Using proteomics and metabolomics to identify therapeutic targets for senescence mediated cancer: genetic complementarity method.

Background: Senescence have emerged as potential factors of lung cancer risk based on findings from many studies. However, the underlying pathogenesis of lung cancer caused by senescence is not clear. In this study, we try to explain the potential pathogenesis between senescence and lung cancer through proteomics and metabonomics. And try to find new potential therapeutic targets in lung cancer patients through network mendelian randomization (MR). Methods: The genome-wide association data of this study was mainly obtained from a meta-analysis and the Transdisciplinary Research in Cancer of the Lung Consortium (TRICL), respectively.And in this study, we mainly used genetic complementarity methods to explore the susceptibility of aging to lung cancer. Additionally, a mediation analysis was performed to explore the potential mediating role of proteomics and metabonomics, using a network MR design. Results: GNOVA analysis revealed a shared genetic structure between HannumAge and lung cancer with a significant genetic correlation estimated at 0.141 and 0.135, respectively. MR analysis showed a relationship between HannumAge and lung cancer, regardless of smoking status. Furthermore, genetically predicted HannumAge was consistently associated with the proteins C-type lectin domain family 4 member D (CLEC4D) and Retinoic acid receptor responder protein 1 (RARR-1), indicating their potential role as mediators in the causal pathway. Conclusion: HannumAge acceleration may increase the risk of lung cancer, some of which may be mediated by CLEC4D and RARR-1, suggestion that CLEC4D and RARR-1 may serve as potential drug targets for the treatment of lung cancer.

Sennoside A restrains TRAF6 level to modulate ferroptosis, inflammation and cognitive impairment in aging mice with Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disease and a momentous cause of dementia in the elderly. Sennoside A (SA) is an anthraquinone compound and possesses decisive protective functions in various human diseases. The purpose of this research was to elucidate the protective effect of SA against AD and investigate its mechanism. METHODS: Male APPswe/PS1dE9 (APP/PS1) transgenic mice with a C57BL/6J background were chosen as AD model. Age-matched nontransgenic littermates (C57BL/6 mice) were negative controls. SA's functions in AD in vivo were estimated by cognitive function analysis, Western blot, hematoxylin-eosin staining, TUNEL staining, Nissl staining, detection of Fe2+ levels, glutathione and malondialdehyde contents, and quantitative real-time PCR. Also, SA's functions in AD in LPS-induced BV2 cells were examined using Cell Counting Kit-8 assay, flow cytometry, quantitative real-time PCR, Western blot, enzyme-linked immunosorbent assay, and analysis of reactive oxygen species levels. Meanwhile, SA's mechanisms in AD were assessed by several molecular experiments. RESULTS: Functionally, SA mitigated cognitive function, hippocampal neuronal apoptosis, ferroptosis, oxidative stress, and inflammation in AD mice. Furthermore, SA reduced BV2 cell apoptosis, ferroptosis, oxidative stress, and inflammation induced by LPS. Rescue assay revealed that SA abolished the high expressions of TRAF6 and p-P65 (NF-κB pathway-related proteins) induced by AD, and this impact was reversed after TRAF6 overexpression. Conversely, this impact was further enhanced after TRAF6 knockdown. CONCLUSIONS: SA relieved ferroptosis, inflammation and cognitive impairment in aging mice with AD through decreasing TRAF6.

PC6 electroacupuncture reduces stress-induced autonomic and neuroendocrine responses in rats.

Stress can trigger cardiovascular disease. Both imbalance of autonomic nervous activity and increase of neurohormonal output are core aspects of stress responses and can lead to cardiovascular disease. PC6 as a very important acupoint is used to prevent and treat cardiovascular disease and to improve stress-related activities. We examined the influence of electroacupuncture (EA) at PC6 on stress-induced imbalance of autonomic nervous activity and increase of neurohormonal output. EA at PC6 relieved increased cardiac sympathetic nervous activity and decreased cardiac vagal nervous activity induced by immobilization stress. Also, EA at PC6 reduced immobilization stress-induced increases of plasma norepinephrine (NE) and adrenaline (E) released from sympatho-adrenal-medullary axis. Finally, EA at PC6 reduced immobilization stress-induced increases of corticotropin-releasing hormone (CRH) in paraventricular hypothalamic nucleus and plasma cortisol (CORT) released from hypothalamic-pituitary-adrenal axis. However, EA at tail had no significant effect on the stress-induced autonomic and neuroendocrine responses. The results demonstrate the role of EA at PC6 regulating the autonomic and neuroendocrine responses induced by stress and provide insight into the prevention and treatment of EA at PC6 for stress-induced cardiovascular disease by targeting autonomic and neuroendocrine systems.

Mongolian medicine Wenguanmu ointment treats eczema by inhibiting the CKLF-1/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The main clinical manifestations of eczema include itching, erythema, swelling and pain. Currently, allergies and TH1/TH2 cytokine imbalances are significant causes of eczema. TCM believes that eczema is mainly caused by incongruity between dry and wet. Wenguanmu ointment is a classic Mongolian medicine, which mainly composed of Xanthoceras sorbifolia Bunge, Coptis chinensis Franch and Bezoar. These ingredients can clear heat and dampness, dispel wind and dehumidification, anti-inflammatoryad analgesic. In this study, it was found that Wenguanmu ointment can treat eczema with anti-inflammatory, analgesic and antipruritic. AIM OF THE STUDY: In this study, the content of main components in Wenguanmu ointment was tested. Moreover, the therapeutic effect and mechanism of Wenguanmu ointment on eczema model mice were studied. MATERIALS AND METHODS: Kunming mice (25 ± 2 g) were randomly divided into 6 groups: Control group; Model group; Vehicle group; Wenguanmu ointment group; Compound dexamethasone acetate cream group; Chushizhiyang ointment group. The eczema mouse model was established by DNCB. HPLC and TLC tests were used to determine the content of the main components in Wenguanmu ointment. HE staining was used to assess skin damage in mice. In order to detect the anti-inflammatory effect of Wenguanmu ointment on eczema, The levels of IgE, TNF-α, IFN-γ, COX-2 and IL-4 in serum was measured by ELISA. Genecards and Online Mendelian Inheritance in Man databases were used to analyze potential target gene predictions, and it was speculated that Wenguanmu ointment was associated with NF-κB signaling pathway and chemokine signaling pathway. To detect this inference, RT-qPCR and western blotting were used to detect protein and mRNA levels of CKLF-1, IκB-α, and NF-κB. RESULTS: Wenguanmu ointment can repress the symptoms of eczema caused by 2, 4-dinitrochlorobenzene, and inhibit the level of serum immunoglobulin E. Simultaneously it restrain the elevation of miscellaneous pro-inflammatory cytokines and chemokines, as well as reducing the expression of CKLF-1 and NF-κB protein in the nucleus, and increasing the protein expression of IκB to improve eczema. CONCLUSIONS: The ameliorating effect of Wenguanmu ointment on eczema lesions can play a importment role by inhibiting the CKLF-1/NF-κB pathway.

Tibial nerve electrical stimulation for fecal incontinence: a systematic review and meta-analysis.

Tibial nerve stimulation (TNS) therapy is widely used to treat fecal incontinence (FI), but still, some controversy exists. This study aimed to determine whether TNS could improve FI from different evaluation angles. A systematic review and meta-analysis were conducted to provide indirect evidence of TNS treatment for FI. We searched for the original studies in PubMed, Embase, Web of Science, Ebsco Medline, Ovid Medline, and Cochrane Central Register of Controlled Trials published before November 31, 2021. The standardized mean difference was the efficacy analysis statistic, and the effect was expressed by the 95% confidence interval (CI). For the case series, we calculated the mean difference of the number of patients evaluated at baseline and last follow-up. Four randomized controlled trials (RCTs, four hundred and sixty participants) and eighteen case series (eight hundred and thirty-eight participants) were included in the study. The results of the RCTs showed that the number of weekly episodes of FI significantly reduced in the TNS group compared with the sham stimulation group. The results of the case series showed that TNS reduced the number of patients with FI per week. The Cleveland Clinic Florida FI Score significantly reduced. The post-treatment results of maximum squeeze pressure and maximum resting pressure were significantly different from baseline. This study showed that TNS to some extent reduced the number of patients with FI, reduced clinical symptoms, and improved anal physiological function. Despite the low quality of overall evidence, TNS still shows some potential as a safe treatment for FI.

[Effect of inhalation of different-concentrations of moxa smoke on apoptosis and regeneration of olfactory epithelial cells in rats].

OBJECTIVE: To observe the effect of long-term inhalation of moxa-smoke on olfactory epithelial cells in rats, in order to explore the safety of moxa-smoke inhalation (MSI). METHODS: A total of 32 SD rats (half male and half female) were randomly divided into 4 groups: normal, low concentration (LCMSI), medium concentration (MCMSI) and high concentration (HCMSI), with 8 rats in each group. Rats of the LCMSI, MCMSI and HCMSI groups were put into closed boxes which were filled with ignited moxa stick-released smoke at concentrations of (0.11±0.05)mg/m3, (0.23±0.05) mg/m3 and (0.53±0.05)mg/m3, respectively. The treatment was given 4 h each time, twice a day for 90 days. Rats of the normal group were fed routinely. The rats' general state and behavior (including fur appearance, activities in cage, response to external stimuli, spirit, stool, diet and water drinking) were recorded, and the olfactory function was assessed by using latency of finding the buried food pellet (BFP) test. The number of apoptotic olfactory epithelial cells was counted after terminal labeling (TUNEL), and the proliferation of basal cells of the nasal mucosa was detected by BrdU incorporation immunohistochemical technique. RESULTS: The latency of BFP was significantly longer in the MCMSI and HCMSI groups than in the normal and LCMSI groups (P<0.01), and had no significant differences between the LCMSI and normal groups, and between the MCMSI and HCMSI groups (P>0.05). The numbers of the apoptotic olfactory epithelial cells and proliferative basal cell in the nasal mucus tissue were markedly more in the LCMSI, MCMSI and HCMSI groups than in the normal group (P<0.01, P<0.05), and obviously more in the MCMSI and HCMSI groups than in the LMCMSI group (P<0.01), and apparently more in the HCMSI group than in the MCMSI group (P<0.01). The general state observation showed that in the first 45 days, only yellowish fur and water intake increase were seen in rats of the 3 moxa smoke inhalation groups, while no obvious changes in rats of the LCMSI group, and decrease in activities, being sensitive to external stimulation and fiddle-footed, and lower spirit in rats of the MCMSI and HCMSI groups in comparison with rats of the normal group after 90 day's MSI. CONCLUSION: Long-term inhalation of medium and high concentrations of moxa smoke may cause a reduction of the olfactory sensitivity and an increase of apoptosis of olfactory epithelial cells and proliferation of basal cells.

[Effect of different concentrations of moxa smoke exposure on nasal mucosal injury and expression of serum IL-1, IL-6 and TNF-α in rats].

OBJECTIVE: To observe the effect of long-term moxa smoke exposure of different concentrations on olfactory function in rats, and provide experimental basis of safety study of moxa smoke produced by moxibustion. METHODS: Forty SD rats were randomly divided into a normal control group, a low-concentration moxa smoke group, a moderate-concentration moxa smoke group and a high-concentration moxa smoke group, 10 rats in each one. The rats in the moxa smoke groups were put into three plexiglass moxibustion boxes with different moxa smoke concentrations, 4 hours per times, twice a day for 90 days. The general state of rats was evaluated before and during the experiment. After the intervention, the olfactory function was evaluated by two-bottle experiment (TBE); the morphology of nasal mucosa was observed by HE staining; the apoptosis of olfactory epithelial cells in nasal mucosa was detected by TUNEL method; the serum levels of interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were detected by ELISA method. RESULTS: In the late stage of moxa smoke exposure (45-90 days into intervention), the behavioral activity of rats in the moderate-concentration moxa smoke group and the high-concentration moxa smoke group was weaker than that in the normal control group, and their response to stimulation was strong, and their mental state was worse. After intervention, the drinking rate of vinegar-water mixture in the moderate-concentration moxa smoke group and the high-concentration moxa smoke group was higher than that in the normal control group and the low-concentration moxa smoke group (P<0.01). The hierarchical structure of nasal mucosa in the moderate-concentration moxa smoke group and the high-concentration moxa smoke group was unclear, disordered, necrotic and inflammatory cell infiltration was serious; the number of apoptotic cells in olfactory epithelium of nasal mucosa in the moderate-concentration moxa smoke group and the high-concentration moxa smoke group was more than that in the normal control group and the low-concentration moxa smoke group (P<0.01), that in the high-concentration moxa smoke group was more than the moderate-concentration group (P<0.01). The serum levels of IL-1, IL-6 and TNF-α in the low-concentration moxa smoke group, the moderate-concentration moxa smoke group and the high-concentration moxa smoke group were higher than the normal control group (P<0.01), and those in the moderate-concentration moxa smoke group and the high-concentration moxa smoke group were higher than the low-concentration moxa smoke group (P<0.01), and those in the high-concentration moxa smoke group were higher than moderate-concentration moxa smoke group (P<0.01). CONCLUSION: The long-term exposure to low, moderate and high concentrations of moxa smoke could cause pathological changes in nasal mucosa and increase the serum levels of IL-1, IL-6 and TNF-α; the moderate and high concentrations of moxa smoke exposure could cause a series of damage to olfactory function and reduce olfactory sensitivity in rats.

[Influence of moxibustion with moxa sticks with different diameters and at different distances from surface of "Zusanli"(ST36) on local skin temperature in rats].

OBJECTIVE: To observe the impact of moxa-stick with different diameters and at different distances on skin temperature in local "Zusanli"(ST36) region, so as to select suitable specifications for moxibustion. METHODS: A total of 120 male SD rats were randomly divided into diameters of 0.5, 0.9, 1.2 and 1.8 cm, and distances of 1, 2, 3, 4 and 5 cm groups, with 6 rats in each group. Moxa-stick with different diameters mentioned above was applied to the right ST36 (right hind limb) for 10 min every time at different distances (between the ignited moxa-stick tip and the skin) mentioned above, and the left ST36 was used as the control point. The skin temperature was detected by using an infrared thermometer. RESULTS: After application of moxibustion to ST36 region, the skin temperature was increased gradually along with the increased diameter of moxa-sticks and decreased along with the increased distance from the ignited moxa-stick tip to the skin. There were no significant changes in the skin temperature of the left control acupoint ST36. The skin temperature was below 40 ℃, between 43 to 55 ℃, over 43℃ and between 43 to 61 ℃, when the moxa-stick was 0.5 cm, 0.9 cm, 1.2 cm and 1.8 cm in diameter, and was kept 1, 2, 3 and 3 to 5 cm away from the skin surface, respectively. When the moxa-stick with a diameter of 1.8 cm was kept at a distance of 1 to 2 cm, the skin temperature reached 71 to 93 ℃ to cause obvious local burn lesion. CONCLUSION: During moxibustion, the ignited moxa-sticks with diameters of 0.5, 0.9, 1.2 and 1.8 cm are suitable to be kept less than 1, 1 to 2, 2 to 3, and 3 to 5 cm away from the skin surface of ST36, respectively.

Effects of electroacupuncture combined with stem cell transplantation on anal sphincter injury-induced faecal incontinence in a rat model.

BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) and acupuncture are known to mitigate tissue damage. This study aimed to investigate the therapeutic effects of combined electroacupuncture (EA) stimulation and BMSC injection in a rat model of anal sphincter injury-induced faecal incontinence (FI). METHODS: 60 Sprague-Dawley rats were randomly divided into five groups: sham-operated control, FI, FI+EA, FI+BMSC, and FI+BMSC+EA. The anorectal tissues were collected on days 1, 3, 7 and 14. Repair of the injured anal sphincter was compared using haematoxylin and eosin (HE) and immunocytochemiscal analyses with sarcomeric α actinin. The expression of stromal cell derived factor-1 (SDF-1) and monocyte chemoattractant protein-3 (MCP-3) was detected by quantitative reverse transcription PCR to evaluate the effects of EA on the homing of BMSCs. RESULTS: The therapeutic effect of combined EA+BMSCs on damaged tissue was the strongest among all the groups as indicated by HE and immunohistochemical staining. The expression of SDF-1 and MCP-3 was significantly increased by combined EA and BMSC treatment when compared with the other groups (P=0.01 to P<0.05), suggesting promotive effects of EA on the homing of BMSCs. CONCLUSION: The combination of EA and BMSC transplantation effectively repaired the impaired anal sphincters. The underlying mechanism might be associated with apparent promotive effects of EA on the homing of BMSCs. Our study provides a theoretical basis for the development of a non-surgical treatment method for FI secondary to muscle impairment.

Inhibitory effects of pine nodule extract and its component, SJ-2, on acetylcholine-induced catecholamine secretion and synthesis in bovine adrenal medullary cells.

Extract of pine nodules (matsufushi) formed by bark proliferation on the surface of trees of Pinus tabulaeformis or Pinus massoniana has been used as an analgesic for joint pain, rheumatism, neuralgia, dysmenorrhea and other complaints in Chinese traditional medicine. Here we report the effects of matsufushi extract and its components on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. We found that matsufushi extract (0.0003-0.005%) and its component, SJ-2 (5-hydroxy-3-methoxy-trans-stilbene) (0.3-100 µM), but not the other three, concentration-dependently inhibited catecholamine secretion induced by acetylcholine, a physiological secretagogue. Matsufushi extract (0.0003-0.005%) and SJ-2 (0.3-100 µM) also inhibited 45Ca2+ influx induced by acetylcholine in a concentration-dependent manner, similar to its effect on catecholamine secretion. They also suppressed 14C-catecholamine synthesis and tyrosine hydroxylase activity induced by acetylcholine. In Xenopus oocytes expressing α3ß4 nicotinic acetylcholine receptors, matsufushi extract (0.00003-0.001%) and SJ-2 (1-100 µM) directly inhibited the current evoked by acetylcholine. The present findings suggest that SJ-2, as well as matsufushi extract, inhibits acetylcholine-induced catecholamine secretion and synthesis by suppression of nicotinic acetylcholine receptor-ion channels in bovine adrenal medullary cells.

Ikarisoside A inhibits acetylcholine-induced catecholamine secretion and synthesis by suppressing nicotinic acetylcholine receptor-ion channels in cultured bovine adrenal medullary cells.

Ikarisoside A is a natural flavonol glycoside derived from plants of the genus Epimedium, which have been used in Traditional Chinese Medicine as tonics, antirheumatics, and aphrodisiacs. Here, we report the effects of ikarisoside A and three other flavonol glycosides on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. We found that ikarisoside A (1-100 µM), but not icariin, epimedin C, or epimedoside A, concentration-dependently inhibited the secretion of catecholamines induced by acetylcholine, a physiological secretagogue and agonist of nicotinic acetylcholine receptors. Ikarisoside A had little effect on catecholamine secretion induced by veratridine and 56 mM K(+). Ikarisoside A (1-100 µM) also inhibited (22)Na(+) influx and (45)Ca(2+) influx induced by acetylcholine in a concentration-dependent manner similar to that of catecholamine secretion. In Xenopus oocytes expressing α3ß4 nicotinic acetylcholine receptors, ikarisoside A (0.1-100 µM) directly inhibited the current evoked by acetylcholine. It also suppressed (14)C-catecholamine synthesis and tyrosine hydroxylase activity induced by acetylcholine at 1-100 µM and 10-100 µM, respectively. The present findings suggest that ikarisoside A inhibits acetylcholine-induced catecholamine secretion and synthesis by suppression of nicotinic acetylcholine receptor-ion channels in bovine adrenal medullary cells.

Efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy: a meta-analysis.

BACKGROUND AND PURPOSE: Despite the successful use of a ketogenic diet in pediatric epilepsy, its application in adults has been limited. The aim of this meta-analysis was to summarize the findings of relevant published studies in order to identify the efficacy of and compliance with a ketogenic diet and its main subtypes (i.e., classic ketogenic diet and modified Atkins diet) in adults with intractable epilepsy, and to provide useful information for clinical practice. METHODS: Electronic searches of PubMed, EMBASE, Google Scholar, and the ISI Web of Science were conducted to identify studies of the efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy; the included studies were reviewed. Meta-analyses were performed using STATA to determine combined efficacy rates and combined rates of compliance with the ketogenic diet and its main subtypes. RESULTS: In total, 12 studies qualified for inclusion, and data from 270 patients were evaluated.The results of the meta-analysis revealed combined efficacy rates of all types of ketogenic diet, a classical ketogenic diet, and a modified Atkins diet were 42%, 52%, and 34%, respectively; the corresponding combined compliance rates were 45%, 38%, and 56%. CONCLUSIONS: The results indicate that a ketogenic diet is a promising complementary therapy in adult intractable epilepsy, and that while a classical ketogenic diet may be more effective, adult patients are likely to be less compliant with it than with a modified Atkins diet.

Differential cardioprotective effects of salvianolic acid and tanshinone on acute myocardial infarction are mediated by unique signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvianolic acid (SAL) and tanshinone (TAN) are major hydrophilic and lipophilic compounds, respectively, from one herbal medicine, Danshen, which has been widely and successfully used for treating cardiovascular diseases in Asian countries. Because few studies have reported different molecular mechanisms between the different compounds in same herb, we investigate if separate molecular pathways are involved in cardioprotective effect by different active components of Danshen. MATERIALS AND METHODS: We used an acute myocardial infarction (MI) model to compare the cardioprotective effects of SAL and TAN in rats. Both infarct size and echocardiographic response were evaluated at 3, 7, 14 and 28 days after surgery. Genes involved in ischemic injury and in responses to SAL or TAN treatment in ischemic hearts were identified by microarray analysis and verified by quantitative real-time RT-PCR. RESULTS: Results showed that both SAL and TAN delay the development of ischemia by decreasing infarct size and improving systolic function post MI. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated different kinetics and gene expression profiles by SAL and TAN. SAL acts in a later period after ischemia, and its effect is probably mediated by downregulation of genes involved in oxidative stress, certain G-protein coupled receptor activities and apoptosis. On the other hand, TAN acts relatively early after ischemic injury and its effect is at least in part mediated by inhibition of intracellular calcium, cell adhesion and alternative complement pathway. Strikingly, we found that TAN, a recently identified member of selective estrogen receptor modifier (SERM), indeed regulates genes known to be involved in estrogen metabolism post MI. CONCLUSIONS: Although both SAL and TAN contribute to the cardioprotective effect of Danshen, there are significant mechanistic and temporal differences between the two: TAN acts at an early stage after ischemic injury mainly by inhibition of intracellular calcium and cell adhesion pathways whereas SAL acts mainly by down-regulating apoptosis.