Nicotinamide mononucleotide enhances fracture healing by promoting skeletal stem cell proliferation.

The process of skeletal regeneration initiated by stem cells following injury, especially in fractures, is significantly impaired by aging and adverse factors. Nicotinamide mononucleotide (NMN), a critical endogenous precursor of nicotinamide adenine dinucleotide (NAD), has garnered extensive attention for its multifaceted regulatory functions in living organisms and its wide-ranging therapeutic potential. However, whether NMN contributes to trauma-induced skeletal regeneration remains unclear. Methods: The transverse femoral shaft fracture model was employed to evaluate the potential advantages of NMN administration for overall repair during the initial fracture stages in male mice through micro-CT analysis, histochemistry, and biomechanical testing. The pro-proliferative function of NMN on skeletal stem cells (SSCs) was investigated through flow cytometry, qRT-PCR, NAD content measurement, and cell proliferation assay. Results: In this study, we observed that the administration of NMN during the initial phase of fracture in mice led to a larger callus and corresponding improvement in micro-CT parameters. NMN enhances the cartilaginous component of the callus by elevating the NAD content, consequently accelerating subsequent endochondral ossification and the fracture healing process. Subsequent analyses elucidated that NMN was beneficial in promoting the expansion of diverse stem cells in vivo and in vitro potentially via modulation of the Notch signaling pathway. Moreover, the depletion of macrophages profoundly obstructs the proliferation of SSCs. Conclusion: Our discoveries provide a potential strategy for enhancing fracture healing through stimulation of callus SSC proliferation at an early stage, shedding light on the translational value of NMN as an enhancer for skeletal regeneration and highlighting the pivotal role of macrophage-stem cell interactions in governing the regenerative influence of NMN on stem cells.

Nicotinamide Mononucleotide: Research Process in Cardiovascular Diseases.

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite that plays a crucial role in diverse biological processes, including energy metabolism, gene expression, DNA repair, and mitochondrial function. An aberrant NAD+ level mediates the development of cardiovascular dysfunction and diseases. Both in vivo and in vitro studies have demonstrated that nicotinamide mononucleotide (NMN), as a NAD+ precursor, alleviates the development of cardiovascular diseases such as heart failure, atherosclerosis, and myocardial ischemia/reperfusion injury. Importantly, NMN has suggested pharmacological activities mostly through its involvement in NAD+ biosynthesis. Several clinical studies have been conducted to investigate the efficacy and safety of NMN supplementation, indicating its potential role in cardiovascular protection without significant adverse effects. In this review, we systematically summarize the impact of NMN as a nutraceutical and potential therapeutic drug on cardiovascular diseases and emphasize the correlation between NMN supplementation and cardiovascular protection.

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Aging and age-related ailments have emerged as critical challenges and great burdens within the global contemporary society. Addressing these concerns is an imperative task, with the aims of postponing the aging process and finding effective treatments for age-related degenerative diseases. Recent investigations have highlighted the significant roles of nicotinamide adenine dinucleotide (NAD+) in the realm of anti-aging. It has been empirically evidenced that supplementation with nicotinamide mononucleotide (NMN) can elevate NAD+ levels in the body, thereby ameliorating certain age-related degenerative diseases. The principal anti-aging mechanisms of NMN essentially lie in its impact on cellular energy metabolism, inhibition of cell apoptosis, modulation of immune function, and preservation of genomic stability, which collectively contribute to the deferral of the aging process. This paper critically reviews and evaluates existing research on the anti-aging mechanisms of NMN, elucidates the inherent limitations of current research, and proposes novel avenues for anti-aging investigations.

Mesenchymal stem cells arouse myocardial NAD+ metabolism to alleviate microgravity-induced cardiac dysfunction.

After prolonged space operations, astronauts showed maladaptive atrophy within mostly left-ventricular myocardium, resulting in cardiac dysfunction. However, the mechanism of cardiac dysfunction under microgravity conditions is unclear, and the relevant prevention and treatment measures also need to be explored. Through simulating the microgravity environment with a tail suspension (TS) model, we found that long-term exposure to microgravity promotes aging of mouse hearts, which is closely related to cardiac dysfunction. The intravenous administration of adipose-derived mesenchymal stem cells (ADSCs) emerged preventive and therapeutic effect against myocardial senescence and the decline in cardiac function. Plasma metabolomics analysis suggests the loss of NAD+ in TS mice and motivated myocardial NAD + metabolism and utilization in ADSCs-treated mice, likely accounting for ADSCs' function. Oral administration of nicotinamide mononucleotide (NMN, a NAD + precursor) showed similar therapeutic effect to ADSCs treatment. Collectively, these data implicate the effect of ADSCs in microgravity-induced cardiac dysfunction and provide new therapeutic ideas for aging-related maladaptive cardiac remodeling.

NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich's Ataxia.

Friedreich's ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur centers in mitochondria. Individuals are cognitively normal but display a loss of motor coordination and cardiac abnormalities. Many ultimately develop heart failure. Administration of nicotinamide adenine dinucleotide-positive (NAD+) precursors has shown promise in human mitochondrial myopathy and rodent models of heart failure, including mice lacking frataxin in cardiomyocytes. We studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. Hearts in these mice do not "fail" per se but become hyperdynamic with small chamber sizes. Data from an ongoing natural history study indicate that hyperdynamic hearts are observed in young individuals with FRDA, suggesting that the mouse model could reflect early pathology. Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased, suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of FRDA and warrant further investigation.

NMN partially rescues cuproptosis by upregulating sirt2 to increase intracellular NADPH.

Cuproptosis is characterized by lipoylated protein aggregation and loss of iron-sulfur (Fe-S) proteins, which are crucial for a wide range of important cellular functions, including DNA replication and damage repair. Sirt2 and sirt4 are lipoamidases that remove the lipoyl moiety from lipoylated proteins using nicotinamide adenine dinucleotide (NAD+) as a cofactor. However, to date, it is not clear whether nicotinamide mononucleotide (NMN), a precursor of NAD+, affects cellular sensitivity to cuproptosis. Therefore, in the current study, cuproptosis was induced by the copper (Cu) ionophore elesclomol (Es) in HeLa cells. It was also found that Es/Cu treatment increased cellular DNA damage level. On the other hand, NMN treatment partially rescued cuproptosis in a dose-dependent manner, as well as reduced cellular DNA damage level. In addition, NMN upregulated the expression of Fe-S protein POLD1, without affecting the aggregation of lipoylated proteins. Mechanistic study revealed that NMN increased the expression of sirt2 and cellular reduced nicotinamide adenine dinucleotide phosphate (NADPH) level. Overexpression of sirt2 and sirt4 did not change the aggregation of lipoylated proteins, however, sirt2, but not sirt4, increased cellular NADPH levels and partially rescued cuproptosis. Inhibition of NAD+ kinase (NADK), which is responsible for generating NADPH, abolished the rescuing function of NMN and sirt2 for Es/Cu induced cell death. Taken together, our results suggested that DNA damage is a characteristic feature of cuproptosis. NMN can partially rescue cuproptosis by upregulating sirt2, increase intracellular NADPH content and maintain the level of Fe-S proteins, independent of the lipoamidase activity of sirt2.

NMN Synbiotics: A Multifaceted Therapeutic Approach for Alzheimer's Disease.

With the aging global population, Alzheimer's disease (AD) has become a significant social and economic burden, necessitating the development of novel therapeutic strategies. This study investigates the therapeutic potential of nicotinamide mononucleotide (NMN) synbiotics, a combination of NMN, Lactiplantibacillus plantarum CGMCC 1.16089, and lactulose, in mitigating AD pathology. APP/PS1 mice were supplemented with NMN synbiotics and compared against control groups. The effects on amyloid-ß (Aß) deposition, intestinal histopathology, tight junction proteins, inflammatory cytokines, and reactive oxygen species (ROS) levels were assessed. NMN synbiotics intervention significantly reduced Aß deposition in the cerebral cortex and hippocampus by 67% and 60%, respectively. It also ameliorated histopathological changes in the colon, reducing crypt depth and restoring goblet cell numbers. The expression of tight junction proteins Claudin-1 and ZO-1 was significantly upregulated, enhancing intestinal barrier integrity. Furthermore, NMN synbiotics decreased the expression of proinflammatory cytokines IL-1ß, IL-6, and TNF-α, and reduced ROS levels, indicative of attenuated oxidative stress. The reduction in Aß deposition, enhancement of intestinal barrier function, decrease in neuroinflammation, and alleviation of oxidative stress suggest that NMN synbiotics present a promising therapeutic intervention for AD by modulating multiple pathological pathways. Further research is required to elucidate the precise mechanisms, particularly the role of the NLRP3 inflammasome pathway, which may offer a novel target for AD treatment.

Therapeutic effect of nicotinamide mononucleotide on Alzheimer's disease through activating autophagy and anti-oxidative stress.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of ß-amyloid (Aß) plaques and neurofibrillary tangles composed of tau protein in the brain. These neuropathological hallmarks contribute to cognitive impairment by inducing neuronal loss in the cerebral cortex and hippocampus. Unfortunately, current therapeutic approaches only target symptomatic relief and do not impede disease progression. Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD+), has emerged as a promising candidate for the treatment of age-related neurodegenerative disorders. NMN supplementation could restore NAD+ levels, thereby alleviating neuronal damage and slowing the progression of AD and other aging-associated diseases. AD is closely associated with autophagic impairment and oxidative stress. Our in vivo experiments demonstrated that NMN could ameliorate pathological and behavioral impairments in AD mice. Specifically, NMN enhanced autophagy and promoted p-tau clearance. Meanwhile, NMN could activate the Nrf2/Keap1/NQO1 pathway, thereby reducing the oxidative stress. Immunofluorescence results demonstrated that NMN could alleviate neuronal damage in AD mice. Furthermore, in vitro results showed that the p-tau clearance and antioxidant stress effects of NMN were suppressed by autophagy inhibitor, chloroquine (CQ) or bafilomycin A1 (BafA1), in Aß-induced PC12 cells. Lastly, when Nrf2 was knocked down, the antioxidant stress, autophagy enhancement, and p-tau clearance effects of NMN were all inhibited. In conclusion, our research indicates that NMN exerts therapeutic effect against AD by activating autophagy and the Nrf2/Keap1/NQO1 pathway through a mutual regulating mechanism of autophagy and antioxidative stress. These findings highlight the promising potential of NMN for the treatment of AD.

Microbial creation of ß-Nicotinamide mononucleotide and its regulation of lipid metabolism in the liver of high-fat diet mice.

ß-Nicotinamide mononucleotide (NMN) is a biologically active nucleotide that regulates the physiological metabolism of the body by rapidly increasing nicotinamide adenine dinucleotide (NAD+). To determine the safety and biological activity of NMN resources, we constructed a recombinant strain of P. pastoris that heterologously expresses nicotinamide-phosphate ribosyltransferase (NAMPT), and subsequently catalyzed and purified the expressed product to obtain NMN. Consequently, this study established a high-fat diet (HFD) obese model to investigate the lipid-lowering activity of NMN. The findings showed that NMN supplementation directly increased the NAD+ levels, and reduced HFD-induced liver injury and lipid deposition. NMN treatment significantly decreased total cholesterol (TC) and triglyceride (TG) in serum and liver, as well as alanine aminotransferase (ALT) and insulin levels in serum (p < .05 or p < .01). In conclusion, this study combined synthetic biology with nutritional evaluation to confirm that P. pastoris-generated NMN modulated lipid metabolism in HFD mice, offering a theoretical framework and evidence for the application of microbially created NMN.

NAMPT Overexpression Drives Cell Growth in Polycystic Liver Disease through Mitochondrial Metabolism Regulation.

A group of genetic diseases known as polycystic liver disease (PLD) are distinguished by the gradual development of fluid-filled hepatic cysts formed from cholangiocytes and commonly related to primary cilia defects. The NAD salvage pathway, which sustains cellular bioenergetics and supplies a required substrate for tasks important to rapidly multiplying cells, has a rate-limiting phase that is mediated by nicotinamide phosphoribosyltransferase (NAMPT). In this study, the efficacy and mechanisms of action of FK866, a novel, high-potency NAMPT inhibitor with a good toxicity profile, were assessed. NAMPT-siRNA and FK866 reduced NAD levels and inhibited the proliferation of PLD cells in a dose-dependent manner. Notably, this pharmacologic and siRNA-mediated suppression of NAMPT was less effective in normal cells at the same concentrations. The addition of nicotinamide mononucleotide (NMN), a byproduct of NAMPT that restores NAD concentration, rescued the cellular viability of PLD cells and verified the on-target action of FK866. In FK866-treated PLD cells, mitochondrial respiration and ATP production were impaired and reactive oxygen species production was induced. Importantly, FK866 treatment was associated with improved effects of octreotide, a drug used for PLD treatment. As a result, the use of NAMPT inhibitors, including FK866 therapy, offers the possibility of a further targeted strategy for the therapeutic treatment of PLD.

Prophylactic nicotinamide mononucleotide (NMN) mitigates CSDS-induced depressive-like behaviors in mice via preserving of ATP level in the mPFC.

Depression is a prevalent psychiatric disorder with accumulating evidence implicating dysregulation of extracellular adenosine triphosphate (ATP) levels in the medial prefrontal cortex (mPFC). It remains unclear whether facilitating endogenous ATP production and subsequently increasing extracellular ATP level in the mPFC can exert a prophylactic effect against chronic social defeat stress (CSDS)-induced depressive-like behaviors and enhance stress resilience. Here, we found that nicotinamide mononucleotide (NMN) treatment effectively elevated nicotinamide adenine dinucleotide (NAD+) biosynthesis and extracellular ATP levels in the mPFC. Moreover, both the 2-week intraperitoneal (i.p.) injection and 3-week oral gavage of NMN prior to exposure to CSDS effectively prevented the development of depressive-like behavior in mice. These protective effects were accompanied with the preservation of both NAD+ biosynthesis and extracellular ATP level in the mPFC. Furthermore, catalyzing ATP hydrolysis by mPFC injection of the ATPase apyrase negated the prophylactic effects of NMN on CSDS-induced depressive-like behaviors. Prophylactic NMN treatment also prevented the reduction in GABAergic inhibition and the increase in excitability in mPFC neurons projecting to the lateral habenula (LHb). Collectively, these findings demonstrate that the prophylactic effects of NMN on depressive-like behaviors are mediated by preventing extracellular ATP loss in the mPFC, which highlights the potential of NMN supplementation as a novel approach for protecting and preventing stress-induced depression in susceptible individuals.

Identification of adrenergic presynaptic and postsynaptic protein locations at neuromuscular junctions, their decrease during aging, and recovery by nicotinamide mononucleotide administration.

Neuromuscular junctions are innervated by motor and sympathetic nerves. The sympathetic modulation of motor innervation shows functional decline during aging, but the cellular and molecular mechanism of this change is not fully known. This study aimed to evaluate the effect of aging on sympathetic nerves and synaptic proteins at mouse neuromuscular junctions. Sympathetic nerves, presynaptic, and postsynaptic proteins of sympathetic nerves at neuromuscular junctions were visualized using immunohistochemistry, and aging-related changes were compared between adult-, aged-, and nicotinamide mononucleotide (NMN) administered aged mice. Sympathetic nerves were detected by anti-tyrosine hydroxylase antibody, and presynaptic protein vesicular monoamine transporter 2 colocalized with the sympathetic nerves. These two signals surrounded motor nerve terminals and acetylcholine receptor clusters. Postsynaptic neurotransmitter receptor ß2-adrenergic receptors colocalized with motor nerve terminals and resided in reduced density at extrasynaptic sarcolemma. The signal intensity of the sympathetic nerve marker did not show a significant difference at neuromuscular junctions between 8.5-month-old adult mice and 25-month-old aged mice. However, the signal intensity of vesicular monoamine transporter 2 and ß2-adrenergic receptors showed age-related decline at neuromuscular junctions. Interestingly, both age-related declines reverted to the adult level after 1 month of oral administration of NMN by drinking water. In contrast, NMN administration did not alter the expression level of sympathetic marker tyrosine hydroxylase at neuromuscular junctions. The results suggest a functional decline of sympathetic nerves at aged neuromuscular junctions due to decreases in presynaptic and postsynaptic proteins, which can be reverted to the adult level by NMN administration.

Alleviation of hepatic insulin resistance and steatosis with NMN via improving endoplasmic reticulum-Mitochondria miscommunication in the liver of HFD mice.

The interaction between endoplasmic reticulum (ER) and mitochondria has been shown to play a key role in hepatic steatosis during chronic obesity. ß-nicotinamide mononucleotide (NMN) has been reported to regulate obesity, however, its molecular mechanism at the subcellular level remains unclear. Here, NMN improved liver steatosis and insulin resistance in chronic high-fat diet (HFD) mice. RNA-seq showed that compared with the liver of HFD mice, NMN intervention enhanced fat digestion and absorption and stimulated the cholesterol metabolism signaling pathways, while impaired insulin resistance and the fatty acid biosynthesis signaling pathways. Mechanistically, NMN ameliorated mitochondrial dysfunction and ER oxidative stress in the liver of HFD mice by increasing hepatic nicotinamide adenine dinucleotide (NAD+) (P < 0.01) levels. This effect increased the contact sites (mitochondria-associated membranes [MAMs]) between ER and mitochondria, thereby promoting intracellular ATP (P < 0.05) production and mitigating lipid metabolic disturbances in the liver of HFD mice. Taken together, this study provided a theoretical basis for restoring metabolic dynamic equilibrium in the liver of HFD mice by increasing MAMs via the nutritional strategy of NMN supplementation.

Integrated transcriptome and metabolome study reveal the therapeutic effects of nicotinamide riboside and nicotinamide mononucleotide on nonalcoholic fatty liver disease.

Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) have received considerable attention as anti-aging and anti-metabolic disease nutraceuticals. However, few studies have focused on their role in ameliorating hepatic metabolic disturbances. In the present study, the effects of NMN and NR on the liver of mice with nonalcoholic fatty liver disease (NAFLD) were investigated via transcriptome and metabolome analyses. NMN and NR reduced body weight gain, improved glucose homeostasis, regulated plasma lipid levels, and ameliorated liver injury, oxidative stress, and lipid accumulation in mice with HFD-induced NAFLD. Integrated transcriptome and metabolome analyses indicated that NMN and NR altered the biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, and linoleic acid metabolism pathways, increased saturated fatty acid (palmitic acid, stearate, and arachidic acid) content, and increased polyunsaturated fatty acid (linoleic acid and eicosapentaenoic acid) content. Quantitative reverse transcription PCR (qRT-PCR) showed that NMN and NR primarily promoted arachidonic acid and linoleic acid catabolism via cytochrome P450 (CYP450) enzymes. This study established a theoretical foundation for the potential use of NMN and NR in future clinical settings.

Nicotinamide Mononucleotide Supplementation Alleviates Doxorubicin-Induced Multi-Organ Fibrosis.

Doxorubicin (DOX) is a potent chemotherapeutic agent known for its multi-organ toxicity, especially in the heart, which limits its clinical application. The toxic side effects of DOX, including DNA damage, oxidative stress, mitochondrial dysfunction and cell apoptosis, are intricately linked to the involvement of nicotinamide adenine dinucleotide (NAD+). To assess the effectiveness of the NAD+ precursor nicotinamide mononucleotide (NMN) in counteracting the multi-organ toxicity of DOX, a mouse model was established through DOX administration, which led to significant reductions in NAD+ in tissues with evident injury, including the heart, liver and lungs. NMN treatment alleviated both multi-organ fibrosis and mortality in mice. Mechanistically, tissue fibrosis, macrophage infiltration and DOX-related cellular damage, which are potentially implicated in the development of multi-organ fibrosis, could be attenuated by NAD+ restoration. Our findings provide compelling evidence for the benefits of NMN supplementation in mitigating the adverse effects of chemotherapeutic drugs on multiple organs.

Ability of NAD and Sirt1 to epigenetically suppress albuminuria.

The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects mediated through epigenetic regulation. In this study, we demonstrated the ability of nicotinamide adenine dinucleotide (NAD) and its metabolites to reduce albuminuria through Sirt1- or Nampt-dependent epigenetic regulation. We previously reported that proximal tubular Sirt1 was lowered before glomerular Sirt1. Repressed glomerular Sirt1 was found to epigenetically elevate Claudin-1. In addition, we reported that proximal tubular Nampt deficiency epigenetically augmented TIMP-1 levels in Sirt6-mediated pathways, leading to type-IV collagen deposition and diabetic fibrosis. Altogether, we propose that the Sirt1/Claudin-1 axis may be crucial in the onset of albuminuria at the early stages of DN and that the Nampt/Sirt6/TIMP-1 axis promotes diabetic fibrosis in the middle to late stages of DN. Finally, administration of NMN, an NAD precursor, epigenetically potentiates the regression of the onset of DN to maintain Sirt1 and repress Claudin-1 in podocytes, suggesting the potential use of NAD metabolites as epigenetic medications for DN.

Nicotinamide Mononucleotide and Nicotinamide Riboside Reverse Ovarian Aging in Rats Via Rebalancing Mitochondrial Fission and Fusion Mechanisms.

PURPOSE: This study examined the effects of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) on folliculogenesis and mitochondrial dynamics (fission and fusion mechanisms) in ovaries of middle-aged female rats. METHODS: Experimental groups were young, middle-aged (control), middle-aged + NMN and middle-aged + NR. NMN was administered at a concentration of 500 mg/kg intraperitoneally but NR at a concentration of 200 mg/kg by gavage. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were analyzed by ELISA. Hematoxylin-eosin staining sections were used for histopathological examination and follicles-counting. Expression levels of mitochondrial fission (Drp1, Mff and Fis1) and fusion (Mfn1, Mfn2, Opa1, Fam73a and Fam73b) genes as well as Sirt1 gene were analyzed by RT-PCR. Expression levels of fission-related proteins (DRP1, MFF, FIS1 and SIRT1) were analyzed by Western Blot. RESULTS: Higher ovarian index, more corpus luteum and antral follicles were detected in NMN and NR groups compared to the control. NMN or NR could rebalance LH/FSH ratio. The control group was determined to possess higher expression levels of fission genes and lower expression levels of fusion genes when compared the young group. In comparison with the control group, both NMN and NR group were found to exhibit less mitochondrial fission but more mitochondrial fussion. Higher gene and protein levels for Sirt1 were measured in NMN and NR groups compared to the control group. CONCLUSION: This study reveals that NMN alone or NR alone can rebalance mitochondrial dynamics by decreasing excessive fission in middle-aged rat ovaries, thus alleviating mitochondrial stress and correcting aging-induced folliculogenesis abnormalities.

Design and preparation of NMN nanoparticles based on protein-marine polysaccharide with increased NAD+ level in D-galactose induced aging mice model.

Nicotinamide mononucleotide (NMN) is being investigated for its ability to address the decline in NAD+ level during aging. This study aimed to construct a delivery system based on ovalbumin and fucoidan nanoparticles to ameliorate the bioaccessibility of NMN by increasing NAD+ level in aging mouse model. The NMN-loaded ovalbumin and fucoidan nanoparticles (OFNPs) were about 177 nm formed by the interplay of hydrogen bonds between ovalbumin and fucoidan. Compared with free NMN, NMN-loaded OFNPs intervention could obviously improve the antioxidant enzyme activity of senescent cell induced by D-galactose. The NMN-loaded OFNPs treatment could ameliorate the loss of weight and organ index induced by senescence, and maintain the water content for the aging mice. The Morris maze test indicated that hitting blind side frequency and escape time of NMN-loaded OFNPs group decreased by 13% and 35% compared with that of free NMN group. Furthermore, the NMN-loaded OFNPs significantly alleviated the age-related oxidative stress and increased the generation of NAD+ 1.34 times by improving the bioaccessibility of NMN. Our data in this study supplied a strategy to enhance the bioavailability of NMN in senescence treatment.

Nicotinamide Mononucleotide improves oocyte maturation of mice with type 1 diabetes.

BACKGROUND: The number of patients with type 1 diabetes rises rapidly around the world in recent years. Maternal diabetes has a detrimental effect on reproductive outcomes due to decreased oocyte quality. However, the strategies to improve the oocyte quality and artificial reproductive technology (ART) efficiency of infertile females suffering from diabetes have not been fully studied. In this study, we aimed to examine the effects of nicotinamide mononucleotide (NMN) on oocyte maturation of mouse with type 1 diabetes mouse and explore the underlying mechanisms of NMN's effect. METHODS: Streptozotocin (STZ) was used to establish the mouse models with type 1 diabetes. The successful establishment of the models was confirmed by the results of body weight test, fasting blood glucose test and haematoxylin and eosin (H&E) staining. The in vitro maturation (IVM) rate of oocytes from diabetic mice was examined. Immunofluorescence staining (IF) was performed to examine the reactive oxygen species (ROS) level, spindle/chromosome structure, mitochondrial function, actin dynamics, DNA damage and histone modification of oocytes, which are potential factors affecting the oocyte quality. The quantitative reverse transcription PCR (RT-qPCR) was used to detect the mRNA levels of Sod1, Opa1, Mfn2, Drp1, Sirt1 and Sirt3 in oocytes. RESULTS: The NMN supplementation increased the oocyte maturation rate of the mice with diabetes. Furthermore, NMN supplementation improved the oocyte quality by rescuing the actin dynamics, reversing meiotic defects, improving the mitochondrial function, reducing ROS level, suppressing DNA damage and restoring changes in histone modifications of oocytes collected from the mice with diabetes. CONCLUSION: NMN could improve the maturation rate and quality of oocytes in STZ-induced diabetic mice, which provides a significant clue for the treatment of infertility of the patients with diabetes.

Nicotinamide mononucleotide maintains cytoskeletal stability and fortifies mitochondrial function to mitigate oocyte damage induced by Triocresyl phosphate.

Triocresyl phosphate (TOCP) was commonly used as flame retardant, plasticizer, lubricant, and jet fuel additive. Studies have shown adverse effects of TOCP on the reproductive system. However, the potential harm brought by TOCP, especially to mammalian female reproductive cells, remains a mystery. In this study, we employed an in vitro model for the first time to investigate the effects of TOCP on the maturation process of mouse oocytes. TOCP exposure hampered the meiotic division process, as evidenced by a reduction in the extrusion of the first polar body from oocytes. Subsequent research revealed the disruption of the oocyte cell cytoskeleton induced by TOCP, resulting in abnormalities in spindle organization, chromosome alignment, and actin filament distribution. This disturbance further extended to the rearrangement of organelles within oocytes, particularly affecting the mitochondria. Importantly, after TOCP treatment, mitochondrial function in oocytes was impaired, leading to oxidative stress, DNA damage, cell apoptosis, and subsequent changes of epigenetic modifications. Supplementation with nicotinamide mononucleotide (NMN) alleviated the harmful effects of TOCP. NMN exerted its mitigating effects through two fundamental mechanisms. On one hand, NMN conferred stability to the cell cytoskeleton, thereby supporting nuclear maturation. On the other hand, NMN enhanced mitochondrial function within oocytes, reducing the excess reactive oxygen species (ROS), restoring meiotic division abnormalities caused by TOCP, preventing oocyte DNA damage, and suppressing epigenetic changes. These findings not only enhance our understanding of the molecular basis of TOCP induced oocyte damage but also offer a promising avenue for the potential application of NMN in optimizing reproductive treatment strategies.