Defective branched-chain amino acid catabolism in dorsal root ganglia contributes to mechanical pain.

Impaired branched-chain amino acid (BCAA) catabolism has recently been implicated in the development of mechanical pain, but the underlying molecular mechanisms are unclear. Here, we report that defective BCAA catabolism in dorsal root ganglion (DRG) neurons sensitizes mice to mechanical pain by increasing lactate production and expression of the mechanotransduction channel Piezo2. In high-fat diet-fed obese mice, we observed the downregulation of PP2Cm, a key regulator of the BCAA catabolic pathway, in DRG neurons. Mice with conditional knockout of PP2Cm in DRG neurons exhibit mechanical allodynia under normal or SNI-induced neuropathic injury conditions. Furthermore, the VAS scores in the plasma of patients with peripheral neuropathic pain are positively correlated with BCAA contents. Mechanistically, defective BCAA catabolism in DRG neurons promotes lactate production through glycolysis, which increases H3K18la modification and drives Piezo2 expression. Inhibition of lactate production or Piezo2 silencing attenuates the pain phenotype of knockout mice in response to mechanical stimuli. Therefore, our study demonstrates a causal role of defective BCAA catabolism in mechanical pain by enhancing metabolite-mediated epigenetic regulation.

Emodin regulates the autophagy via the miR-371a-5p/PTEN axis to inhibit hepatic malignancy.

Emodin has been reported to fulfill an important function in suppressing the vicious outcome of liver cancer. We aimed to elucidate the partial underlying molecular mechanism of emodin in inhibiting liver cancer, and we applied miRNA-sequence analysis and corresponding molecular functional experiments to find that the inhibitory effect of emodin on liver cancer was partly mediated by cellular autophagy through the miR-371a-5p/PTEN axis. The expression level of miR-371a-5p was down-regulated after emodin treatment in liver cancer cell lines (LCCLs). Restoring the expression level of miR-371a-5p attenuated the suppression of emodin on LCCLs. Additionally, we performed the prediction in relevant online databases and found that PTEN might functioned as a downstream target of miR-371a-5p to participate in the regulation on the above process. What's more, the detection of autophagy-related protein markers showed that LC3II was elevated accompanied by the decreased P62. The above results revealed that PTEN functioned as a key target to regulate the autophagy in the process where emodin inhibited the malignant outcome of LCCLs via miR-371a-5p, which further provided a theoretical basis for the application of traditional Chinese medicine (TCM) on clinical tumors.

Hypoxia-triggered O-GlcNAcylation in the brain drives the glutamate-glutamine cycle and reduces sensitivity to sevoflurane in mice.

BACKGROUND: Hypersensitivity to general anaesthetics predicts adverse postoperative outcomes in patients. Hypoxia exerts extensive pathophysiological effects on the brain; however, whether hypoxia influences sevoflurane sensitivity and its underlying mechanisms remain poorly understood. METHODS: Mice were acclimated to hypoxia (oxygen 10% for 8 h day-1) for 28 days and anaesthetised with sevoflurane; the effective concentrations for 50% of the animals (EC50) showing loss of righting reflex (LORR) and loss of tail-pinch withdrawal response (LTWR) were determined. Positron emission tomography-computed tomography, O-glycoproteomics, seahorse analysis, carbon-13 tracing, site-specific mutagenesis, and electrophysiological techniques were performed to explore the underlying mechanisms. RESULTS: Compared with the control group, the hypoxia-acclimated mice required higher concentrations of sevoflurane to present LORR and LTWR (EC50LORR: 1.61 [0.03]% vs 1.46 [0.04]%, P<0.01; EC50LTWR: 2.46 [0.14]% vs 2.22 [0.06]%, P<0.01). Hypoxia-induced reduction in sevoflurane sensitivity was correlated with elevation of protein O-linked N-acetylglucosamine (O-GlcNAc) modification in brain, especially in the thalamus, and could be abolished by 6-diazo-5-oxo-l-norleucine, a glutamine fructose-6-phosphate amidotransferase inhibitor, and mimicked by thiamet-G, a selective O-GlcNAcase inhibitor. Mechanistically, O-GlcNAcylation drives de novo synthesis of glutamine from glucose in astrocytes and promotes the glutamate-glutamine cycle, partially via glycolytic flux and activation of glutamine synthetase. CONCLUSIONS: Intermittent hypoxia exposure decreased mouse sensitivity to sevoflurane anaesthesia through enhanced O-GlcNAc-dependent modulation of the glutamate-glutamine cycle in the brain.

miR-550a-5p promotes the proliferation and migration of hepatocellular carcinoma by targeting GNE via the Wnt/ß-catenin signaling pathway.

Liver cancer is one of the most common tumors with a high malignant degree in the world. Its diagnosis and treatment are very difficult and limited. More novel and powerful DAT strategies are urgently needed to break this situation. An increasing number of studies have shown that microRNAs (miRNAs) could be used not only as biomarkers for the diagnosis and prognosis of hepatocellular carcinoma (HCC) but also as important targets for molecular targeted therapy. However, the role of miR-550a-5p in HCC and its specific mechanism remain unclear. Here we proposed and verified the hypothesis that the miR-550a-5p could regulate the progression of HCC and was positively associated with poor prognosis. We found that decreased miR-550a-5p would inhibit the proliferation and migration of HCC cell lines (HCs) by performing relevant assays. Interestingly, knocking down GNE could reverse the above effect of miR-550a-5p on HCs. Meanwhile, the western blot results showed that the Wnt/ß-catenin signaling pathway was at least partly involved in the regulation of HCC by miR-550a-5p. In addition, we also found that miR-550a-5p could suppress the growth of HCC in vivo via a xenograft tumor model assay. All in all, we draw a conclusion that the miR-550a-5p/GNE axis functioned as an important role in promoting the progression of HCC via the Wnt/ß-catenin signaling pathway.

Statistical Analysis of the Consistency of HRV Analysis Using BCG or Pulse Wave Signals.

Ballistocardiography (BCG) is considered a good alternative to HRV analysis with its non-contact and unobtrusive acquisition characteristics. However, consensus about its validity has not yet been established. In this study, 50 healthy subjects (26.2 ± 5.5 years old, 22 females, 28 males) were invited. Comprehensive statistical analysis, including Coefficients of Variation (CV), Lin's Concordance Correlation Coefficient (LCCC), and Bland-Altman analysis (BA ratio), were utilized to analyze the consistency of BCG and ECG signals in HRV analysis. If the methods gave different answers, the worst case was taken as the result. Measures of consistency such as Mean, SDNN, LF gave good agreement (the absolute value of CV difference < 2%, LCCC > 0.99, BA ratio < 0.1) between J-J (BCG) and R-R intervals (ECG). pNN50 showed moderate agreement (the absolute value of CV difference < 5%, LCCC > 0.95, BA ratio < 0.2), while RMSSD, HF, LF/HF indicated poor agreement (the absolute value of CV difference ≥ 5% or LCCC ≤ 0.95 or BA ratio ≥ 0.2). Additionally, the R-R intervals were compared with P-P intervals extracted from the pulse wave (PW). Except for pNN50, which exhibited poor agreement in this comparison, the performances of the HRV indices estimated from the PW and the BCG signals were similar.

Opioid-sparing effects of ultrasound-guided erector spinae plane block for adult patients undergoing surgery: A systematic review and meta-analysis.

BACKGROUND: Erector spinae plane block (ESPB) is a new method of administering analgesics to patients perioperatively. The aim of this meta-analysis was to evaluate the opioid-sparing effects of erector spinae plane block in patients during the perioperative period compared to conventional analgesia and identify its role in the development of opioid-free anesthesia. METHODS: Relevant study articles were retrieved from PubMed, the Web of Science, Medline via Ovid, Embase via Ovid, and the Cochrane Central Register of Controlled Trials (CENTRAL) on June 11, 2020. We included randomized controlled trials (RCTs) comparing the use of ESPB with control (no/sham block). The primary outcome was opioid consumption at 24 h after surgery and intraoperative opioid consumption. A random-effects model was used to calculate the standardized mean difference (SMD) and odds ratio (OR) with 95% confidence interval (CI) if there was significant heterogeneity in the data; otherwise, the fixed-effect model was used. RESULTS: A total of 25 randomized controlled trials involving 1461 patients were included. The use of ultrasound-guided ESPB was associated with reduced opioid consumption at 24 h after surgery [SMD: -2.14, 95% CI: -2.61 to -1.67, p < 0.001] and during the intraoperative period [SMD: -2.30, 95% CI: -3.21 to -1.40, p < 0.001]. In addition, it took a longer time to administer the first rescue analgesia in the ESPB group [SMD: 3.60, 95% CI: 2.23-4.97, p < 0.001] and the group was associated with lower incidences of postoperative nausea or vomiting (PONV) [OR: 0.50, 95% CI: 0.34-0.72, p < 0.001]. CONCLUSIONS: Ultrasound-guided ESPB could provide an opioid-sparing effect and effective analgesia in adults undergoing surgeries with general anesthesia, and then promote opioid-free anesthesia development.

Bioluminescence imaging of exogenous & endogenous cysteine in vivo with a highly selective probe.

Cysteine (Cys) is a semi-essential amino acid that exerts a vital role in numerous biological functions. A noninvasive method for in vivo imaging of cysteine could represent a valuable tool for research cysteine and its complex contributions in living organisms. Thus, we developed a turn-on bioluminescence probe (CBP) not only for detecting exogenous and endogenous cysteine in vitro and in vivo, but also for visualizing these cysteines in whole animal. The current applications may help shed light on the complex mechanisms of cysteine in miscellaneous physiological and pathological processes.

The Oncogene PIM1 Contributes to Cellular Senescence by Phosphorylating Staphylococcal Nuclease Domain-Containing Protein 1 (SND1).

BACKGROUND The oncogene PIM1, encoding a constitutively active serine/threonine protein kinase, is involved in the regulation of cell proliferation, survival, differentiation, and apoptosis. There is a growing body of literature on the role of PIM1-mediated cellular senescence, but the precise mechanism remains unclear. MATERIAL AND METHODS Silver staining and LC-MS/MS analysis were performed to investigate the protein interacting with PIM1. Immunofluorescence, Co-IP, and Western blot assay were used to assess the interaction of PIM1 and SND1. EdU incorporation and CCK8 assay were used to detect cell proliferation and immunohistochemistry was used to detect the level of the indicated protein. RESULTS We found that PIM1 can bind directly and phosphorylate SND1. In addition, decreased expression of SND1 leads to the upregulation of SASP. SND1 is involved in cellular senescence induced by PIM1. CONCLUSIONS We investigated the role of PIM1 in oncogene-induced normal cellular senescence. Our results promote further understanding of the mechanisms underlying OIS and suggest potential applications for preventing tumorigenesis.

Individualized clinical management of patients at risk for Alzheimer's dementia.

INTRODUCTION: Multidomain intervention for Alzheimer's disease (AD) risk reduction is an emerging therapeutic paradigm. METHODS: Patients were prescribed individually tailored interventions (education/pharmacologic/nonpharmacologic) and rated on compliance. Normal cognition/subjective cognitive decline/preclinical AD was classified as Prevention. Mild cognitive impairment due to AD/mild-AD was classified as Early Treatment. Change from baseline to 18 months on the modified Alzheimer's Prevention Cognitive Composite (primary outcome) was compared against matched historical control cohorts. Cognitive aging composite (CogAging), AD/cardiovascular risk scales, and serum biomarkers were secondary outcomes. RESULTS: One hundred seventy-four were assigned interventions (age 25-86). Higher-compliance Prevention improved more than both historical cohorts (P = .0012, P < .0001). Lower-compliance Prevention also improved more than both historical cohorts (P = .0088, P < .0055). Higher-compliance Early Treatment improved more than lower compliance (P = .0007). Higher-compliance Early Treatment improved more than historical cohorts (P < .0001, P = .0428). Lower-compliance Early Treatment did not differ (P = .9820, P = .1115). Similar effects occurred for CogAging. AD/cardiovascular risk scales and serum biomarkers improved. DISCUSSION: Individualized multidomain interventions may improve cognition and reduce AD/cardiovascular risk scores in patients at-risk for AD dementia.

Two novel heterozygous HTRA1 mutations in two pedigrees with cerebral small vessel disease families.

Heterozygous HTRA1 mutations, recently, have been reported as a cause of autosomal dominant hereditary cerebral small vessel disease (CSVD). We herein describe clinical and neuroimaging findings in two familial CSVD with two different heterozygous HTRA1 mutations. Detailed clinical and neuroimaging examination were conducted in probands and their available family members. A next-generation sequencing-based comprehensive gene panel was used to investigate their causative mutations. A novel heterozygous missense variant c.527T>C (p.V176A) and a novel heterozygous nonsense variant c.589C>T (p.R197X) in HTRA1 gene were detected in probands of family 1 and family 2, respectively. Co-segregation analysis in family 1 showed eight family members were mutation carriers. All alive male patients showed typical clinical and neuroimaging features of CSVD. All alive female mutation carriers were clinical or neuroimaging asymptomatic. Screening of HTRA1 should be considered in patients with familial CSVD. A male predominance may exist in patients with heterozygous HTRA1 mutations and need to be further investigated.

Dual Modulation of Nociception and Cardiovascular Reflexes during Peripheral Ischemia through P2Y1 Receptor-Dependent Sensitization of Muscle Afferents.

Numerous musculoskeletal pain disorders are based in dysfunction of peripheral perfusion and are often comorbid with altered cardiovascular responses to muscle contraction/exercise. We have recently found in mice that 24 h peripheral ischemia induced by a surgical occlusion of the brachial artery (BAO) induces increased paw-guarding behaviors, mechanical hypersensitivity, and decreased grip strength. These behavioral changes corresponded to increased heat sensitivity as well as an increase in the numbers of chemosensitive group III/IV muscle afferents as assessed by an ex vivo forepaw muscles/median and ulnar nerves/dorsal root ganglion (DRG)/spinal cord (SC) recording preparation. Behaviors also corresponded to specific upregulation of the ADP-responsive P2Y1 receptor in the DRGs. Since group III/IV muscle afferents have separately been associated with regulating muscle nociception and exercise pressor reflexes (EPRs), and P2Y1 has been linked to heat responsiveness and phenotypic switching in cutaneous afferents, we sought to determine whether upregulation of P2Y1 was responsible for the observed alterations in muscle afferent function, leading to modulation of muscle pain-related behaviors and EPRs after BAO. Using an afferent-specific siRNA knockdown strategy, we found that inhibition of P2Y1 during BAO not only prevented the increased mean blood pressure after forced exercise, but also significantly reduced alterations in pain-related behaviors. Selective P2Y1 knockdown also prevented the increased firing to heat stimuli and the BAO-induced phenotypic switch in chemosensitive muscle afferents, potentially through regulating membrane expression of acid sensing ion channel 3. These results suggest that enhanced P2Y1 in muscle afferents during ischemic-like conditions may dually regulate muscle nociception and cardiovascular reflexes. SIGNIFICANCE STATEMENT: Our current results suggest that P2Y1 modulates heat responsiveness and chemosensation in muscle afferents to play a key role in the development of pain-related behaviors during ischemia. At the same time, under these pathological conditions, the changes in muscle sensory neurons appear to modulate an increase in mean systemic blood pressure after exercise. This is the first report of the potential peripheral mechanisms by which group III/IV muscle afferents can dually regulate muscle nociception and the exercise pressor reflex. These data provide evidence related to the potential underlying reasons for the comorbidity of muscle pain and altered sympathetic reflexes in disease states that are based in problems with peripheral perfusion and may indicate a potential target for therapeutic intervention.

Muscle IL1ß Drives Ischemic Myalgia via ASIC3-Mediated Sensory Neuron Sensitization.

UNLABELLED: Musculoskeletal pain is a significantly common clinical complaint. Although it is known that muscles are quite sensitive to alterations in blood flow/oxygenation and a number of muscle pain disorders are based in problems of peripheral perfusion, the mechanisms by which ischemic-like conditions generate myalgia remain unclear. We found, using a multidisciplinary experimental approach, that ischemia and reperfusion injury (I/R) in male Swiss Webster mice altered ongoing and evoked pain-related behaviors in addition to activity levels through enhanced muscle interleukin-1 beta (IL1ß)/IL1 receptor signaling to group III/IV muscle afferents. Peripheral sensitization depended on acid-sensing ion channels (ASICs) because treatment of sensory afferents in vitro with IL1ß-upregulated ASIC3 in single cells, and nerve-specific knock-down of ASIC3 recapitulated the results of inhibiting the enhanced IL1ß/IL1r1 signaling after I/R, which was also found to regulate afferent sensitization and pain-related behaviors. This suggests that targeting muscle IL1ß signaling may be a potential analgesic therapy for ischemic myalgia. SIGNIFICANCE STATEMENT: Here, we have described a novel pathway whereby increased inflammation within the muscle tissue during ischemia/reperfusion injury sensitizes group III and IV muscle afferents via upregulation of acid-sensing ion channel 3 (ASIC3), leading not only to alterations in mechanical and chemical responsiveness in individual afferents, but also to pain-related behavioral changes. Furthermore, these I/R-induced changes can be prevented using an afferent-specific siRNA knock-down strategy targeting either ASIC3 or the upstream mediator of its expression, interleukin 1 receptor 1. Therefore, this knowledge may contribute to the development of alternative therapeutics for muscle pain and may be especially relevant to pain caused by issues of peripheral circulation, which is commonly observed in disorders such as complex regional pain syndrome, sickle cell anemia, or fibromyalgia.

Upregulation of P2Y1 in neonatal nociceptors regulates heat and mechanical sensitization during cutaneous inflammation.

Abstract: The upregulation of various channels and receptors classically linked to sensory transduction from the periphery tightly correspond with changes in the responsiveness of specific subpopulations of primary afferents to mechanical and heat stimulation of the skin at different ages. Previous reports in adults have suggested that the purinergic adenosine diphosphate receptor, P2Y1 can specifically regulate sensory neuron responsiveness to heat stimuli in addition to neurochemical alterations in primary afferents during cutaneous inflammation. To determine if the upregulation of P2Y1 found in the dorsal root ganglia of neonatal mice with cutaneous inflammation initiated at postnatal day 7 (P7) was responsible for the specific alteration in heat sensitivity found in faster conducting ("A"-fiber) nociceptors, we assessed the response properties of cutaneous afferents using an ex vivo hairy hindpaw skin-saphenous nerve-dorsal root ganglion-spinal cord preparation in conjunction with nerve-targeted knockdown of P2Y1. We found that P2Y1 knockdown during neonatal cutaneous inflammation was sufficient to reduce the sensitization of "A"-fiber nociceptors to heat stimuli. Surprisingly, we also found that nerve-specific downregulation of P2Y1 could reduce the observed sensitization of these afferent subtypes to mechanical deformation of the skin. Immunocytochemical analysis of dorsal root ganglia showed that P2Y1 may mediate its effects through modulation of the injury-induced increase of transient receptor potential vanilloid type 1 receptor. This suggests that the upregulation of P2Y1 in cutaneous nociceptors during early life peripheral inflammation can regulate the sensitization of myelinated nociceptors to both mechanical and heat stimuli possibly through modulation of transient receptor potential vanilloid type 1 expression.

Video Head Impulse Test for Early Diagnosis of Vestibular Neuritis Among Acute Vertigo.

BACKGROUND: This study assesses the value of the video head impulse test (vHIT) for early diagnosis of vestibular neuritis (VN) among acute vertigo. METHODS: Thirty-three cases of vestibular neuritis (VN), 96 patients with other acute vertigo (AV), and 50 cases of normal controls used vHIT to quantitatively test a pair of horizontal vestibulo-ocular reflection (VOR) gains, two pairs of vertical VOR gains, and the corresponding three pairs of VOR gain asymmetry. The peculiarity of VOR gains in VN and the differences between VN and other AV, normal controls by vHIT, were collected and analyzed. RESULTS: There were statistically significant differences in the three pairs of VOR gains asymmetry between VN and other AV, and normal controls (P<0.01). The sensitivity was 87.9% and specificity was 94.3% in differentiating VN from normal and other acute vertigo by vHIT. CONCLUSIONS: This study shows vHIT has advantages in the diagnosis of VN in acute vertigo with good sensitivity and specificity and indicates a widespread clinical application.

Harnessing the potential of hydrogels for advanced therapeutic applications: current achievements and future directions.

The applications of hydrogels have expanded significantly due to their versatile, highly tunable properties and breakthroughs in biomaterial technologies. In this review, we cover the major achievements and the potential of hydrogels in therapeutic applications, focusing primarily on two areas: emerging cell-based therapies and promising non-cell therapeutic modalities. Within the context of cell therapy, we discuss the capacity of hydrogels to overcome the existing translational challenges faced by mainstream cell therapy paradigms, provide a detailed discussion on the advantages and principal design considerations of hydrogels for boosting the efficacy of cell therapy, as well as list specific examples of their applications in different disease scenarios. We then explore the potential of hydrogels in drug delivery, physical intervention therapies, and other non-cell therapeutic areas (e.g., bioadhesives, artificial tissues, and biosensors), emphasizing their utility beyond mere delivery vehicles. Additionally, we complement our discussion on the latest progress and challenges in the clinical application of hydrogels and outline future research directions, particularly in terms of integration with advanced biomanufacturing technologies. This review aims to present a comprehensive view and critical insights into the design and selection of hydrogels for both cell therapy and non-cell therapies, tailored to meet the therapeutic requirements of diverse diseases and situations.

Protein phosphatase 2Cm-regulated branched-chain amino acid catabolic defect in dorsal root ganglion neurons drives pain sensitization.

Maladaptive changes of metabolic patterns in the lumbar dorsal root ganglion (DRG) are critical for nociceptive hypersensitivity genesis. The accumulation of branched-chain amino acids (BCAAs) in DRG has been implicated in mechanical allodynia and thermal hyperalgesia, but the exact mechanism is not fully understood. This study aimed to explore how BCAA catabolism in DRG modulates pain sensitization. Wildtype male mice were fed a high-fat diet (HFD) for 8 weeks. Adult PP2Cmfl/fl mice of both sexes were intrathecally injected with pAAV9-hSyn-Cre to delete the mitochondrial targeted 2 C-type serine/threonine protein phosphatase (PP2Cm) in DRG neurons. Here, we reported that BCAA catabolism was impaired in the lumbar 4-5 (L4-L5) DRGs of mice fed a high-fat diet (HFD). Conditional deletion of PP2Cm in DRG neurons led to mechanical allodynia, heat and cold hyperalgesia. Mechanistically, the genetic knockout of PP2Cm resulted in the upregulation of C-C chemokine ligand 5/C-C chemokine receptor 5 (CCL5/CCR5) axis and an increase in transient receptor potential ankyrin 1 (TRPA1) expression. Blocking the CCL5/CCR5 signaling or TRPA1 alleviated pain behaviors induced by PP2Cm deletion. Thus, targeting BCAA catabolism in DRG neurons may be a potential management strategy for pain sensitization.

Diagnostic value of isolated plasma biomarkers and its combination in neurodegenerative dementias: A multicenter cohort study.

BACKGROUND: Plasma amyloid-ß (Aß), phosphorylated tau-181 (p-tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) potentially aid in the diagnosis of neurodegenerative dementias. We aim to conduct a comprehensive comparison between different biomarkers and their combination, which is lacking, in a multicenter Chinese dementia cohort consisting of Alzheimer's disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). METHODS: We enrolled 92 demented patients [64 AD, 16 FTD, and 12 PSP with dementia] and 20 healthy controls (HC). Their plasma Αß, p-tau181, NfL, and GFAP were detected by highly sensitive-single molecule immunoassays. Αß pathology in patients was measured by cerebrospinal fluid or/and amyloid positron emission tomography. RESULTS: All plasma biomarkers tested were significantly altered in dementia patients compared with HC, especially Aß42/Aß40 and NfL showed significant performance in distinguishing AD from HC. A combination of plasma Aß42/Aß40, p-tau181, NfL, and GFAP could discriminate FTD or PSP well from HC and was able to distinguish AD and non-AD (FTD/PSP). CONCLUSIONS: Our results confirmed the diagnostic performance of individual plasma biomarkers Aß42/Aß40, p-tau181, NfL, and GFAP in Chinese dementia patients and noted that a combination of these biomarkers may be more accurate in identifying FTD/PSP patients and distinguishing AD from non-AD dementia.

Association between dietary vitamin C and telomere length: A cross-sectional study.

Background: Currently, telomere length is known to reflect the replication potential and longevity of cells, and many studies have reported that telomere length is associated with age-related diseases and biological aging. Studies have also shown that vitamin C acts as an oxidant and free radical scavenger to protect cells from oxidative stress and telomere wear, thus achieving anti-aging effects. At present, there are few and incomplete studies on the relationship between vitamin C and telomere length, so this study aims to explore the relationship between vitamin C and telomere length. Methods: This study used cross-sectional data from the National Health and Nutrition Examination Surveys (NHANES) database from 1999 to 2002, a total of 7,094 participants were selected from all races in the United States. Male participants accounted for 48.2% and female participants accounted for 51.8%. The correlation between vitamin C and telomere length was assessed using a multiple linear regression model, and the effect of dietary vitamin C on telomere length was obtained after adjusting for confounding factors such as age, gender, race, body mass index (BMI), and poverty income ratio (PIR). Results: This cross-sectional study showed that vitamin C was positively correlated with telomere length, with greater dietary vitamin C intake associated with longer telomeres (ß = 0.03, 95% CI: 0.01-0.05, P = 0.003). Conclusion: This study shows that vitamin C intake is positively correlated with human telomere length, which is of guiding significance for our clinical guidance on people's health care, but our study need to be confirmed by more in-depth and comprehensive other research results.

Obesity by High-Fat Diet Increases Pain Sensitivity by Reprogramming Branched-Chain Amino Acid Catabolism in Dorsal Root Ganglia.

Obesity is a significant health concern as a result of poor-quality diet, for example, high-fat diet (HFD). Although multiple biological and molecular changes have been identified to contribute to HFD-induced pain susceptibility, the mechanisms are not fully understood. Here, we show that mice under 8 weeks of HFD were sensitive to mechanical and thermal stimuli, which was coupled with an accumulation of branched-chain amino acids (BCAAs) in lumbar dorsal root ganglia (DRG) due to local BCAA catabolism deficiency. This HFD-induced hyperalgesic phenotype could be exacerbated by supply of excessive BCAAs or mitigated by promotion of BCAA catabolism via BT2 treatment. In addition, our results suggested that HFD-related pain hypersensitivity was associated with a pro-inflammatory status in DRG, which could be regulated by BCAA abundance. Therefore, our study demonstrates that defective BCAA catabolism in DRG facilitates HFD-induced pain hypersensitivity by triggering inflammation. These findings not only reveal metabolic underpinnings for the pathogenesis of HFD-related hyperalgesia but also offer potential targets for developing diet-based therapy of chronic pain.

HTR1D functions as a key target of HOXA10-AS/miR-340-3p axis to promote the malignant outcome of pancreatic cancer via PI3K-AKT signaling pathway.

Competing endogenous RNAs (ceRNAs) are a newly discovered class of molecular regulators involved in many diseases, especially tumors. Therefore, exploration of the potential ceRNA regulatory network regarding the occurrence and development of pancreatic cancer will provide a new theoretical basis for its diagnosis and treatment. Based on the above background, we applied a bioinformatics approach to mine the public database The Cancer Genome Atlas (TCGA) and performed a series of subsequent molecular biology assays to confirm the hypothesis that HOXA10-AS/ miR-340-3p/HTR1D axis could modulate the malignant progression of pancreatic cancer. Here, our present study demonstrated that the expression level of HTR1D, positively correlated with the level of lncRNA HOXA10-AS and negatively associated with the level of miR-340-3p, was significantly increased in pancreatic cancer cell lines (PCs) compared with that in normal HPDE6-C7 cells. Knocking down HTR1D obviously inhibited the proliferation and migration of PCs and promoted apoptosis by upregulating p-AKT. Elevated miR-340-3p blocked the progression of pancreatic cancer by downregulating HTR1D. Lessened level of lncRNA HOXA10-AS reduced the sponging of miR-340-3p, resulting in an increase of miR-340-3p and a subsequent decrease of HTR1D to ultimately suppress the malignant biological behaviors of cancer. These data illustrated that the HOXA10-AS/miR-340-3p/HTR1D ceRNA axis acted a crucial part in the malignant biological behavior of pancreatic cancer in an AKT-dependent manner.