Ovarian cancer is the most fatal of all the reproductive cancers within the female population, mainly due to its late diagnosis that limits surgery and medical treatment. Classically, ovarian cancer therapy has included conventional chemotherapy, and other therapeutic approaches are now being used to treat these patients, but the outcomes of the disease are still poor. Therefore, new strategies are needed to improve life expectancy and life quality of ovarian cancer patients. Considering that, we investigated the effect of the nutritional supplement Ocoxin Oral Solution (OOS) in ovarian cancer models. OOS contains several nutritional supplements, some of them with demonstrated antitumoral action. In vitro studies showed that OOS inhibited the proliferation of several ovarian cancer cell lines, especially of those representative of the endometrioid subtype, in a time- and dose-dependent manner. A fast cell death induction after OOS treatment was observed, and when the molecular mechanisms leading to this effect were investigated, an activation of the DNA damage checkpoint was detected, as shown by activation (phosphorylation) of CHK1 and CHK2 kinases that was followed by the phosphorylation of the target protein histone H2AX. When tested in animal models of ovarian cancer, OOS reduced tumor growth without any observed secondary effects. Moreover, such reduction in tumor proliferation was caused by the induction of DNA damage as corroborated by the in vivo phosphorylation of CHK2 and Histone H2AX. Finally, OOS potentiated the action of carboplatin or olaparib, the standard of care treatments used in ovarian clinics, opening the possibility of including OOS in combination with those standard of care agents in patients with ovarian cancer.

Brown fat is a therapeutic target for the treatment of obesity-associated metabolic diseases. However, nutritional intervention strategies for increasing the mass and activity of human brown adipocytes have not yet been established. To identify vitamins required for brown adipogenesis and adipocyte browning, chemical compound-induced brown adipocytes (ciBAs) were converted from human dermal fibroblasts under serum-free and vitamin-free conditions. Choline was found to be essential for adipogenesis. Additional treatment with pantothenic acid (PA) provided choline-induced immature adipocytes with browning properties and metabolic maturation, including uncoupling protein 1 (UCP1) expression, lipolysis, and mitochondrial respiration. However, treatment with high PA concentrations attenuated these effects along with decreased glycolysis. Transcriptome analysis showed that a low PA concentration activated metabolic genes, including the futile creatine cycle-related thermogenic genes, which was reversed by a high PA concentration. Riboflavin treatment suppressed thermogenic gene expression and increased lipolysis, implying a metabolic pathway different from that of PA. Thiamine treatment slightly activated thermogenic genes along with decreased glycolysis. In summary, our results suggest that specific B vitamins and choline are uniquely involved in the regulation of adipocyte browning via cellular energy metabolism in a concentration-dependent manner.

The CRISPR-based regulation tools enable fine-tuning of gene transcription, showing potential in areas of biomanufacturing and live therapeutics. However, the cell toxicity and PAM specificity of existing CRISPR-based regulation systems limit their broad application. The development of new and less-toxic CRISPR-controlled expression systems remains highly desirable for expanding the application scope of CRISPR-based tools. Here, we reconstituted the type I CRISPR-Cas system from Escherichia coli to finely tune gene expression in Bacillus subtilis. Through engineering the 5\' untranslated region (UTR) of mRNAs of cas genes, we remarkably improved the efficacy of the type I CRISPRi system. The improved type I CRISPRi system was applied in engineering the D-pantothenic acid (DPA)-producing B. subtilis, which was generated by strengthening the metabolic flux toward β-alanine and (R)-pantoate via enhancing expression of key enzymes at both transcriptional and translational levels. Through controlling the expression of pdhA with the CRISPRi system for fine-tuning the metabolic flux toward DPA and the TCA cycle, we elevated the DPA titer to 0.88 g/L in shake flasks and 12.81 g/L in fed-batch fermentations without the addition of the precursor β-alanine. The type I CRISPRi system and the strategy for fine-tuning metabolic flux reported here not only enrich the CRISPR toolbox in B. subtilis and facilitate DPA production through microbial fermentation but also provide a paradigm for programming important organisms to produce value-added chemicals with cheap raw materials.

Phytoextraction of lead (Pb) is a challenging task due to its extremely low mobility within soil and plant systems. In this study, we tested the influence of some novel chelating agents for Pb-phytoextraction using sunflower. The Pb was applied at control (0.0278 mM) and 4.826 mM Pb as Pb(NO3)2 through soil-spiking. After 10 days of Pb addition, four different organic ligands (aspartic, ascorbic, tartaric, and pantothenic acids) were added to the soil at 1 mM concentration each. respectively. In the absence of any chelate, sunflower plants grown at 4.826 mM Pb level accumulated Pb concentrations up to 104 µg g-1 DW in roots, whereas 64 µg g-1 DW in shoot. By contrast, tartaric acid promoted significantly Pb accumulation in roots (191 µg g-1 DW; + 45.5%) and shoot (131.6 µg g-1 DW; + 51.3%). Pantothenic acid also resulted in a significant Pb-uptake in the sunflower shoots (123 µg g-1 DW; + 47.9%) and in roots (177.3 µg g-1 DW; + 41.3%). The least effective amongst the chelates tested was aspartic acid, but it still contributed to + 40.1% more Pb accumulation in the sunflower root and shoots. In addition, plant growth, biochemical, and ionomic parameters were positively regulated by the organic chelates used. Especially, an increase in leaf Ca, P, and S was evident in Pb-stressed plants in response to chelates. These results highlight that the use of biocompatible organic chelates positively alters plant physio-biochemical traits contributing to higher Pb-sequestration in sunflower plant parts.

Fungal infections, a leading cause of mortality among eukaryotic pathogens, pose a growing global health threat due to the rise of drug-resistant strains. New therapeutic strategies are urgently needed to combat this challenge. The PCA pathway for biosynthesis of Co-enzyme A (CoA) and Acetyl-CoA (AcCoA) from vitamin B5 (pantothenic acid) has been validated as an excellent target for the development of new antimicrobials against fungi and protozoa. The pathway regulates key cellular processes including metabolism of fatty acids, amino acids, sterols, and heme. In this study, we provide genetic evidence that disruption of the PCA pathway in Saccharomyces cerevisiae results in a significant alteration in the susceptibility of fungi to a wide range of xenobiotics, including clinically approved antifungal drugs through alteration of vacuolar morphology and drug detoxification. The drug potentiation mediated by genetic regulation of genes in the PCA pathway could be recapitulated using the pantazine analog PZ-2891 as well as the celecoxib derivative, AR-12 through inhibition of fungal AcCoA synthase activity. Collectively, the data validate the PCA pathway as a suitable target for enhancing the efficacy and safety of current antifungal therapies.

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of calcium D-pantothenate for the renewal of its authorisation as a nutritional feed additive for all animal species. The additive calcium D-pantothenate is already authorised for use in all animal species (3a841). The applicant provided evidence that the additive currently in the market complies with the existing conditions of the authorisation and that the production process has not been modified. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that the additive remains safe for all animal species, consumers and the environment. Calcium D-pantothenate is not irritant to skin and eyes and is not a skin sensitiser. The present application for renewal of the authorisation does not include any modification proposal that would have an impact on the efficacy of the additive, and therefore, there is no need for re-assessing the efficacy.

Excessive fat deposition leads to obesity and cardiovascular diseases with abnormal metabolism. Pantothenic acid (PA) is a major B vitamin required for energy metabolism. However, the effect of PA on lipid metabolism and obesity has not been explored. We investigated the effects and molecular mechanism of PA on fat accumulation as well as the influence of adipogenic marker genes in both adult male mice and primary adipocytes. First, we demonstrated that PA attenuates weight gain in mice fed high-fat diet (HFD). Besides, PA supplementation substantially improved glucose tolerance and lipid metabolic disorder in obese mice. Furthermore, PA significantly inhibited white adipose tissue (WAT) deposition as well as fat droplets visualized by magnification in both chow and HFD group. More importantly, PA obviously suppressed the mRNA levels of CD36, IL-6, and TNF-α to alleviate inflammation and reduced the levels of PPARγ, aP2, and C/EBPα genes that are related to lipid metabolism in inguinal white adipose tissue (ing-WAT) and epididymal white adipose tissue (ei-WAT). In vitro, PA supplementation showed a lower lipid droplet aggregation as well as reduced expression levels of adipogentic genes. Finally, we identified that PA inhibits the phosphorylation levels of p38 and JNK in murine primary adipocytes. Collectively, our data demonstrated for the first time that PA attenuates lipid metabolic disorder as well as fat deposition by JNK/p38 MAPK signaling pathway.

Vitamin B5 [D-pantothenic acid (D-PA)] is an essential water-soluble vitamin that is widely used in the food and feed industries. Currently, the relatively low fermentation efficiency limits the industrial application of D-PA. Here, a plasmid-free D-PA hyperproducer was constructed using systematic metabolic engineering strategies. First, pyruvate was enriched by deleting the non-phosphotransferase system, inhibiting pyruvate competitive branches, and dynamically controlling the TCA cycle. Next, the (R)-pantoate pathway was enhanced by screening the rate-limiting enzyme PanBC and regulating the other enzymes of this pathway one by one. Then, to enhance NADPH sustainability, NADPH regeneration was achieved through the novel \"PEACES\" system by (1) expressing the NAD + kinase gene ppnk from Clostridium glutamicum and the NADP + -dependent gapCcae from Clostridium acetobutyricum and (2) knocking-out the endogenous sthA gene, which interacts with ilvC and panE in the D-PA biosynthesis pathway. Combined with transcriptome analysis, it was found that the membrane proteins OmpC and TolR promoted D-PA efflux by increasing membrane fluidity. Strain PA132 produced a D-PA titer of 83.26 g/L by two-stage fed-batch fermentation, which is the highest D-PA titer reported so far. This work established competitive producers for the industrial production of D-PA and provided an effective strategy for the production of related products.

Background: Attention deficit hyperactivity disorder (ADHD) is a common childhood neurodevelopmental disorder that begins before age 12. Given the role of B group vitamins in cell metabolism, synthesis of nucleotides, and neurotransmitters, the present study systematically investigated the plasma levels of vitamins B9 and B12 in children with ADHD. Methods: We searched electronic databases including Web of Science, MEDLINE, EMBASE, Scopus, Iran MEDEX, Cochran database, and SID from conception to June 2023. Full-text case-control or cross-sectional studies were included in this study. Participants in the case group were children with ADHD aged 6-12 years. Review Manager Software (RevMan 5.4) was used for statistical analyses. Standardized mean differences (SMD) with 95% CIs were used to determine the differences between the two groups. Results: Six studies were included in the present meta-analysis. They included 982 children, of whom, 204 were girls and 744 were boys. The mean age of the children was 8.86±2.03 years. The level of vitamin B9 was significantly different between children with and without ADHD [SMD -0.80, 95% CI (-1.55, -0.04)]. Vitamin B12 was significantly lower in children with ADHD [SMD -0.29, 95% CI (-0.42, -0.16)]. However, due to high heterogeneity (I2 = 93%), sensitivity analysis was used, I2 fell to 21%, and significant difference was observed between the two groups [SMD -0.19, 95% CI (-0.34, -0.04)]. Conclusion: The results of this systematic review showed that the level of vitamins B9 and B12 in children with ADHD was significantly lower than that in healthy children.

OBJECTIVE: To study the clinical and neurophysiological features of children with low cognitive tempo (NCT), as well as the effectiveness of the drug Pantogam in the treatment of this pathology.
METHODS: A total of 90 children aged 8 to 10 years were examined. Of these, the main study group consisted of 30 children with NCT, the comparison group consisted of 30 children with a combined type of attention deficit hyperactivity disorder ADHD (ADHD-K), the control group consisted of 30 children without neuropsychiatric disorders. The study used clinical, neurophysiological (electroencephalography (EEG)) and parametric methods. The CMAS scale of apparent anxiety (The Children\'s Form of Manifest Anxiety Scale), the SNAP-IY scale (assessment of the degree of inattention, hyperactivity and impulsivity), the TOVA computer test (the Test of Variables of Attention), the scale «SCT» (Sluggish Cognitive Tempo) for assessing manifestations of low cognitive tempo, the «RAM» technique for quantifying working memory. Pantogam was used to treat patients at a dose of 750 mg per day for 8 weeks.
RESULTS: Patients with NCT are characterized by more pronounced attention disorders compared with healthy peers and with children with ADHD-K, and they have a decrease in mainly not selective attention, but the overall level of functional activity. Also, the group of children with NCT has an increased level of anxiety compared to the group of children with ADHD. A comparative analysis of the level of impulsivity showed that children with NCT are less characterized by a deficit in inhibition processes. According to the quantitative analysis of the EEG, specific changes in functional activity in the frontal and central regions of the cerebral cortex were revealed (a statistically significant increase in the ratio of absolute theta rhythm to beta1 rhythm, compared with other groups), reflecting insufficient cortical arousal and less focused neural states. When re-evaluating the condition of children with NCT after a course of therapy with Pantogam, an improvement in the form of a decrease in the degree of inattention, the severity of memory impairment and a decrease in reaction time was recorded in 60% of cases. According to quantitative EEG analysis, there was a significant decrease in the ratio of absolute theta rhythm to beta1 rhythm in the central leads of both hemispheres and in the parietal-temporal leads of the left hemisphere, indicating an increase in the level of overall activation of the cerebral cortex after a course of treatment.
CONCLUSIONS: Clinical and neurophysiological differences were revealed in patients with NCT and with combined ADHD. It has been shown that the use of Pantogam for the treatment of children with NCT leads not only to a decrease in the main manifestations of this disorder, but also to an improvement in the functional state of the brain.
UNASSIGNED: Изучить клинические и нейрофизиологические особенности детей с низким когнитивным темпом (НКТ), а также эффективность применения препарата Пантогам в лечении данной патологии.
UNASSIGNED: Были обследованы 90 детей в возрасте от 8 до 10 лет. Из них основную исследуемую группу составили 30 детей с НКТ, группу сравнения — 30 детей с комбинированным типом синдрома дефицита внимания с гиперактивностью (СДВГ-К), контрольную группу — 30 детей без психоневрологических расстройств. В исследовании применялись клинический, нейрофизиологический (электроэнцефалография (ЭЭГ)) и параметрический методы. Использовались шкала явной тревожности CMAS (The Children’s Form of Manifest Anxiety Scale), шкала SNAP-IY (оценка степени невнимательности, гиперактивности и импульсивности), компьютерный тест TOVA (the Test of Variables of Attention), шкала SCT (Sluggish Cognitive Tempo) для оценки проявлений низкого когнитивного темпа, методика «Оперативная память» для количественной оценки рабочей памяти. Для лечения пациентов использовался препарат Пантогам в дозе 750 мг/сут в течение 8 нед.
UNASSIGNED: Пациенты с НКТ характеризуются более выраженными нарушениями внимания по сравнению со здоровыми сверстниками и детьми с СДВГ-К, причем у них отмечается снижение преимущественно не селективного внимания, а общего уровня функциональной активности. Также у группы детей с НКТ отмечается повышенный уровень тревожности по сравнению с группой детей с СДВГ. Сравнительный анализ уровня импульсивности показал, что для детей с НКТ менее характерен дефицит процессов торможения. По данным количественного анализа ЭЭГ выявлены специфические изменения функциональной активности во фронтальных и центральных областях коры головного мозга (статистически значимое, по сравнению с другими группами, увеличение отношения абсолютных мощностей тета-ритма к бета1-ритму), отражающие недостаточное возбуждение коры и менее сфокусированные нейронные состояния. При повторной оценке состояния детей с НКТ после курса терапии препаратом Пантогам улучшение в виде снижения степени невнимательности, выраженности нарушения оперативной памяти и уменьшения времени реакции было зарегистрировано в 60% случаев. По данным количественного анализа ЭЭГ отмечалось значимое уменьшение отношения абсолютных мощностей тета-ритма к бета1-ритму в центральных отведениях обоих полушарий и в теменно-височных отведениях левого полушария, свидетельствующее об увеличении уровня общей активации коры головного мозга после курса лечения.
UNASSIGNED: Выявлены клинические и нейрофизиологические различия у пациентов с НКТ и с комбинированным СДВГ. Показано, что применение препарата Пантогам для лечения детей с НКТ приводит не только к уменьшению основных проявлений этого расстройства, но и к улучшению функционального состояния головного мозга.