Predictive value of preoperative routine examination for the prognosis of patients with pT2N0M0 or pT3N0M0 colorectal cancer.

BACKGROUND: In recent years, the incidence of colorectal cancer (CRC) has been increasing. With the popularization of endoscopic technology, a number of early CRC has been diagnosed. However, despite current treatment methods, some patients with early CRC still experience postoperative recurrence and metastasis. AIM: To search for indicators associated with early CRC recurrence and metastasis to identify high-risk populations. METHODS: A total of 513 patients with pT2N0M0 or pT3N0M0 CRC were retrospectively enrolled in this study. Results of blood routine test, liver and kidney function tests and tumor markers were collected before surgery. Patients were followed up through disease-specific database and telephone interviews. Tumor recurrence, metastasis or death were used as the end point of study to find the risk factors and predictive value related to early CRC recurrence and metastasis. RESULTS: We comprehensively compared the predictive value of preoperative blood routine, blood biochemistry and tumor markers for disease-free survival (DFS) and overall survival (OS) of CRC. Cox multivariate analysis demonstrated that low platelet count was significantly associated with poor DFS [hazard ratio (HR) = 0.995, 95% confidence interval (CI): 0.991-0.999, P = 0.015], while serum carcinoembryonic antigen (CEA) level (HR = 1.008, 95%CI: 1.001-1.016, P = 0.027) and serum total cholesterol level (HR = 1.538, 95%CI: 1.026-2.305, P = 0.037) were independent risk factors for OS. The cutoff value of serum CEA level for predicting OS was 2.74 ng/mL. Although the OS of CRC patients with serum CEA higher than the cutoff value was worse than those with lower CEA level, the difference between the two groups was not statistically significant (P = 0.075). CONCLUSION: For patients with T2N0M0 or T3N0M0 CRC, preoperative platelet count was a protective factor for DFS, while serum CEA level was an independent risk factor for OS. Given that these measures are easier to detect and more acceptable to patients, they may have broader applications.

Discovery of MT-1207: A Novel, Potent Multitarget Inhibitor as a Promising Clinical Candidate for the Treatment of Hypertension.

Herein, a series of novel arylpiperazine (piperidine) derivatives were designed, synthesized, and evaluated for mechanisms of action through in vitro and in vivo studies. The most promising compound, II-13 (later named as MT-1207), is a potent α1 and 5-HT2A receptor antagonist with remarkable IC50 in the picomolar level. Importantly, in the in vivo assay, II-13 achieved an effective blood pressure (BP) reduction in the 2K2C rat model without damaging renal function. Compound II-13, with its significant advantages in terms of pharmacological effects, pharmacokinetic parameters, and a large safety window, was extensively investigated. Moreover, data also showed that compound II-13 had fewer side effects in a postural BP assay and could prevent the onset of postural hypotension. Together, these results suggested that compound II-13 is a highly potent antihypertensive drug candidate with multitarget mechanisms of action in preclinical models. Currently, MT-1207 is in phase II hypertensive clinical trials in China.

Dietary cooking oils and cardiometabolic measurements in an elderly Chinese population.

OBJECTIVE: To investigate three features of dietary cooking oil intake, namely, the consumption, cooking style, and composition of fatty acids in relation to several cardiometabolic measurements in an elderly Chinese population. METHODS: The elderly (≥ 65 years) participants for this study were recruited from two community health centers in the urban area of Shanghai. A questionnaire was administered to collect information on dietary oil consumption (low, medium and high) and cooking styles (fry or stir-fry vs. others) and the composition of fatty acids (poly-unsaturated vs. mono-unsaturated). The cardiometabolic measurements included anthropometry, blood pressure, fasting plasma glucose and serum lipids. RESULTS: The 1186 study participants had a mean age of 70.9 ± 5.4 years. The mean dietary oil consumption was 35.0 g/d, being low (< 25 g/d), medium (25-49 g/d) and high (≥ 50 g/d) in 485,467 and 234 participants, respectively. The proportion of the fry or stir-fry cooking style and oils rich in mono-unsaturated fatty acids was 30.4% and 27.4%, respectively. Both before and after adjustment for sex, age, current smoking and alcohol intake, dietary oil consumption was significantly (P ≤ 0.02) and positively associated with the prevalence of treated hypertension and fasting plasma glucose concentration. With similar adjustments as above and additional adjustment for dietary oil consumption, the fry or stir-fry cooking style was significantly (P ≤ 0.048) and positively associated with body mass index, but inversely with systolic and diastolic blood pressure and serum low-density lipoprotein cholesterol, and the dietary intake of oils rich in mono-unsaturated fat acids was significantly (P ≤ 0.02) and positively associated with diastolic blood pressure, serum triglycerides, total cholesterol and low-density lipoprotein cholesterol, and the prevalence of hypertriglyceridemia and hypercholesterolemia. CONCLUSIONS: This study showed that both the consumption and composition of fatty acids of the dietary oils mattered with regard to several cardiometabolic measurements in an elderly Chinese population.

Application and challenge of pancreatic organoids in therapeutic research.

The in-vivo non-human primate animal and in-vitro cell disease models play a crucial part in the study of the mechanisms underlying the occurrence and development of pancreatic diseases, but with increasingly prominent limitations with in-depth research. Organoids derived from human pluripotent and adult stem cells resemble human in-vivo organs in their cellular composition, spatial tissue structure and physiological function, making them as an advantageous research tool. Up until now, numerous human organoids, including pancreas, have been effectively developed, demonstrating significant potential for research in organ development, disease modeling, drug screening, and regenerative medicine. However, different from intestine, liver and other organs, the pancreas is the only special organ in the human body, consisting of an exocrine gland and an endocrine gland. Thus, the development of pancreatic organoid technology faces greater challenges, and how to construct a composite pancreatic organoid with exocrine and endocrine gland is still difficult in current research. By reviewing the fundamental architecture and physiological role of the human pancreas, along with the swiftly developing domain of pancreatic organoids, we summarize the method and characteristics of human pancreatic organoids, and its application in modeling pancreatic diseases, as a platform for individualized drug screening and in regenerative medicine study. As the first comprehensive review that focus on the pharmacological study of human pancreatic organoid, the review hopes to help scholars to have a deeper understanding in the study of pancreatic organoid.

Mechanistic insights into the changes of biological activity and physicochemical characteristics in Lacticaseibacillus paracasei fortified milk powder during storage.

To clarify the change mechanism of biological activity and physicochemical characteristics in Lacticaseibacillus paracasei JY025 fortified milk powder (LFMP) during storage, morphological observation, JY025 survival, storage stability, and metabolomics of LFMP were determined during the storage period in this study. The results showed that the LFMP had a higher survival rate of JY025 compared with the bacterial powder of JY025 (LBP) during storage, which suggested that milk powder matrix could reduce strain JY025 mortality under prolonged storage in the LFMP samples. The fortification of strain JY025 also affected the stability of milk powder during the storage period. There was lower water activity and higher glass transition temperature in LFMP samples compared with blank control milk powder (BCMP) during storage. Moreover, the metabolomics results of LFMP indicated that vitamin degradation, Maillard reaction, lipid oxidation, tricarboxylic acid cycle, and lactobacilli metabolism are interrelated and influence each other to create complicated metabolism networks.

Analysis of Leaf and Soil Nutrients, Microorganisms and Metabolome in the Growth Period of Idesia polycarpa Maxim.

Idesia polycarpa Maxim is an emerging oil plant species. Understanding its microecological characteristics and internal mechanisms can serve as a basis for field management and the screening and application of growth-promoting bacteria during the growth phase of young trees. This study used three-year-old young I. polycarpa to analyze the tree's root morphology, soil, and leaf nutrient status variations from May to October. In addition, differences in the rhizosphere soil, leaf metabolites, and microorganisms were observed. The results showed that, from May to October, the total nitrogen (TN) in the soil significantly decreased, whereas the TN, total potassium (TK), and total phosphorus (TP) in the leaves differed (p < 0.05). The leaf-dominant bacteria changed from Pseudomonadota to Firmicutes phylum. In addition, the relative abundance of soil and leaf-dominant bacteria decreased. The study found that the soil and leaf differential metabolites were mainly sugars and phenolic acids. The soil bacterial community showed a significant correlation with soil pH, available potassium (AK), available phosphorus (AP), and TN (p < 0.05). Further, the soil fungal community was significantly correlated with pH and AK (p < 0.001). TP, pH, and TK were the main factors influencing the leaf bacterial community, while the leaf fungal community was significantly correlated with five factors, including pH, TC, and TN. The root morphology was also mainly affected by pH, Pedomicrobium sp., Talaromyces sp., Penicillium sp., and D-Mannitol 2.

Low Levels of Metrnl are Linked to the Deterioration of Diabetic Kidney Disease.

Objective: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Metrnl is a secreted protein that plays an important role in kidney disease. The aim of this study was to investigate DKD-related factors and the correlation between serum Metrnl levels and the severity of DKD. Methods: Ninety-six type 2 diabetes mellitus (T2DM) patients and 45 DKD patients were included in the study. A range of parameters were measured simultaneously, including waist-to-hip ratio (WHR), body mass index (BMI), urinary albumin/creatinine ratio (UACR), monocyte-lymphocyte ratio (MLR), albumin/globulin (A/G), liver and kidney function, blood lipid profile, islet function, and others. Subsequently, the related factors and predictive significance of DKD were identified. The correlation between the relevant factors of DKD and serum Metrnl levels with DKD was evaluated. Results: The duration of the disease (OR: 1.12, 95% CI: 1.01-1.24, P=0.031), hypertension (OR: 4.86, 95% CI: 1.16-20.49, P=0.031), fasting blood glucose (OR: 1.23, 95% CI: 1.03-1.48, P=0.025), WHR (OR: 2.53, 95% CI: 1.03-6.22, P=0.044), and MLR (OR: 1.91, 95% CI: 1.18-3.08, P=0.008) are independent risk factors for DKD (P < 0.05). Conversely, A/G (OR: 0.13, 95% CI: 0.02-0.76, P=0.024) and Metrnl (OR: 0.99, 95% CI: 0.98-1.00, P=0.001) have been identified as protective factors against DKD. Furthermore, the level of Metrnl was negatively correlated with the severity of DKD (rs=-0.447, P<0.001). The area under receiver operating characteristic (ROC) curves for the diagnostic accuracy of Metrnl for DKD is 0.765 (95% CI: 0.686-0.844). Conclusion: The duration of the disease, hypertension, fasting blood glucose, WHR, and MLR are major risk factors for DKD. Metrnl and A/G are protective factors for DKD. Serum Metrnl concentrations are inversely correlated with DKD severity.

Chronic vascular pathogenesis results in the reduced serum Metrnl levels in ischemic stroke patients.

Metrnl is a secreted protein involved in neurite outgrowth, insulin sensitivity, immunoinflammatory responses, blood lipids and endothelial protection. In this study, we investigated the role of Metrnl in ischemic stroke. Fifty-eight ischemic stroke patients (28 inpatient patients within 2 weeks of onset and 30 emergency patients within 24 h of onset) and 20 healthy controls were enrolled. Serum Metrnl was measured by enzyme-linked immunosorbent assay. We showed that serum Metrnl levels were significantly reduced in both inpatient and emergency patient groups compared with the controls. Different pathological causes for ischemic stroke such as large artery atherosclerosis and small artery occlusion exhibited similar reduced serum Metrnl levels. Transient ischemic attack caused by large artery atherosclerosis without brain infarction also had lower serum Metrnl levels. Metrnl was correlated with some metabolic, inflammatory and clotting parameters. Reduced serum Metrnl was associated with the severity of intracranial arterial stenosis and the presence of ischemic stroke. In order to elucidate the mechanisms underlying the reduced serum Metrnl levels, we established animal models of ischemic stroke in normal mice, atherosclerotic apolipoprotein E-knockout mice and Metrnl-knockout mice by middle cerebral artery occlusion (MCAO) using intraluminal filament or electrocoagulation. We demonstrated that serum Metrnl levels were significantly lower in atherosclerosis mice than normal mice, whereas acute ischemic stroke injury in normal mice and atherosclerosis mice did not alter serum Metrnl levels. Metrnl knockout did not affect acute ischemic stroke injury and death. We conclude that reduced serum Metrnl levels are attributed to the chronic vascular pathogenesis before the onset of ischemic stroke. Metrnl is a potential target for prevention of ischemic stroke.

Anti-stroke biologics: from recombinant proteins to stem cells and organoids.

The use of biologics in various diseases has dramatically increased in recent years. Stroke, a cerebrovascular disease, is the second most common cause of death, and the leading cause of disability with high morbidity worldwide. For biologics applied in the treatment of acute ischaemic stroke, alteplase is the only thrombolytic agent. Meanwhile, current clinical trials show that two recombinant proteins, tenecteplase and non-immunogenic staphylokinase, are most promising as new thrombolytic agents for acute ischaemic stroke therapy. In addition, stem cell-based therapy, which uses stem cells or organoids for stroke treatment, has shown promising results in preclinical and early clinical studies. These strategies for acute ischaemic stroke mainly rely on the unique properties of undifferentiated cells to facilitate tissue repair and regeneration. However, there is a still considerable journey ahead before these approaches become routine clinical use. This includes optimising cell delivery methods, determining the ideal cell type and dosage, and addressing long-term safety concerns. This review introduces the current or promising recombinant proteins for thrombolysis therapy in ischaemic stroke and highlights the promise and challenges of stem cells and cerebral organoids in stroke therapy.

Current and recent cigarette smoking in relation to cardiovascular and non-cardiovascular mortality in an elderly male Chinese population.

OBJECTIVE: To investigate the association between current and former smoking and the risk of mortality in elderly Chinese men. METHODS: Our study participants were elderly (≥ 60 years) men recruited in a suburban town of Shanghai. Cigarette smoking status was categorized as never smoking, remote (cessation > 5 years) and recent former smoking (cessation ≤ 5 years), and light-to-moderate (≤ 20 cigarettes/day) and heavy current smoking (> 20 cigarettes/day). Cox proportional hazards models and restricted cubic splines were used to examine the associations of interest. RESULTS: The 1568 participants had a mean age of 68.6 ± 7.1 years. Of all participants, 311 were never smokers, 201 were remote former smokers, 133 were recent former smokers, 783 were light-to-moderate current smokers and 140 were heavy current smokers. During a median follow-up of 7.9 years, all-cause, cardiovascular and non-cardiovascular deaths occurred in 267, 106 and 161 participants, respectively. Heavy current smokers had the highest risk of all-cause and non-cardiovascular mortality, with an adjusted hazard ratio (HR) of 2.30 (95% CI: 1.34-4.07) and 3.98 (95% CI: 2.03-7.83) versus never smokers, respectively. Recent former smokers also had a higher risk of all-cause (HR = 1.62, 95% CI: 1.04-2.52) and non-cardiovascular mortality (HR = 2.40, 95% CI: 1.32-4.37) than never smokers. Cox regression restricted cubic spline models showed the highest risk of all-cause and non-cardiovascular mortality within 5 years of smoking cessation and decline thereafter. Further subgroup analyses showed interaction between smoking status and pulse rate (≥ 70 beats/min vs. < 70 beats/min) in relation to the risk of all-cause and non-cardiovascular mortality, with a higher risk in current versus never smokers in those participants with a pulse rate below 70 beats/min. CONCLUSIONS: Cigarette smoking in elderly Chinese confers significant risks of mortality, especially when recent former smoking is considered together with current smoking.

Metrnl deficiency retards skin wound healing in mice by inhibiting AKT/eNOS signaling and angiogenesis.

Meteorin-like (Metrnl) is a novel secreted protein with various biological activities. In this study, we investigated whether and how Metrnl regulated skin wound healing in mice. Global Metrnl gene knockout mice (Metrnl-/-) and endothelial cell-specific Metrnl gene knockout mice (EC-Metrnl-/-) were generated. Eight-mm-diameter full-thickness excisional wound was made on the dorsum of each mouse. The skin wounds were photographed and analyzed. In C57BL/6 mice, we observed that Metrnl expression levels were markedly increased in skin wound tissues. We found that both global and endothelial cell-specific Metrnl gene knockout significantly retarded mouse skin wound healing, and endothelial Metrnl was the key factor affecting wound healing and angiogenesis. The proliferation, migration and tube formation ability of primary human umbilical vein endothelial cells (HUVECs) were inhibited by Metrnl knockdown, but significantly promoted by addition of recombinant Metrnl (10 ng/mL). Metrnl knockdown abolished the proliferation of endothelial cells stimulated by recombinant VEGFA (10 ng/mL) but not by recombinant bFGF (10 ng/mL). We further revealed that Metrnl deficiency impaired VEGFA downstream AKT/eNOS activation in vitro and in vivo. The damaged angiogenetic activity in Metrnl knockdown HUVECs was partly rescued by addition of AKT activator SC79 (10 µM). In conclusion, Metrnl deficiency retards skin wound healing in mice, which is related to impaired endothelial Metrnl-mediated angiogenesis. Metrnl deficiency impairs angiogenesis by inhibiting AKT/eNOS signaling pathway.

The generation and properties of human cortical organoids as a disease model for malformations of cortical development.

As three-dimensional "organ-like" aggregates, human cortical organoids have emerged as powerful models for studying human brain evolution and brain disorders with unique advantages of human-specificity, fidelity and manipulation. Human cortical organoids derived from human pluripotent stem cells can elaborately replicate many of the key properties of human cortical development at the molecular, cellular, structural, and functional levels, including the anatomy, functional neural network, and interaction among different brain regions, thus facilitating the discovery of brain development and evolution. In addition to studying the neuro-electrophysiological features of brain cortex development, human cortical organoids have been widely used to mimic the pathophysiological features of cortical-related disease, especially in mimicking malformations of cortical development, thus revealing pathological mechanism and identifying effective drugs. In this review, we provide an overview of the generation of human cortical organoids and the properties of recapitulated cortical development and further outline their applications in modeling malformations of cortical development including pathological phenotype, underlying mechanisms and rescue strategies.

Mitochondrial transplantation as a promising therapy for mitochondrial diseases.

Mitochondrial diseases are a group of inherited or acquired metabolic disorders caused by mitochondrial dysfunction which may affect almost all the organs in the body and present at any age. However, no satisfactory therapeutic strategies have been available for mitochondrial diseases so far. Mitochondrial transplantation is a burgeoning approach for treatment of mitochondrial diseases by recovery of dysfunctional mitochondria in defective cells using isolated functional mitochondria. Many models of mitochondrial transplantation in cells, animals, and patients have proved effective via various routes of mitochondrial delivery. This review presents different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application. Despite some unknowns and challenges, mitochondrial transplantation would provide an innovative approach for mitochondrial medicine.

Hepatic Nampt Deficiency Aggravates Dyslipidemia and Fatty Liver in High Fat Diet Fed Mice.

Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. Thus far, hepatic Nampt has not been extensively explored in terms of its effects on serum lipid stability and liver lipids metabolism. In this study, hepatocyte-specific Nampt knockout (HC-Nampt-/-) mice were generated by Cre/loxP system. Nampt mRNA expression was reduced in the liver, but not in other tissues, in HC-Nampt-/- mice compared with wild-type (WT) mice. Hepatic Nampt deficiency had no effect on body weight and fasting blood glucose, and it did not induce atherosclerosis in mice under both normal chow diet (NCD) and high fat diet (HFD). At baseline state under NCD, hepatic Nampt deficiency also did not affect liver weight, liver function index, including alanine aminotransferase, aspartate aminotransferase, albumin and alkaline phosphatase, and serum levels of lipids, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-esterified fatty acids (NEFA). However, under HFD, deficiency of hepatic Nampt resulted in increased liver weight, liver function index, and serum levels of TG, TC, HDL-C, and NEFA. Meanwhile, histopathological examination showed increased fat accumulation and fibrosis in the liver of HC-Nampt-/- mice compared with WT mice. Taken together, our results show that hepatic Nampt deficiency aggravates dyslipidemia and liver damage in HFD fed mice. Hepatocyte Nampt can be a protective target against dyslipidemia and fatty liver.

Angiogenesis after ischemic stroke.

Owing to its high disability and mortality rates, stroke has been the second leading cause of death worldwide. Since the pathological mechanisms of stroke are not fully understood, there are few clinical treatment strategies available with an exception of tissue plasminogen activator (tPA), the only FDA-approved drug for the treatment of ischemic stroke. Angiogenesis is an important protective mechanism that promotes neural regeneration and functional recovery during the pathophysiological process of stroke. Thus, inducing angiogenesis in the peri-infarct area could effectively improve hemodynamics, and promote vascular remodeling and recovery of neurovascular function after ischemic stroke. In this review, we summarize the cellular and molecular mechanisms affecting angiogenesis after cerebral ischemia registered in PubMed, and provide pro-angiogenic strategies for exploring the treatment of ischemic stroke, including endothelial progenitor cells, mesenchymal stem cells, growth factors, cytokines, non-coding RNAs, etc.

Alcohol intake and dyslipidemia in male patients with hypertension and diabetes enrolled in a China multicenter registry.

Alcohol consumption is a proven risk factor of dyslipidemia. In the present analysis, we investigated the association of alcohol intake with dyslipidemia, an emerging epidemic in China, in male patients with hypertension and diabetes mellitus. Our study participants were from a nationwide registry (n = 1181). A questionnaire was administered to collect information on alcohol intake. Dyslipidemia was defined as an elevated concentration of serum triglycerides (≥2.3 mmol/L), total (≥6.2 mmol/L) or low-density lipoprotein (LDL) cholesterol (≥4.1 mmol/L), or a reduced high-density lipoprotein (HDL) cholesterol (< 1.0 mmol/L). Serum concentrations of triglycerides (1.60 mmol/L) and total (4.93 mmol/L) and LDL cholesterol (2.95 mmol/L) were highest with current usual drinking, with a significant P value for trend from never (n = 679) to ever (n = 107) and to rare (n = 187) and usual drinkers (n = 208, P ≤ .002). Serum HDL cholesterol (1.13 mmol/L) was lowest in ever drinkers, with a nonsignificant P value for trend (P = .22). The prevalence was highest in usual drinkers for hypertriglyceridemia (27.4%) and total (12.5%) and LDL hypercholesterolemia (8.7%), and in ever drinkers for low HDL cholesterol (34.6%). The P value for trend was significant for hypertriglyceridemia and total hypercholesterolemia (P ≤ .01), but not for LDL hypercholesterolemia or low HDL cholesterol (P ≥ .26). The between-province ecological analysis showed that the proportion of usual drinking was significantly associated with the prevalence of any dyslipidemia across 10 China provinces (r = .42, P < .0001). In conclusion, alcohol drinkers showed a worse lipid profile in patients with hypertension and diabetes mellitus. Usual drinking ecologically explained the between-province variation in the prevalence of dyslipidemia.

Distribution of Nicotinamide Mononucleotide after Intravenous Injection in Normal and Ischemic Stroke Mice.

OBJECTIVE: This study determined for the first time the distribution of intravenous nicotinamide mononucleotide (NMN) and its metabolite nicotinamide adenine dinucleotide (NAD) in normal and ischemic stroke mice, examined the therapeutic effect of NMN on ischemic brain infarction, and evaluated acute toxicity of NMN after intravenous injection of NMN. METHODS: NMN and NAD levels were determined using ultra-high-performance liquid chromatography tandem mass spectrometry in biological samples from mice with or without middle cerebral artery occlusion (MCAO) at different time points post intravenous NMN injection (300 mg/kg). Brain infarction was evaluated 24 h post-MCAO. 2 g/kg NMN was used in the acute toxicity test. RESULTS: Under either normal or MCAO conditions, serum NMN levels sharply increased after intravenous NMN administration and then decreased rapidly within 15 min, while serum NAD levels remained unchanged during 30 min observation. Both substances displayed tissue accumulation over time and stored faster under MCAO conditions, with kidney having the highest concentrations. Particularly, NMN accumulated earlier than NAD in the brain. Moreover, NMN reduced cerebral infarction at 24 h post-MCAO. No acute toxicity was observed for 14 days. NRK1 and SLC12A8 involved in two pathways of NMN uptake exhibited the highest expressions in kidney and colon, respectively, among 11 different tissues. CONCLUSION: NMN distributes to various tissues after intravenous injection and has the ability to enter the brain to boost NAD levels, and exhibits safety and therapeutic effect on acute ischemic stroke injury. High renal distribution of NMN indicates its importance in the kidney.

Milk yield variation partially attributed to blood oxygen-mediated neutrophil activation in lactating dairy goats.

Blood oxygen is an essential component for numerous biological processes of mammalian animals. Milk production of ruminants largely relies on the supply of nutrients, such as glucose, amino acids and fatty acids. To define the regulatory role of blood oxygen availability in regard to milk production, seventy-five healthy Guanzhong dairy goats with similar body weight, days in milk and parities were selected. For each animal, milk yield was recorded and milk sample was collected to determine compositions. Milk vein blood was collected to determine parameters including blood gas, physio-biochemistry and haematology. Another blood sample was prepared for transcriptome and RT-qPCR. Results showed that both pressure of oxygen (pO2) in the milk vein (positively) and numbers of neutrophils in mammary vein (negatively) were associated with milk yield of the animals. To learn the role of pO2 in blood cell functionality, twelve animals (six with higher yield (H-group) and six with lower yield (L-group)) from seventy-five goats were selected. Compared with animals in L-group, goats in H-group were higher in pO2 but lower in pCO2, lactate, lactate dehydrogenase activity and neutrophil abundance in milk vein, compared with L-group. The blood transcriptome analysis suggested that compared with L-group, animals in H-group were depressed in functionality including neutrophil activation and metabolic pathways including glycolysis, NF-κB and HIF-1. Our result revealed that lower milk production could be associated with neutrophil activation responding to low pO2 in the mammary vein. In the meantime, we highlighted the potential importance of blood oxygen as a milk yield regulator.

Metrnl regulates cognitive dysfunction and hippocampal BDNF levels in D-galactose-induced aging mice.

Aging is one of the main risk factors for cognitive dysfunction. During aging process, the decrease of brain-derived neurotrophic factor (BDNF) and the impairment of astrocyte function contribute to the cognitive impairment. Metrnl, a neurotrophic factor, promotes neural growth, migration and survival, and supports neural function. In this study, we investigated the role of Metrnl in cognitive functions. D-galactose (D-gal)-induced aging model was used to simulate the process of aging. Cognitive impairment was assessed by the Morris water maze test. We showed that Metrnl expression levels were significantly increased in the hippocampus of D-gal-induced aging mice. Metrnl knockout did not affect the cognitive functions in the baseline state, but aggravated the cognitive impairment in the D-gal-induced aging mice. Furthermore, Metrnl knockout significantly reduced hippocampal BDNF, TrkB, and glial fibrillary acidic protein (GFAP) levels in the D-gal-induced aging mice. In the D-gal-induced aging cell model in vitro, Metrnl levels in the hippocampal astrocytes were significantly increased, and Metrnl knockdown and overexpression regulated the BDNF levels in primary hippocampal astrocytes rather than in neurons. We conclude that Metrnl regulates cognitive functions and hippocampal BDNF levels during aging process. As a neurotrophic factor and an endogenous protein, Metrnl is expected to become a new candidate for the treatment or alleviation of aging-related cognitive dysfunction.

Humanized cerebral organoids-based ischemic stroke model for discovering of potential anti-stroke agents.

Establishing a stoke experimental model, which is better in line with the physiology and function of human brain, is the bottleneck for the development of effective anti-stroke drugs. A three-dimensional cerebral organoids (COs) from human pluripotent stem cells can mimic cell composition, cortical structure, brain neural connectivity and epigenetic genomics of in-vivo human brain, which provides a promising application in establishing humanized ischemic stroke model. COs have been used for modeling low oxygen condition-induced hypoxic injury, but there is no report on the changes of COs in response to in vitro oxygen-glucose deprivation (OGD)-induced damage of ischemic stroke as well as its application in testing anti-stroke drugs. In this study we compared the cell composition of COs at different culture time and explored the cell types, cell ratios and volume size of COs at 85 days (85 d-CO). The 85 d-CO with diameter more than 2 mm was chosen for establishing humanized ischemic stroke model of OGD. By determining the time-injury relationship of the model, we observed aggravated ischemic injury of COs with OGD exposure time, obtaining first-hand evidence for the damage degree of COs under different OGD condition. The sensitivity of the model to ischemic injury and related treatment was validated by the proven pan-Caspase inhibitor Z-VAD-FMK (20 µM) and Bcl-2 inhibitor navitoclax (0.5 µM). Neuroprotective agents edaravone, butylphthalide, P7C3-A20 and ZL006 (10 µM for each) exerted similar beneficial effects in this model. Taken together, this study establishes a humanized ischemic stroke model based on COs, and provides evidence as a new research platform for anti-stroke drug development.