Towards personalized nicotinamide mononucleotide (NMN) supplementation: Nicotinamide adenine dinucleotide (NAD) concentration.

Nicotinamide mononucleotide (NMN) is a precursor of nicotinamide adenine dinucleotide (NAD), which declines with age. Supplementation of NMN has been shown to improve blood NAD concentration. However, the optimal NMN dose remains unclear. This is a post-hoc analysis of a double-blinded clinical trial involving 80 generally healthy adults aged 40-65 years. The participants received a placebo or daily 300 mg, 600 mg, or 900 mg NMN for 60 days. Blood NAD concentration, blood biological age, homeostatic model assessment for insulin resistance, 6-minute walk test, and 36-item short-form survey (SF-36) were measured at baseline and after supplement. A significant dose-dependent increase in NAD concentration change (NADΔ) was observed following NMN supplementation, with a large coefficient of variation (29.2-113.3%) within group. The increase in NADΔ was associated with an improvement in the walking distance of 6-minute walk test and the SF-36 score. The median effect dose of NADΔ for the 6-minute walk test and SF-36 score was 15.7 nmol/L (95% CI: 10.9-20.5 nmol/L) and 13.5 nmol/L (95% CI; 10.5-16.5 nmol/L), respectively. Because of the high interindividual variability of the NADΔ after NMN supplementation, monitoring NAD concentration can provide valuable insights for tailoring personalized dosage regimens and optimizing NMN utilization.

Population Pharmacokinetic/Pharmacodynamic Analysis of the Glucokinase Activator PB201 in Healthy Volunteers and Patients with Type 2 Diabetes Mellitus: Facilitating the Clinical Development of PB201 in China.

PB201 is an orally active, partial glucokinase activator targeting both pancreatic and hepatic glucokinase. As the second glucokinase activator studied beyond phase I, PB201 has demonstrated promising glycemic effects as well as favorable pharmacokinetic (PK) and safety profiles in patients with type 2 diabetes mellitus (T2DM). This study aims to develop a population PK/pharmacodynamic (PD) model for PB201 using the pooled data from nine phase I/II clinical trials conducted in non-Chinese healthy volunteers and a T2DM population and to predict the PK/PD profile of PB201 in a Chinese T2DM population. We developed the PK/PD model using the non-linear mixed-effects modeling approach. All runs were performed using the first-order conditional estimation method with interaction. The pharmacokinetics of PB201 were well fitted by a one-compartment model with saturable absorption and linear elimination. The PD effects of PB201 on reducing the fasting plasma glucose and glycosylated hemoglobin levels in the T2DM population were described by indirect response models as stimulating the elimination of fasting plasma glucose, where the production of glycosylated hemoglobin was assumed to be stimulated by fasting plasma glucose. Covariate analyses revealed enhanced absorption of PB201 by food and decreased systemic clearance with ketoconazole co-administration, while no significant covariate was identified for the pharmacodynamics. The population PK model established for non-Chinese populations was shown to be applicable to the Chinese T2DM population as verified by the PK data from the Chinese phase I study. The final population PK/PD model predicted persistent and dose-dependent reductions in fasting plasma glucose and glycosylated hemoglobin levels in the Chinese T2DM population receiving 50/50 mg, 100/50 mg, and 100/100 mg PB201 twice daily for 24 weeks independent of co-administration of metformin. Overall, the proposed population PK/PD model quantitatively characterized the PK/PD properties of PB201 and the impact of covariates on its target populations, which allows the leveraging of extensive data in non-Chinese populations with the limited data in the Chinese T2DM population to successfully supported the waiver of the clinical phase II trial and facilitate the optimal dose regimen design of a pivotal phase III study of PB201 in China.

The efficacy and safety of ß-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial.

In animal studies, ß-nicotinamide mononucleotide (NMN) supplementation increases nicotinamide adenine dinucleotide (NAD) concentrations and improves healthspan and lifespan with great safety. However, it is unclear if these effects can be transferred to humans. This randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial included 80 middle-aged healthy adults being randomized for a 60-day clinical trial with once daily oral dosing of placebo, 300 mg, 600 mg, or 900 mg NMN. The primary objective was to evaluate blood NAD concentration with dose-dependent regimens. The secondary objectives were to assess the safety and tolerability of NMN supplementation, next to the evaluation of clinical efficacy by measuring physical performance (six-minute walking test), blood biological age (Aging.Ai 3.0 calculator), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and subjective general health assessment [36-Item Short Form Survey Instrument (SF-36)]. Statistical analysis was performed using the Per Protocol analysis with significant level set at p = 0.05. All 80 participants completed the trial without trial protocol violation. Blood NAD concentrations were statistically significantly increased among all NMN-treated groups at day 30 and day 60 when compared to both placebo and baseline (all p ≤ 0.001). Blood NAD concentrations were highest in the groups taking 600 mg and 900 mg NMN. No safety issues, based on monitoring adverse events (AEs), laboratory and clinical measures, were found, and NMN supplementation was well tolerated. Walking distance increase during the six-minute walking test was statistically significantly higher in the 300 mg, 600 mg, and 900 mg groups compared to placebo at both days 30 and 60 (all p < 0.01), with longest walking distances measured in the 600 mg and 900 mg groups. The blood biological age increased significantly in the placebo group and stayed unchanged in all NMN-treated groups at day 60, which resulted in a significant difference between the treated groups and placebo (all p < 0.05). The HOMA-IR showed no statistically significant differences for all NMN-treated groups as compared to placebo at day 60. The change of SF-36 scores at day 30 and day 60 indicated statistically significantly better health of all three treated groups when compared to the placebo group (p < 0.05), except for the SF-36 score change in the 300 mg group at day 30. NMN supplementation increases blood NAD concentrations and is safe and well tolerated with oral dosing up to 900 mg NMN daily. Clinical efficacy expressed by blood NAD concentration and physical performance reaches highest at a dose of 600 mg daily oral intake. This trial was registered with ClinicalTrials.gov, NCT04823260, and Clinical Trial Registry - India, CTRI/2021/03/032421.

Research hotspots and trends on neuropathic pain-related mood disorders: a bibliometric analysis from 2003 to 2023.

Introduction: Neuropathic Pain (NP) is often accompanied by mood disorders, which seriously affect the quality of life of patients. This study aimed to analyze the hotspots and trends in NP-related mood disorder research using bibliometric methods and to provide valuable predictions for future research in this field. Methods: Articles and review articles on NP-related mood disorders published from January 2003 to May 2023 were retrieved from the Web of Science Core Collection. We used CiteSpace to analyze publications, countries, institutions, authors, cited authors, journals, cited journals, references, cited references, and keywords. We also analyzed collaborative network maps and co-occurrence network maps. Results: A total of 4,540 studies were collected for analysis. The number of publications concerning NP-related mood disorders every year shows an upward trend. The United States was a major contributor in this field. The University of Toronto was the most productive core institution. C GHELARDINI was the most prolific author, and RH DWORKIN was the most frequently cited author. PAIN was identified as the journal with the highest productivity and citation rate. The current research hotspots mainly included quality of life, efficacy, double-blind methodology, gabapentin, pregabalin, postherpetic neuralgia, and central sensitization. The frontiers in research mainly focused on the mechanisms associated with microglia activation, oxidative stress, neuroinflammation, and NP-related mood disorders. Discussion: In conclusion, the present study provided insight into the current state and trends in NP-related mood disorder research over the past 20 years. Consequently, researchers will be able to identify new perspectives on potential collaborators and cooperative institutions, hot topics, and research frontiers in this field.

Possible mechanism underlying analgesic effect of Tuina in rats may involve piezo mechanosensitive channels within dorsal root ganglia axon.

OBJECTIVE: To demonstrate the analgesic effect of Tuina mainly from mechanically sensitive ion channels in peripheral myelinated nerve fibers. METHODS: A total of 40 healthy and pathogen-free adult male Sprague-Dawley rats were used in the study [weight: (220.0 ¡À 1.4) g, Shanghai Slac Laboratory Animal Co., Ltd., Shanghai, China; license No. Shanghai ICP 05033115]. The rats were housed in cages with free access to water and food in a temperature-controlled room [(22 ¡À 1) ¡æ and 12-h/12-h light-dark cycle. Thirty-two rats were randomly divided into five groups: naive, sham, chronic compression of dorsal root ganglion (CCD), Tuina (7 d) and Tuina (21 d). CCD rat model was established via unilateral DRG compression by ""L"" liked steel bar. Chinese Tuina treatment was accepted once per day. Behavior monitoring of paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were tested. The expression of Piezo1 and Piezo2 in myelinated nerve fiber were analyzed by immunohistochemistry and Western-blotting. RESULTS: There was a high expression of Piezo2 and a low expression of Piezo1 in the naive and CCD groups. In contrast, the expression of Piezo2 was down regulated and Piezo1 was increased after a period of Tuina. There was significant difference (P¡Ü0.05) between the groups. CONCLUSION: Our findings suggest that Tuina therapy can increase the expression of Piezo2 and decrease the expression of Piezo1 in the test rats. The different changes in the expressions of Piezo1 and Piezo2 may play an important role in alleviating CCD-induced allodynia and hyperalgesia.

Hot food and beverage consumption and the risk of esophageal squamous cell carcinoma: A case-control study in a northwest area in China.

BACKGROUND: This study was trying to investigate the association of hot food and beverage consumption and the risk of esophageal squamous cell carcinoma in Hotan, a northwest area of China with high risk of esophageal squmous cell carcinoma. METHODS: A population-based case-control study was designed. For the study, 167 patients diagnosed with esophageal squamous cell carcinoma were selected from Hotan during 2014 to 2015, and 167 community-based controls were selected from the same area, matched with age and sex. Information involved of temperature of food and beverage intake was obtained by face-to-face interview. Logistic regression analyses were performed to investigate the association between temperature of food and beverage intake and the risk of esophageal squamous cell carcinoma. RESULTS: The temperature of the food and beverage consumed by the esophageal squamous cell carcinoma patients was significantly higher than the controls. High temperature of tea, water, and food intake significantly increased the risk of esophageal squamous cell carcinoma by more than 2-fold, with adjusted odds ratio 2.23 (1.45-2.90), 2.13 (1.53-2.66), and 2.98 (1.89-4.12). CONCLUSIONS: Intake of food and beverage with high temperature was positively associated with the incidence of esophageal squamous cell carcinoma in Northwestern China.

18F-FDG PET/CT makes a significant contribution to diagnosis of malignancy in patients with cervical lymphadenopathy: a study using optimal scale regression tests.

BACKGROUND: The specificity and precision of lymphadenopathy assessment using US, CT and MRI are generally unsatisfactory, while fluorodeoxyglucose-positron emission tomography/computed tomography ((18)F-FDG PET/CT) can support this process by providing additional information about the lymph node features. However, which image features of (18)F-FDG PET/CT play the key role in the diagnosis and cutoffs of malignant cervical lymphadenopathy still needs to be determined by further studies. Our study aimed to identify (18)F-FDG PET/CT abnormalities that would assist in making a reliable diagnosis of malignant cervical lymphadenopathy in enlarged cervical lymph nodes of patients with unknown primary diseases. METHODS: One hundred and ninety-one consecutive patients of cervical lymphadenopathy with unknown primary causes were examined by (18)F-FDG PET/CT from May 2007 to October 2011 and a definite diagnosis was established by pathologic biopsy. (18)F-FDG PET/CT images were evaluated to identify the relevant abnormalities. All image features were analyzed by optimal scale regression tests to determine the important factors that were predictive for the diagnosis of malignant cervical lymphadenopathy and the cutoffs. RESULTS: The factors studied in (18)F-FDG PET/CT images for predicting malignant cervical lymphadenopathy were sex, age, node location, size, shape, margins, maximum standard uptake value (SUV), mean SUV, FDG uptake pattern and number of nodes. It was found that mean SUV, maximum SUV, FDG uptake pattern, location, size and margins were the important risk factors of cervical lymph nodes that could predict malignant cervical lymphadenopathy. Signs of mean SUV ≥ 2.5 (or maximum SUV ≥ 3.5), nodular FDG uptake pattern, location of IIA, III, IV, VB, VI and VII regions, size ≥ 1.5 cm and vague margins had their optimal diagnostic accuracy (Ac) and Youden index (YI), further, combination of any three factors of these six important risk factors would led to the best diagnostic Ac of 96% and YI of 0.93. CONCLUSIONS: Signs of mean SUV, maximum SUV, FDG uptake pattern, location, size and margins of node in (18)F-FDG PET/CT imaging are important predictive factors of malignant cervical lymphadenopathy. A combination of multiple factors may yield a higher diagnostic efficacy.

Epigenetic regulation of gene expression as an anticancer drug target.

Epigenetic processes play a key regulatory role in cancer. Hypermethylation in the CpG islands of the promoter regions of many tumour suppressor genes leads to the recruitment of co-repressors, altered chromatin structure, and ultimately transcriptional silencing. Key components in the regulation of DNA methylation are DNA methyltransferases (DNMT1, 2, 3A and 3B) and methyl CpG-binding proteins, which recognize methyl cytosine residues and recruit transcriptional repressor complexes, including histone deacetylases (HDAC). DNMT1 is responsible for the maintenance of DNA methylation patterns during replication. Inhibitors of this enzyme may potentially lead to DNA hypomethylation, and re-expression of tumour suppressor genes. Several DNMT inhibitors are currently being evaluated in preclinical and clinical studies, include various analogues of adenosine, cytidine or deoxycytidine. However, such drugs have had limited clinical success, perhaps because of cytotoxicity associated with their incorporation into DNA. Non-nucleoside small molecule inhibitors of DNMTs can directly block DNMT activity, and may be able to circumvent this cytotoxicity. Post-translational modifications of histones play a key role, not only in regulating chromatin structure and gene expression, but also in genomic stability. Histone acetylation (HAT) and histone deacetylation (HDAC) affect chromatin condensation, with concomitant effects on gene transcription. A further range of compounds is being evaluated for clinical use as HDAC inhibitors, including hydroxamic acids such as Trichostatin A (TSA) and Suberoyl anilide bishydroxamide (SAHA). MicroRNAs are also found to play a key role in cancer development, and novel approaches to their regulation may provide a susceptible anticancer drug target. Because of the interdependence of epigenetic processes, combinations of these approaches may have maximum clinical efficacy.

Quinazolines as novel anti-inflammatory histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors regulate many biological responses, including anti-inflammatory and anti-cancer effects. We sought to identify novel classes of HDAC inhibitors from in-house compound libraries. Initially, compounds from 26 different structural classes that showed anti-inflammatory effects in a pre-screen in HEK293T cells were tested in vitro for HDAC inhibition, using a commercial fluorescence assay. The known HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) were used as positive controls. Examples of three different structural classes (anilinoacridines, phenylpyrrolocarbazoles and benzofurylquinazolines) showed significant inhibition in the HDAC assay, and small subsets of these were also evaluated, seeking initial structure-activity relationships (SAR) for each class. Several of the most effective compounds from this HDAC screen were evaluated for their effects on the expression of the pro-inflammatory gene, IL1-alpha, and the cancer-related genes, p53, p21, E-cadherin and C-MYC. While the benzofurylquinazolines increased the expression level of the pro-inflammatory gene IL1-alpha as well as p21 and p53 in the PC3 cell line, a phenylpyrrolocarbazole had the converse effect on p53 expression. Several of the compounds showed in vitro HDAC inhibition ability in PC3, HCT116 and NIH-3T3 cell lines comparable to that of SAHA.