Oral Administration of Nicotinamide Mononucleotide with Bioenhancer BioPerine® Increases the Serum Concentration of Nicotinamide Adenine Dinucleotide in Healthy Human Volunteers: A Pilot, Open-Label, Cross-Over Study

Background: Bioenhancers augment the bioavailability of co-administered molecules without showing any significant effect on their own. Piperine, an alkaloid from Piper nigrum, is an established natural bioenhancer. Nicotinamide mononucleotide (NMN), an antiaging supplement, is the precursor of coenzyme nicotinamide adenine dinucleotide (NAD) that plays an important role in intracellular redox reactions. Objective: The study compared the serum concentrations of NAD in normal healthy participants, supplemented with NMN 500 mg and NMN 500 mg + 5 mg BioPerine® (95% piperine). Methods: In a randomized, open-label, crossover study, NMN (500 mg) was compared to NMN + BioPerine® (500 mg + 5 mg) in 6 healthy adults, aged 18 - 45 years. The participants received a single oral dose of NMN or NMN + BioPerine® capsules with 240 mL water, and blood samples were collected over 8hr. After a 4-day washout period, the same procedures were repeated as per the crossover design. Total NAD (NADtotal), including oxidized NAD (the oxidized) and its reduced form NADH, was measured in human serum samples. Results: The maximum concentration (Cmax) of NAD in serum was higher with NMN + BioPerine® (282 pmol/mL) compared to NMN (246 pmol/mL) alone. In the presence of BioPerine®, the NAD concentrations reached 257 pmol/mL during the first 2 hr, whereas a comparable serum concentration (246 pmol/mL) was attained only after 6 hr in NMN alone. The AUC0-8hr was 1738 pmol/mL/hr in NMN compared to 2004 pmol/mL/hr in NMN+ BioPerine®. The time to reach peak concentration (t1/2) was similar (6hr) in both groups. No clinically relevant adverse events (AE) were observed, and safety parameters remained within normal ranges in all the participants with both formulations. Conclusion: These results reveal that BioPerine® can effectively increase the NAD concentrations in the serum following NMN supplementation in healthy volunteers. The present study was registered prospectively with the Clinical Trials Registry-India (CTRI/2023/11/059982).

Nicotinamide adenine dinucleotide treatment confers resistance to neonatal ischemia and hypoxia:effects on neurobehavioral phenotypes

Neonatal hypoxic-ischemic brain injury is the main cause of hypoxic-ischemic encephalopathy and cerebral palsy.Currently,there are few effective clinical treatments for neonatal hypoxic-ischemic brain injury.Here,we investigated the neuroprotective and molecular mechanisms of exogenous nicotinamide adenine dinucleotide,which can protect against hypoxic injury in adulthood,in a mouse model of neonatal hypoxic-ischemic brain injury.In this study,nicotinamide adenine dinucleotide(5 mg/kg)was intraperitoneally administered 30 minutes befo re surgery and every 24 hours thereafter.The results showed that nicotinamide adenine dinucleotide treatment improved body weight,brain structure,adenosine triphosphate levels,oxidative damage,neurobehavioral test outcomes,and seizure threshold in experimental mice.Tandem mass tag proteomics revealed that numerous proteins were altered after nicotinamide adenine dinucleotide treatment in hypoxic-ischemic brain injury mice.Parallel reaction monitoring and western blotting confirmed changes in the expression levels of proteins including serine(or cysteine)peptidase inhibitor,clade A,member 3N,fibronectin 1,5'-nucleotidase,cytosolic IA,microtubule associated protein 2,and complexin 2.Proteomics analyses showed that nicotinamide adenine dinucleotide ameliorated hypoxic-ischemic injury through inflammation-related signaling pathways(e.g.,nuclear factor-kappa B,mitogen-activated protein kinase,and phosphatidylinositol 3 kinase/protein kinase B).These findings suggest that nicotinamide adenine dinucleotide treatment can improve neurobehavioral phenotypes in hypoxic-ischemic brain injury mice through inflammation-related pathways.

Effects of different concentrations of nicotinamide on hematopoietic stem cells cultured in vitro

BACKGROUND In vitro expansion to increase numbers of hematopoietic stem cells(HSCs)in cord blood could improve clinical efficacy of this vital resource.Nicotinamide(NAM)can promote HSC expansion ex vivo,but its effect on hematopoietic stem and progenitor cells(HSPCs,CD34^(+)CD38)and functional subtypes of HSCs-shortterm repopulating HSCs(ST-HSCs,CD34^(+)CD38CD45RACD49f^(+))and long-term repopulating HSCs(LT-HSCs,CD34^(+)CD38CD45RACD49f^(+)CD90^(+))is not yet known.As a sirtuin 1(SIRT1)inhibitor,NAM participates in regulating cell adhesion,polarity,migration,proliferation,and differentiation.However,SIRT1 exhibits dual effects by promoting or inhibiting differentiation in different tissues or cells.We propose that the concentration of NAM may influence proliferation,differentiation,and SIRT1 signaling of HSCs.AIM To evaluate the effects and underlying mechanisms of action of different concentrations of NAM on HSC proliferation and differentiation.METHODS CD34^(+)cells were purified from umbilical cord blood using MacsCD34 beads,and cultured for 10-12 d in a serum-free medium supplemented with cytokines,with different concentrations of NAM added according to experimental requirements.Flow cytometry was used to detect phenotype,cell cycle distribution,and apoptosis of the cultured cells.Real-time polymerase chain reaction was used to detect the transcription levels of target genes encoding stemness-related factors,che mokines,components of hypoxia pathways,and antioxidant enzymes.Dichloro-dihydro-fluorescein diacetate probes were used to evaluate intracellular production of reactive oxygen species(ROS).Determination of the effect of different culture conditions on the balance of cytokine by cytometric bead array.RESULTS Compared with the control group,the proportion and expansion folds of HSPCs(CD34^(+)CD38)incubated with 5 mmol/L or 10 mmol/L NAM were significantly increased(all P<0.05).The ST-HSCs ratio and fold expansion of the 5 mmol/L NAM group were significantly higher than those of the control and 10 mmol/L NAM groups(all P<0.001),whereas the LT-HSCs ratio and fold expansion of the 10 mmol/L NAM group were significantly higher than those of the other two groups(all P<0.05).When the NAM concentration was>10 mmol/L,cell viability significantly decreased.In addition,compared with the 5 mmol/L NAM group,the proportion of apoptotic cells in the 10 mmol/L NAM group increased and the proportion of cells in S and G2 phase decreased.Compared with the 5 mmol/L NAM group,the HSCs incubated with 10 mmol/L NAM exhibited significantly inhibited SIRT1 expression,increased intracellular ROS content,and downregulated expression of genes encoding antioxidant enzymes(superoxide dismutase 1,peroxiredoxin 1).CONCLUSION Low concentrations(5 mmol/L)of NAM can better regulate the balance between proliferation and differentiation,thereby promoting expansion of HSCs.These findings allow adjustment of NAM concentrations according to expansion needs.

Nicotinamide adenine dinucleotide phosphate oxidase in pancreatic diseases:Mechanisms and future perspectives

Pancreatitis and pancreatic cancer(PC)stand as the most worrisome ailments affecting the pancreas.Researchers have dedicated efforts to unraveling the mechanisms underlying these diseases,yet their true nature continues to elude their grasp.Within this realm,oxidative stress is often believed to play a causal and contributory role in the development of pancreatitis and PC.Excessive accumulation of reactive oxygen species(ROS)can cause oxidative stress,and the key enzyme responsible for inducing ROS production in cells is nicotinamide adenine dinucleotide phosphate hydrogen oxides(NOX).NOX contribute to pancreatic fibrosis and inflammation by generating ROS that injure acinar cells,activate pancreatic stellate cells,and mediate macrophage polarization.Excessive ROS production occurs during malignant transformation and pancreatic carcinogenesis,creating an oxidative microenvironment that can cause abnormal apoptosis,epithelial to mesenchymal transition and genomic instability.Therefore,understanding the role of NOX in pancreatic diseases contributes to a more in-depth exploration of the exact pathogenesis of these diseases.In this review,we aim to summarize the potential roles of NOX and its mechanism in pancreatic disorders,aiming to provide novel insights into understanding the mechanisms underlying these diseases.

Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology

Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.

Functions of nuclear factor Y in nervous system development,function and health

Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes,one of the most common motifs found in gene promoters and enhancers.Over the last 30 years,research has revealed that the nuclear factor Y complex controls many aspects of brain development,including differentiation,axon guidance,homeostasis,disease,and most recently regeneration.However,a complete understanding of transcriptional regulatory networks,including how the nuclear factor Y complex binds to specific CCAAT boxes to perform its function remains elusive.In this review,we explore the nuclear factor Y complex’s role and mode of action during brain development,as well as how genomic technologies may expand understanding of this key regulator of gene expression.

The effects of exercise interventions on brain-derived neurotrophic factor levels in children and adolescents:a meta-analysis

Brain-derived neurotrophic factor is a crucial neurotrophic factor that plays a significant role in brain health. Although the vast majority of meta-analyses have confirmed that exercise interventions can increase brain-derived neurotrophic factor levels in children and adolescents, the effects of specific types of exercise on brain-derived neurotrophic factor levels are still controversial. To address this issue, we used meta-analytic methods to quantitatively evaluate, analyze, and integrate relevant studies. Our goals were to formulate general conclusions regarding the use of exercise interventions, explore the physiological mechanisms by which exercise improves brain health and cognitive ability in children and adolescents, and provide a reliable foundation for follow-up research. We used the Pub Med, Web of Science, Science Direct, Springer, Wiley Online Library, Weipu, Wanfang, and China National Knowledge Infrastructure databases to search for randomized controlled trials examining the influences of exercise interventions on brain-derived neurotrophic factor levels in children and adolescents. The extracted data were analyzed using Review Manager 5.3. According to the inclusion criteria, we assessed randomized controlled trials in which the samples were mainly children and adolescents, and the outcome indicators were measured before and after the intervention. We excluded animal experiments, studies that lacked a control group, and those that did not report quantitative results. The mean difference(MD;before versus after intervention) was used to evaluate the effect of exercise on brain-derived neurotrophic factor levels in children and adolescents. Overall, 531 participants(60 children and 471 adolescents, 10.9–16.1 years) were included from 13 randomized controlled trials. Heterogeneity was evaluated using the Q statistic and I^(2) test provided by Review Manager software. The meta-analysis showed that there was no heterogeneity among the studies(P = 0.67, I^(2) = 0.00%). The combined effect of the interventions was significant(MD = 2.88, 95% CI: 1.53–4.22, P < 0.0001), indicating that the brain-derived neurotrophic factor levels of the children and adolescents in the exercise group were significantly higher than those in the control group. In conclusion, different types of exercise interventions significantly increased brain-derived neurotrophic factor levels in children and adolescents. However, because of the small sample size of this meta-analysis, more high-quality research is needed to verify our conclusions. This metaanalysis was registered at PROSPERO(registration ID: CRD42023439408).

Telencephalic stab wound injury induces regenerative angiogenesis and neurogenesis in zebrafish:unveiling the role of vascular endothelial growth factor signaling and microglia

After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.

Age-related driving mechanisms of retinal diseases and neuroprotection by transcription factor EB-targeted therapy

Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.

Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination

During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.

The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson's disease

Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.

GLP-1、Betacellulin、Activin A、bFGF和Nicotinamide联合诱导小鼠胚胎干细胞分化为胰岛素分泌细胞

【目的】探讨体外联合应用GLP-1、betacellulin、activinA、bFGF和nicotinamide5种生长因子能否将小鼠胚胎干细胞(ES细胞)诱导分化为胰岛素分泌细胞。【方法】以GLP-1、betacellulin、activinA、bFGF和nicoti-namide5种生长因子诱导E14.1小鼠ES细胞30d后,应用RT-PCR、DTZ染色和免疫组化检测分化细胞胰岛素表达,以流式细胞仪检测胰岛素分泌细胞的分化率,用RIA法测定培养液中胰岛素水平。【结果】分化细胞可检测到胰岛素mRNA表达,DTZ染色和胰岛素免疫组化染色阳性,胰岛素分泌细胞的分化率平均为13.6%±3.7%,在5.6mmol/L和25mmol/L葡萄糖浓度作用下培养液中胰岛素水平分别为(0.04±0.01)ng/mL和(0.09±0.02)ng/mL。【结论】体外联合应用GLP-1、betacellulin、activinA、bFGF和nicotinamide5种生长因子能将小鼠ES细胞诱导分化为胰岛素分泌细胞,但胰岛素分泌功能较差。

Nicotinamide adenine dinucleotide phosphate oxidase activation and neuronal death after ischemic stroke

Nicotinamide adenine dinucleotide phosphate oxidase(NOX) is a multisubunit enzyme complex that utilizes nicotinamide adenine dinucleotide phosphate to produce superoxide anions and other reactive oxygen species. Under normal circumstances, reactive oxygen species mediate a number of important cellular functions, including the facilitation of adaptive immunity. In pathogenic circumstances, however,excess reactive oxygen species generated by NOX promotes apoptotic cell death. In ischemic stroke, in particular, it has been shown that both NOX activation and derangements in glucose metabolism result in increased apoptosis. Moreover, recent studies have established that glucose, as a NOX substrate, plays a vital role in the pathogenesis of reperfusion injury. Thus, NOX inhibition has the potential to mitigate the deleterious impact of hyperglycemia on stroke. In this paper, we provide an overview of this research,coupled with a discussion of its implications for the development of NOX inhibition as a strategy for the treatment of ischemic stroke. Both inhibition using apocynin, as well as the prospect of developing more specific inhibitors based on what is now understood of the biology of NOX assembly and activation, will be highlighted in the course of our discussion.

OTOTOXIC MODEL OF OXALIPLATIN AND PROTECTION FROM NICOTINAMIDE ADENINE DINUCLEOTIDE

Oxaliplatin, an anticancer drug commonly used to treat colorectal cancer and other tumors, has a number of serious side effects, most notably neuropathy and ototoxicity. To gain insights into its ototoxic profile, oxaliplatin was applied to rat cochlear organ cultures. Consistent with it neurotoxic propensity, oxaliplatin selectively damaged nerve fibers at a very low dose 1 μM. In contrast, the dose required to damage hair cells and spiral ganglion neurons was 50 fold higher (50 μM). Oxailiplatin-induced cochlear lesions initial-ly increased with dose, but unexpectedly decreased at very high doses. This non-linear dose response could be related to depressed oxaliplatin uptake via active transport mechanisms. Previous studies have demon-strated that axonal degeneration involves biologically active processes which can be greatly attenuated by nicotinamide adenine dinucleotide (NAD+). To determine if NAD+would protect spiral ganglion axons and the hair cells from oxaliplatin damage, cochlear cultures were treated with oxaliplatin alone at doses of 10 μM or 50 μM respectively as controls or combined with 20 mM NAD+. Treatment with 10 μM oxaliplatin for 48 hours resulted in minor damage to auditory nerve fibers, but spared cochlear hair cells. However, when cochlear cultures were treated with 10 μM oxaliplatin plus 20 mM NAD+, most auditory nerve fibers were intact. 50 μM oxaliplatin destroyed most of spiral ganglion neurons and cochlear hair cells with apop-totic characteristics of cell fragmentations. However, 50 μM oxaliplatin plus 20 mM NAD+treatment great-ly reduced neuronal degenerations and hair cell missing. The results suggested that NAD+provides signifi-cant protection against oxaliplatin-induced neurotoxicity and ototoxicity, which may be due to its actions of antioxidant, antiapoptosis, and energy supply.

Effects of nicotinamide and riboflavin on the biodesulfurization activity of dibenzothiophene by Rhodococcus erythropolis USTB-03

Rhodococcus erythropolis USTB-03 is a promising bacterial strain for the biodesulfurization of dibenzothiophene （DBT） via a sulfurspecific pathway in which DBT is converted to 2-hydroxybiphenyl （2HBP） as an end product. The effects of nicotinamide and riboflavin on the sulfur specific activity （SA） of DBT biodesulfurization by R. erythropolis USTB-03 were investigated. Both nicotinamide and riboflavin were found to enhance the expression of SA, which was not previously reported. When R. erythropolis USTB-03 was grown on a medium containing nicotinamide of 10.0 mmol or riboflavin of 50.0 μmol, SA was raised from 68.0 or so to more than 130 mmol 2HBP/（kg dry cells.h）. When R. erythropolis USTB-03 was grown in the presence of both nicotinamide of 5.0 mmol and riboflavin of 25.0 μmol, SA was further increased to 159.0 mmol 2HBP/（kg dry cells.h）. It is suggested that the biological synthesis of reduced form of flavin mononucleotide （FMNH2）, an essential coenzyme for the activities of biodesulfurization enzyme Dsz C and A, might be enhanced by nicotinamide and riboflavin, which was responsible for the increased SA of R. erythropolis USTB-03.

Physiological Role of Humic Acid and Nicotinamide on Improving Plant Growth, Yield, and Mineral Nutrient of Wheat (<i>Triticum durum</i>) Grown under Newly Reclaimed Sandy Soil

Humic acid is not a fertilizer as it does not directly provide nutrients to plants, but is a compliment to fertilizer. Nicotinamide (Vitamin pp) is a stress-associated compound that can induce and regulate secondary metabolic accumulation and/or the manifestation of defense metabolism in plants. A field experiment was conducted at the experimental station of National Research center at El-Nubaria region, Egypt, to study the role of foliar application of humic acid (as soil conditioner 13 cm/l) and/or priming grains in nicotinamide (vitamin pp 5 mg/l) in saving irrigation water, decreasing fertilizer dose of NPK and at the same time increasing durum wheat (Triticum durum) cultivars’ (Beni Sweif-1 and Beni Sweif-3) productivity grown under newly reclaimed sandy soil exposed to drought for three weeks continuously. The results showed that plant treated with humic acid or nicotinamide increased significantly all morphological criteria (plant height, leaves number, fresh and dry weights of shoots), metabolism (photosynthetic pigment, total soluble sugar, total carbohydrates, total amino acids and proline), mineral contents (N, P, K, Ca and Mg) and yield (grain, straw and biology) of both cultivars amended with either recommended or half recommended doses of NPK. Foliar application of humic acid to plant priming in Vitamin pp induced significant increases in all studied parameters (morphology, chemical and yield) of plants amended with recommended or half recommended doses of NPK as compared with control plants. The maximum yields of grain, straw and biology of both cultivars were obtained in response to triple treatment (humic acid + nicotinamide + recommended dose of NPK) or (humic acid + nicotinamide + half recommended dose of NPK) respectively.

Nicotinamide overload may play a role in the development of type 2 diabetes

AIM： To investigate whether nicotinamide overload plays a role in type 2 diabetes. METHODS： Nicotinamide metabolic patterns of 14 diabetic and 14 non-diabetic subjects were compared using HPLC. Cumulative effects of nicotinamide and N^1-methylnicotinamide on glucose metabolism, plasma HzO2 levels and tissue nicotinamide adenine dinucleotide （NAD） contents of adult Sprague-Dawley rats were observed. The role of human sweat glands and rat skin in nicotinamide metabolism was investigated using sauna and burn injury, respectively. RESULTS： Diabetic subjects had significantly higher plasma N^1-methylnicotinamide levels 5 h after a 100-mg nicotinamide load than the non-diabetic subjects （0.89 ± 0.13 μmol/L vs 0.6 ± 0.13 μmol/L, P 〈 0.001）. Cumulative doses of nicotinamide （2 g/kg） significantly increased rat plasma Nl-methylnicotinamide concentrations associated with severe insulin resistance, which was mimicked by Nl-methy-Inicotinamide. Moreover, cumulative exposure to N^1- methylnicotinamide （2 g/kg） markedly reduced rat muscle and liver NAD contents and erythrocyte NAD/ NADH ratio, and increased plasma H2O2 levels. Decrease in NAD/NADH ratio and increase in H2O2 generation were also observed in human erythrocytes after exposure to N^1-methylnicotinamide in vitro. Sweating eliminated excessive nicotinamide （5.3-fold increase in sweat nicotinamide concentration 1 h after a 100-mg nicotinamide load）. Skin damage or aldehyde oxidase inhibition with tamoxifen or olanzapine, both being notorious for impairing glucose tolerance, delayed N^1- methylnicotinamide clearance. CONCLUSION： These findings suggest that nicotinamide overload, which induced an increase in plasma N^1- methylnicotinamide, associated with oxidative stress and insulin resistance, plays a role in type 2 diabetes.

Thermodynamics of Stability Constant of Binary Complex of Nicotinamide with Mn^(++)

The stability constants of the binary complexes of Mn2+ with nicotinamide (NA) were determined from potentiometric pH titrations data at 15.0 , 25.0 and 35.0oC and I = 0.1,0.2,0.4 mol L-1 (NaClO4). The formation of binary 1:1 , 1:2 NA-Mn complexes at three different temperatures and the influence of three different ionic strength on their stability were reported. The thermodynamic parameters (DGof, DSof, DHof) for the complex formation reaction were estimated from stability constant at different temperatures.

Synthesis and Crystal Structure of an Inclusion Compound Constructed through Self-assembly of Nicotinamide and Dicyanamide Coordination Bridges

A novel inclusion compound of [Mn（dca）2（3-nic）2]n·（3-nic）2n（1,dca = dicyanamide,3-nic = nicotinamide） has been prepared and characterized by single-crystal X-ray diffraction,elemental analysis and IR.This complex crystallizes in the triclinic system,space group P1 with a = 7.5979（8）,b = 7.7128（9）,c = 14.5346（17）,α = 100.094（2）,β = 92.444（2）,γ = 116.736（2）o,V = 741.72（15） 3,Z = 1,Dc = 1.512 g/cm3,Mr = 675.55,μ = 0.507 mm-1,F（000） = 347,S = 1.023,the final R = 0.0400 and wR = 0.1010.The inclusion compound is constructed by a three-dimensional host network that consists of dca,3-nic and Mn2＋ with coordination and hydrogen-bonding interactions.In the network,one-dimensional rectangular channels are formed,and the guest molecules（3-nic） are included in the channels.The guest molecules interlink with the host through strong hydrogen bonds.

Nicotinamide mononucleotide supplementation improves the quality of porcine oocytes under heat stress

Background:Elevated ambient temperature-caused heat stress is a major concern for livestock production due to its negative impact on animal feed intake,growth,reproduction,and health.Particularly,the germ cells are extremely sensitive to the heat stress.However,the effective approach and strategy regarding how to protect mammalian oocytes from heat stress-induced defects have not been determined.Methods:Germinal vesicle(GV)porcine oocytes were cultured at 41.5℃ for 24 h to induce heat stress,and then cultured at 38.5℃ to the specific developmental stage for subsequent analysis.Nicotinamide mononucleotide(NMN)was dissolved in water to 1 mol/L for a stock solution and further diluted with the maturation medium to the final concentrations of 10μmol/L,20μmol/L,50μmol/L or 100μmol/L,respectively,during heat stress.Immunostaining and fluorescence intensity quantification were applied to assess the effects of heat stress and NMN supplementation on the key processes during the oocyte meiotic maturation.Results:Here,we report that NMN supplementation improves the quality of porcine oocytes under heat stress.Specifically,we found that heat stress resulted in oocyte maturation failure by disturbing the dynamics of meiotic organelles,including the cytoskeleton assembly,cortical granule distribution and mitochondrial function.In addition,heat stress induced the production of excessive reactive oxygen species(ROS)and DNA damage,leading to the occurrence of apoptosis in oocytes and subsequent embryonic development arrest.More importantly,we validated that supplementation of NMN during heat stress restored the meiotic defects during porcine oocyte maturation.Conclusions:Taken together,our study documents that NMN supplementation is an effective approach to improve the quality of oocytes under heat stress by promoting both nuclear and cytoplasmic maturation.