Ghrelin improves cognition via activation of the cAMP- CREB signalling pathway in depressed male C57BL/6J mice.

BACKGROUND: Depression leads to a cognitive decline and decreases in ghrelin are observed in depression. Ghrelin affects the level of Brain-derived nerve growth factor (BDNF) through the cAMP-CREB signalling pathway, and lower BDNF levels lead to cognitive decline. Therefore, it is reasonable to assume that in depression, lower ghrelin causes a decrease in BDNF levels and cognitive decline though the cAMP- CREB signalling pathway. METHODS: A total of 120 C57BL/6J male mice were randomly divided into six groups of 20 mice: non-depression groups (sham group, ghrelin group, and ghrelin + (D-lys3)-GHRP-6 group) and depression groups (depression group, depression + ghrelin group and depression + ghrelin + (D-lys3)-GHRP group). A depression mouse model was established by injecting normal saline, ghrelin or ghrelin + (D-lys3) -GHRP-6 into the lateral ventricle of each group. Cognition, hippocampal long-term potentiation (LTP), ghrelin mRNA and protein level, BDNF level and CREB level in the hippocampus were detected. RESULTS: In the depression mouse model groups, all comparison indexes (cognition and hippocampal levels of LTP, ghrelin mRNA and proteins, and BDNF and CREB) had significant negative changes. In the mice with depression, ghrelin or ghrelin + (D-lys3)-GHRP-6 was injected, and all the comparison indicators showed significant positive changes. Supplementation of ghrelin+(D-lys3))-GHRP-6 resulted in more significant positive changes in all comparison indexes than those of ghrelin alone. CONCLUSIONS: In the depression model, lower ghrelin causes hippocampal BDNF to decrease and results in cognitive decline via the cAMP-CREB signalling pathway.

Cerebellar fastigial nucleus electrostimulation attenuates inflammation in a Post-Infarction rat model by activating cholinergic anti-inflammatory pathway.

There are negative correlations between indices of heart rate variability (HRV) and markers of inflammation. The inflammation plays an important role in myocardial damages after myocardial infarction (MI). Our previous study found that fastigial nucleus electrostimulation (FNS) improved abnormal HRV in a rat model of MI. Whether it can reduce inflammation and improve cardiac function after MI and the underlying mechanisms remain unknown. 66 Sprague Dawley rats were randomly divided into 4 groups as follows: i) Sham group (sham operation); ii) MI group (left anterior descending coronary artery ligation); iii) FNS + MI group (left fastigial nucleus electrostimulation plus MI); iv) FNL + FNS + MI group (left fastigial nucleus lesion plus FNS plus MI). The serum expressions of acetylcholine (ACh), pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and anti-inflammatory cytokines IL-10 were measured by ELISA. Subsequently, the infarct size, the infiltration of inflammatory cells, the fibrotic area, and cardiac function were also evaluated. Additionally, the expressions of the cholinergic anti-inflammatory pathway (CAP)-related proteins in infarct tissue, such as nuclear factor kappa B (NF-κB) and singal transducers and activators of transcription 3 (STAT3), were determined by Western blot. We found that FNS significantly increased ACh and IL-10 levels in serum, and decreased TNF-α and IL-6 levels. FNS significantly attenuated inflammatory cell infiltration, reduced infarct size, decreased fibrosis, increased left ventricular ejection fraction, and reduced mortality. Besides, the ratios of phosphorylated-STAT3/STAT3 and phosphorylated-NF-κB/NF-κB in infarct tissue significantly elevated after MI. FNS reduced the ratios of p-STAT3/STAT3 and p-NF-κB/NF-κB in infarct tissue. The protective effects of FNS were partially reversed by the fastigial nucleus lesion. Our data suggested that FNS can alleviate the inflammation after MI, and its cardiac neuroprotective mechanism may be achieved by increasing vagal tone, releasing ACh, and further activating the CAP via α7 nicotinic acetylcholine receptor. The precise mechanism remains to be elucidated.

Efficacy and Safety of Mesenchymal Stem Cell Therapy in Patients with Acute Myocardial Infarction: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND AND OBJECTIVES: The adjuvant treatment of stem cell therapy for acute myocardial infarction (AMI) has been studied in multiple clinical trials, but many questions remain to be addressed, such as efficacy, safety, identification of the optimal cell type, tractable route of delivery, transplant dosage, and transplant timing. The current meta-analysis aimed to explore the issues of mesenchymal stem cells (MSCs) transplantation in patients with AMI based on published randomized controlled trials (RCTs) and guide the design of subsequent clinical trials of MSCs therapy for AMI. METHODS: The Cochrane Library, PubMed, EMBASE databases were searched for relevant clinical trials from January 1, 2000, to January 23, 2021. Results from RCTs involving MSCs transplantation for the treatment of AMI were identified. According to the Cochrane systematic review method, the literature quality, including studies, was evaluated and valid data was extracted. Rev- Man 5.3 and Stata 15.1 software were used for Meta-analysis. RESULTS: After literature search and detailed evaluation, 9 randomized controlled trials enrolling 460 patients were included in the quantitative analysis. Pooled analyses indicated that MSCs therapy was associated with a significantly greater improvement in overall left ventricular ejection fraction (LVEF), and the effect was maintained for up to 24 months. No significant difference in favor of MSCs treatment in left ventricular (LV) volume and in the risk of rehospitalization as a result of heart failure (HF) was noted, compared with the controls. For transplantation dose, the LVEF of patients accepting a MSCs dose of 107-108 cells was significantly increased by 2.62% (95% CI 1.54 to 3.70; P < 0.00001; I2 =0%), but this increase was insignificant in the subgroup that accepted a MSCs dose of < 107 cells (1.65% in LVEF, 95% CI, 0.03 to 3.27; P =0.05; I2 =75%) or >108 cells (4.65% in LVEF, 95% CI, -4.55 to 13.48; P =0.32; I2 =95%), compared with the controls. For transplantation timing, a significant improvement of LVEF of 3.18% was achieved in the group of patients accepting a MSCs infusion within 2 to 14 days after percutaneous coronary intervention (PCI) (95% CI, 2.89 to 3.47; P <0.00001; I2 = 0). There was no association between MSCs therapy and major adverse events. CONCLUSION: Results from our systematic review suggest that MSCs therapy for patients with AMI appears to be safe and might induce a significant increase in LVEF with a limited impact on LV volume and rehospitalization caused by HF. The effect was maintained for up to 24 months. MSCs dose of 107-108 cells was more likely to achieve better clinical endpoints than <107 or >108 cells. The optimal time window for cell transplantation might be within 2-14 days after PCI. This meta-analysis was registered with PROSPERO, number CRD 42021241104.

The genomic landscape of Cronkhite-Canada syndrome: Possible clues for pathogenesis.

OBJECTIVES: Cronkhite-Canada syndrome (CCS) is a rare hamartomatous polyposis syndrome with a proposed association with chronic autoimmune inflammation. To date, genetic background of patients with CCS remains less investigated. In this study we aimed to explore the genomic landscape of CCS. METHODS: Whole exome sequencing was performed on peripheral blood samples extracted from 18 patients with CCS. Potential function-impacting germline variants were filtered by R software. Through systematic data analysis, a number of genetic variants were identified. Enrichment analysis was performed using the R package ClusterProfiler. RESULTS: Overall, 3960 low-frequency (<0.05 or not reported in the Exome Aggregation Consortium East Asian, 1000 Genomes, or ESP6500 database) potentially function-impacting germline variants were identified, with 18 genes (FDFT1, LOC400863, MUC3A, MUC4, ZNF806, GXYLT1, MUC6, PABPC3, PSPH, ZFPM1, CIC, LOC283710, ARSD, GOLGA6L2, LOC388282, SLC25A5, TMEM247, WDR89) involved over half the patients. Functional enrichment of these genes revealed several biological processes in relation to innate immune responses and glycosylation. Only one likely pathogenic germline variant of an hamartomatous polyposis syndrome-associated gene, PTCH1, was detected in one patient. CONCLUSIONS: CCS has genomic alteration patterns completely distinct from those of traditional hamartomatous polyposis syndrome. The germline mutation landscape indicates potential roles of innate immune responses and glycosylation in the pathogenesis of CCS.

[Association of variations in MyoD family of genes with body measurement traits in goat].

Single nucleotide polymorphisms (SNPs) of hircine myf-5, myf-6 genes and 5'flanking region of the myoD gene (myoD 5') were analyzed by PCR-SSCP in Boer goat and Xuhuai white goat. Three genotypes were found at the myf-5 locus of Xuhuai white goat, denoted AA, AB and BB, while all of Boer goats were of AA genotype. Only AA and AB genotypes were found at myf-6 and myoD 5' loci. The effects of genotypes of myf-5, myf-6 and myoD 5'flanking region loci on body measurement traits were estimated. The results showed that genotypes at the myf-5 locus were significantly associated with hucklebone width and hucklebone width index in Xuhuai white goat (P<0.05). Genotypes at the myf-6 locus were significantly associated with withers heights and hucklebone width index in Boer goat (P<0.05), but no significant associations were found for any traits in Xuhuai white goat. The myoD 5' locus was not significantly associated with any traits in both types of goat.

[Metabolic syndrome complicated by peripheral arterial disease: clinical study of 2115 cases].

OBJECTIVE: To investigate the prevalence of peripheral arterial disease (PAD) complicated in metabolic syndrome (MS) and its risk factors. METHODS: The clinical data of 2115 in-patients and out-patients with MS, 1132 males and 983 females, aged 67.6 +/- 5.1 (32 approximately 91), diagnosed and treated in several hospitals in Beijing and Shanghai, were collected. The patients underwent measurement of the systolic pressures of the brachial artery and ankle artery so as to calculate the ankle-brachial index (ABI). An ABI less than 0.9 was considered to be indicative of significant PAD. The data underwent statistical analysis. RESULTS: 476 patients (22.5%) were found to have PAD, among which 246 were male aged 71.3 +/- 9.4 (51.68%) and 230 were female (48.32%) aged 71.2 +/- 8.2. The risk of PAD among then MS patients became higher along with the increase of age (OR = 1.069, 95% CI = 1.054 - 1.083), gender (OR = 1.498, 95% CI = 1.091 - 2.058), smoking status (OR = 1.763, 95% CI = 1.294 - 2.402), history of coronary heart disease, history of diabetes mellitus, and history of stroke were independently associated with low ABI (ABI < 0.9) (all P < 0.05). Higher blood urea nitrogen, creatine (CRE), and uric acid values of the female MS patients complicated by PAD was 7 mmol/L +/- 4 mmol/L, 101 mmol/L +/- 77 mmol/L, and 343 mmol/L +/- 115 mmol/L respectively, all significantly higher than those of the female MS patients not complicated by PAD (6 mmol/L +/- 4 mmol/L, 84 mmol/L +/- 70 mmol/L, and 308 mmol/L +/- 100 mmol/L respectively, P < 0.0001, P = 0.002, and P < 0.001). However, the BUN value of the male patients with MS complicated by PAD was 7.2 mmol/L +/- 4.9 mmol/L, significantly higher than that of the male MS patients nor complicated b PAD (6.5 mmol/L +/- 4.3 mmol/L, P = 0.036), however, he values of CRE and UA of the male MS patients complicated and not complicated by PAD were not significantly different (both P > 0.05), only the value of BUN of the of the male MS patients complicated by PAD was 7.2 +/- 4.9 at high risk of PAD in female patients, NOT in male patients except BUN value (P < 0.05). CONCLUSION: Patients with MS have high risk of complication by PAD, especially when they become older. Female patients with MS are more likely to have a trend towards kidney dysfunction.

[Analysis of POU1F1 gene polymorphisms in Qinchuan cattle and Chinese Holstein cattle].

PCR-RFLP was applied to analyze the polymorphisms of POU1F1 gene in 218 Qinchuan cattle (QQ) and Chinese Holstein cattle (HC). Results demonstrated Hinf I polymorphisms in the 451 bp PCR product in the two populations. The frequencies of alleles A/B in QQ and HC populations were 0.232/0.768 and 0.132/0.868, respectively. The frequencies of three genotypes AA, AB and BB were 0.030/0.403/0.567 and 0.007/0.251/0.742, respectively. Qinchuan cattle population was at Hardy-Weinberg equilibrium at this locus, but Chinese Holstein cattle population was not. The gene heterozygosity/effective allele gene number/Shannon information entropy/polymorphism information content of Qinchuan cattle and Chinese Holstein cattle populations were listed for 0.356/1.553/0.541/0.292 and 0.229/1.297/0.390/0.203, respectively. All indices were higher in the Qinchuan cattle population.

[The effect of CSN1 S2, CSN3 and beta-lg genes on milk performance in Xinong Saanen dairy goat].

PCR-RFLP technique was applied to analyze correlation between the polymorphisms of CSN1 S2 (alpha(s2) casein), CSN3 (kappa casein) and beta-lg (beta-lactoglobulin) genes and milk performance in 69 individuals of Xinong Saanen dairy goat. The results showed that there was significant correlation between different genotypes of CSN1 S2 locus and milk yield:average milk yield of individuals with genotype FF was less than that of genotype NN (P < 0.05); the second lactation milk yield of individuals with genotype NN was over 90 kg higher than that with genotype FF (P < 0.01). This indicates that allele F of CSN1 S2 locus probably has significant negative effect on milk yield. The results of CSN3 gene digested with endonuclease Hind III cleavage showed that no significant difference of milk yield between genotype DE and genotype EE was detected in first, second, third and fourth lactation milk yield and average milk yield (P > 0.05). The results of CSN3 gene with endonuclease Taq I cleavage showed that no significant difference of milk yield among individuals with genotype TT, TC and CC was detected (P > 0.05). No polymorphism was detected in PCR products of CSN3 gene digested with endonuclease Hae III. The analysis of beta-lg gene's 5' flanking region (710 bp) by PCR-RFLP in Xinong Saanen dairy goat showed that milk yield of individuals with genotype AA was higher than that with genotype AB in second, third lactation milk yield and average milk yield (P < 0.05). The results implied that allele A of beta-lg gene's 5' flanking region is probably related to high milk yield.

[Polymorphism Analysis of the CSN1S2 Gene Digested.].

PCR-RFLP was applied to analyze the polymorphism of CSN1S2 gene in 170 goats that comprised of five goat breeds, namely Xinong Saanen dairy goat, Guanzhong dairy goat, Shaannan white goat, Angora goat and Boer goat. A 310 bp -long PCR product was digested with Alw26I and demonstrated polymorphism in five goat populations that were all at Hardy-Weinberg equilibrium (P>0.05). For Xinong Saanen dairy goat, Guanzhong dairy goat, Shaannan white goat, Angora goat and Boer goat, gene heterozygosity/effective allele gene number/Shaanon information entropy /Polymorphism information content were 0.1589/1.1889/0.2955/0.1463, 0.4114/1.6981/0.6017/0.5171, 0.1653/1.1980/0.3046/0.1516, 0646/1.0691/0.1463/ 0.0625, 0.0541/1.0572/0.1270/ 0.0526, respectively. According to the heredity diversity indexes described above of the five goat breeds, Guanzhong dairy goat had the most abundant heredity diversity and showed high polymorphism, and Xinong Saanen dairy goat and Shaannan white goat were inferior, while Angora goat and Boer goat had the lowest genetic variability.

Phylogeography and domestication of Chinese swamp buffalo.

To further probe into whether swamp buffaloes were domesticated once or multiple times in China, this survey examined the mitochondrial DNA (mtDNA) Control Region (D-loop) diversity of 471 individuals representing 22 populations of 455 Chinese swamp buffaloes and 16 river buffaloes. Phylogenetic analysis revealed that Chinese swamp buffaloes could be divided into two distinct lineages, A and B, which were defined previously. Of the two lineages, lineage A was predominant across all populations. For predominant lineage A, Southwestern buffalo populations possess the highest genetic diversity among the three hypothesized domestication centers (Southeastern, Central, and Southwestern China), suggesting Southwestern China as the most likely location for the domestication of lineage A. However, a complex pattern of diversity is detected for the lineage B, preventing the unambiguous pinpointing of the exact place of domestication center and suggesting the presence of a long-term, strong gene flow among swamp buffalo populations caused by extensive migrations of buffaloes and frequent human movements along the Yangtze River throughout history. Our current study suggests that Southwestern China is the most likely domestication center for lineage A, and may have been a primary center of swamp buffalo domestication. More archaeological and genetic evidence is needed to show the process of domestication.