 µg/mL), aldose reductase (17.42 ± 0.87 µg/mL), and sorbitol dehydrogenase (29.57 ± 1.46 µg/mL). It also induced significant inhibition of proliferation in breast (MCF7 IC50 = 41.79 ± 1.07, MDAMB231 IC50 = 55.37 ± 2.11µg/mL) and colon (49.57 ± 1.46 µg/mL) cancer cells. The results of the phytochemical screening indicated a higher level of polyphenols and flavonoids in the extract and the LCMS analysis revealed the presence of various bioactive constituents including artemisinin.

Multi-Omics Analysis Revealed a Significant Alteration of Critical Metabolic Pathways Due to Sorafenib-Resistance in Hep3B Cell Lines.

Hepatocellular carcinoma (HCC) is the second prominent cause of cancer-associated death worldwide. Usually, HCC is diagnosed in advanced stages, wherein sorafenib, a multiple target tyrosine kinase inhibitor, is used as the first line of treatment. Unfortunately, resistance to sorafenib is usually encountered within six months of treatment. Therefore, there is a critical need to identify the underlying reasons for drug resistance. In the present study, we investigated the proteomic and metabolomics alterations accompanying sorafenib resistance in hepatocellular carcinoma Hep3B cells by employing ultra-high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). The Bruker Human Metabolome Database (HMDB) library was used to identify the differentially abundant metabolites through MetaboScape 4.0 software (Bruker). For protein annotation and identification, the Uniprot proteome for Homo sapiens (Human) database was utilized through MaxQuant. The results revealed that 27 metabolites and 18 proteins were significantly dysregulated due to sorafenib resistance in Hep3B cells compared to the parental phenotype. D-alanine, L-proline, o-tyrosine, succinic acid and phosphatidylcholine (PC, 16:0/16:0) were among the significantly altered metabolites. Ubiquitin carboxyl-terminal hydrolase isozyme L1, mitochondrial superoxide dismutase, UDP-glucose-6-dehydrogenase, sorbitol dehydrogenase and calpain small subunit 1 were among the significantly altered proteins. The findings revealed that resistant Hep3B cells demonstrated significant alterations in amino acid and nucleotide metabolic pathways, energy production pathways and other pathways related to cancer aggressiveness, such as migration, proliferation and drug-resistance. Joint pathway enrichment analysis unveiled unique pathways, including the antifolate resistance pathway and other important pathways that maintain cancer cells' survival, growth, and proliferation. Collectively, the results identified potential biomarkers for sorafenib-resistant HCC and gave insights into their role in chemotherapeutic drug resistance, cancer initiation, progression and aggressiveness, which may contribute to better prognosis and chemotherapeutic outcomes.

Trehalose Regulates Starch, Sorbitol, and Energy Metabolism to Enhance Tolerance to Blue Mold of "Golden Delicious" Apple Fruit.

The efficacy of trehalose on the lesion diameter of apples (cv. Golden Delicious) inoculated with Penicillium expansum was evaluated to screen the optimal concentration. The changes in gene expression and activity of the enzyme in starch, sorbitol, and energy metabolism were also investigated in apples after trehalose treatment. The results revealed that trehalose dipping reduced the lesion diameter of apples inoculated with P. expansum. Trehalose suppressed the activities and gene expressions of ß-amylase, NAD-sorbitol dehydrogenase, and NADP-sorbitol dehydrogenase, whereas it decreased the sorbitol 6-phosphate dehydrogenase gene expression and amylose, amylopectin, total starch, and reducing sugar contents. Additionally, trehalose improved the gene expressions and activities of α-amylase, starch-branching enzymes, total amylase, H+-ATPase, and Ca2+-ATPase, as well as soluble sugar, adenosine triphosphate, and adenosine diphosphate contents and energy charge in apples. These findings imply that trehalose could induce tolerance to the blue mold of apple fruit by regulating starch, sorbitol, and energy metabolism.

The Impact of Some Natural Phenolic Compounds on α-Glucosidase and Sorbitol Dehydrogenase Enzymes, and Anti-leukemia Cancer Potential, Spin Density Distributions, and in silico Studies.

In this study, some phenolic compounds including 4-Hexylresorcinol, 5-Pentadecylresorcinol, 5-Tricosylresorcinol, Bilobol, and Urushiol were tested against α-glycosidase enzyme from Saccharomyces cerevisiae and sorbitol dehydrogenase enzymes from sheep liver. These compounds determined good inhibition properties against α-glycosidase and sorbitol dehydrogenase (SDH) enzymes. IC50 values were record in the range of 1.45±0.20-24.532±3.83 µM for α-glycosidase and 6.20±0.96-108.22±18.02 µM for SDH. These inhibitor compounds can be selective drug candidates as anti-diabetic agents, because of they have inhibition properties against both enzymes. In this study, the anti-oxidant activities of the molecules were compared with density functional theory (DFT) calculations. Comparison was made with the experimental enzymes by molecular modeling calculations. In the cellular and molecular part of the recent study, the treated cells with some phenolic compounds were assessed by molecularly targeted therapy (MTT) assay for cytotoxicity and anti-acute lymphoblastic leukemia potentials on Clone 15 HL-60, HL-60, HL-60/MX1, and HL-60/MX2 cell lines. The IC50 of these compounds were µg/mL level against these cell lines.

Association of SORD mutation with autosomal recessive asymmetric distal hereditary motor neuropathy.

BACKGROUND: The aim of this study was to identify the underlying genetic defect in a family segregating autosomal recessive asymmetric hereditary motor neuropathy (HMN). Asymmetric HMN has not been associated earlier with SORD mutations. METHODS: For this study, we have recruited a family and collected blood samples from affected and normal individuals of a family. Detailed clinical examination and electrophysiological studies were carried out. Whole exome sequencing was performed to detect the underlying genetic defect in this family. The potential variant was validated using the Sanger sequencing approach. RESULTS: Clinical and electrophysiological examination revealed asymmetric motor neuropathy with normal nerve conduction velocities and action potentials. Genetic analysis identified a homozygous mononucleotide deletion mutation (c.757delG) in a SORD gene in a patient. This mutation is predicted to cause premature truncation of a protein (p.A253Qfs*27). CONCLUSIONS: Interestingly, the patient with homozygous SORD mutation demonstrates normal motor and nerve conduction velocities and action potentials. The affected individual describes in this study has a unique presentation of asymmetric motor neuropathy predominantly affecting the right side more than the left as supported by the clinical examination. This is the first report of SORD mutation from Saudi Arabia and this study further expands the phenotypic spectrum of SORD mutation.

Long read sequencing overcomes challenges in the diagnosis of SORD neuropathy.

Biallelic mutations in sorbitol dehydrogenase (SORD) have been recently identified as a common cause of recessive axonal Charcot-Marie-Tooth neuropathy (CMT2). We aimed to assess a novel long-read sequencing approach to overcome current limitations in SORD neuropathy diagnostics due to the SORD2P pseudogene and the phasing of biallelic mutations in recessive disease. We conducted a screen of our Australian whole exome sequencing (WES) CMT cohort to identify individuals with homozygous or compound heterozygous SORD variants. Individuals detected with SORD mutations then underwent long-read sequencing, clinical assessment, and serum sorbitol analysis. An individual was detected with compound heterozygous truncating mutations in SORD exon 7, NM_003104.5:c.625C>T (p.Arg209Ter) and NM_003104.5:c.757del (p.Ala253GlnfsTer27). Subsequent Oxford Nanopore Tech (ONT) long-read sequencing was used to successfully differentiate SORD from the highly homologous non-functional SORD2P pseudogene and confirmed that the mutations were biallelic through haplotype-resolved analysis. The patient presented with axonal sensorimotor polyneuropathy (CMT2) and ulnar neuropathy without compression at the elbow. Burning neuropathic pain in the forearms and feet was also reported and was exacerbated by alcohol consumption and improved with alcohol cessation. UPLC-tandem mass spectrometry confirmed that the patient had elevated serum sorbitol levels (12.0 mg/L) consistent with levels previously observed in patients with biallelic SORD mutations. This represents a novel clinical presentation and expands the phenotype associated with biallelic SORD mutations causing CMT2. Our study is the first report of long-read sequencing for an individual with CMT and demonstrates the utility of this approach for clinical genomics.

Clinical and pathological study of SORD-related distal motor neuropathy caused by novel compound heterozygous mutations in a Chinese patient.

Sorbitol dehydrogenase (SORD) has been identified as the causative gene of autosomal recessive distal hereditary motor neuropathies (dHMN). Here, we describe a 25-year-old woman who presented with progressive weakness of both lower limbs for the previous 10 years. Electrophysiological results suggested only a reduction in the compound muscle action potential (CMAP) amplitude of both the tibial and left deep peroneal nerves and neurogenic changes in needle EMG. A heterozygous c.757delG variant with a splicing c.786 + 1 G>A variant in the SORD gene was identified. A sural nerve biopsy revealed slight axon separation from the myelin sheath and thin myelin sheaths in very few nerve fibres and thickening of the microvasculature basement membrane. Our study expands the pathological and mutation spectrum of the SORD-related neuropathy.

Juvenile amyotrophic lateral sclerosis associated with biallelic c.757delG mutation of sorbitol dehydrogenase gene.

Mutation in the sorbitol dehydrogenase gene (SORD) has been recently described to cause axonal Charcot-Marie-Tooth disease (CMT), intermediate CMT, and distal hereditary motor neuropathy (dHMN). We herein report the case of a 24-year-old patient diagnosed with juvenile amyotrophic lateral sclerosis (JALS) who carried the homozygous c.757delG mutation in SORD. No other pathogenic variant in frequent JALS-causative genes was found. Our findings expand the phenotype related to SORD mutation, a new and potentially treatable genetic disease.

Molecular docking and inhibition studies of vulpinic, carnosic and usnic acids on polyol pathway enzymes.

Aldose reductase (AR) and sorbitol dehydrogenase (SDH) are important enzymes of the polyol pathway. In the current study, inhibitory effects of vulpinic acid (VA) carnosic acid (CA) and usnic acid (UA) on purified AR and SDH enzymes were determined. These enzymes inhibition could be essential to prevent diabetic complications. AR and SDH enzymes were purified from sheep kidney. Then, VA, CA and UA were tested in various concentrations against these enzymes activity in vitro. KI values were found to be as 1.46 ± 0.04, 5.13 ± 0.25 and 11.71 ± 0.27 µΜ for VA, CA and UA, respectively, for AR. KI constants were found to be as 15.32 ± 0.34, 145.60 ± 2.17 and 213.40 ± 2.64 µΜ VA, CA and UA, respectively, for SDH. These findings indicate that VA, CA and UA could be useful in the treatment of diabetic complications.Communicated by Ramaswamy H. Sarma.

Variation in the promoter of the sorbitol dehydrogenase gene MdSDH2 affects binding of the transcription factor MdABI3 and alters fructose content in apple fruit.

Fructose (Fru) content is a key determinant of fruit sweetness and quality. An F1 hybrid population of the apple cultivars 'Honeycrisp' × 'Qinguan' was used to investigate the quantitative trait locus (QTL) regions and genes controlling Fru content in fruit. A stable QTL on linkage group (LG) 01 in 'Honeycrisp' was detected on the single nucleotide polymorphism (SNP) genetic linkage maps. In this region, a sorbitol dehydrogenase (SDH) gene, MdSDH2, was detected and showed promoter variations and differential expression patterns between 'Honeycrisp' and 'Qinguan' fruits as well as their hybrids. A SNP variant (A/G) in the MdSDH2 promoter region (SDH2p-491) affected the binding ability of the transcription factor MdABI3, which can affect the expression of MdSDH2. Promoter sequences with an A nucleotide at SDH2p-491 had stronger binding affinity for MdABI3 than those with a G. Among 27 domesticated apple cultivars and wild relatives, this SNP (A/G) was associated with Fru content. Our results indicate that MdSDH2 can alter Fru content as the major regulatory gene and that ABA signaling might be involved in Fru content accumulation in apple fruit.

Circadian effects of ionizing radiation on reproductive function and clock genes expression in male mouse.

BACKGROUND: Exposure to the ionizing radiation (IR) encountered outside the magnetic field of the Earth poses a persistent threat to the reproductive functions of astronauts. The potential effects of space IR on the circadian rhythms of male reproductive functions have not been well characterized so far. METHODS: Here, we investigated the circadian effects of IR exposure (3 Gy X-rays) on reproductive functional markers in mouse testicular tissue and epididymis at regular intervals over a 24-h day. For each animal, epididymis was tested for sperm motility, and the testis tissue was used for daily sperm production (DSP), testosterone levels, and activities of testicular enzymes (glucose-6-phosphate dehydrogenase (G6PDH), sorbitol dehydrogenase (SDH), lactic dehydrogenase (LDH), and acid phosphatase (ACP)), and the clock genes mRNA expression such as Clock, Bmal1, Ror-α, Ror-ß, or Ror-γ. RESULTS: Mice exposed to IR exhibited a disruption in circadian rhythms of reproductive markers, as indicated by decreased sperm motility, increased daily sperm production (DSP), and reduced activities of testis enzymes such as G6PDH, SDH, LDH, and ACP. Moreover, IR exposure also decreased mRNA expression of five clock genes (Clock, Bmal1, Ror-α, Ror-ß, or Ror-γ) in testis, with alteration in the rhythm parameters. CONCLUSION: These findings suggested potential health effects of IR exposure on reproductive functions of male astronauts, in terms of both the daily overall level as well as the circadian rhythmicity.