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Cerebroprotein hydrolysate‐I (CH‐I)，a mixture of peptides extracted from porcine brain tissue，has shown a neuroprotective effect, but its role in brain senescence is unclear. In the present study, we established a senescence model of PC12 cells and mice to investigate the effect of CH‐I on brain senescence via JAK2/STAT3 pathway. The results showed that CH‐I could improve cell viability, inhibit the apoptosis of cells, and reduce the senescence‐positive cells induced by D‐galactose. In vivo, CH‐I improved the learning ability and memory of aging mice, reduced neuronal damage in mice hippocampus. Mechanism studies showed that CH‐I could adjust BDNF protein expressions, activate JAK2/STAT3 pathway, and finally enhance telomerase activity. All these findings indicated that CH‐I showed a neuroprotective effect against brain senescence. These results might provide further reference and support for the application of CH‐I in delaying aging., Cerebroprotein hydrolysate‐I prevent D‐gal induced senescence of PC12 cells Cerebroprotein hydrolysate‐I prevent hippocampal senescence in mice induced by D‐gal Cerebroprotein hydrolysate‐I regulate telomerase by JAK2/STAT3 pathway to delay senescence ​

Liver fibrosis, with the characterization of progressive accumulation of extracellular matrix (ECM), is the common pathologic feature in the process of chronic liver disease. Hepatic stellate cells (HSCs) which are activated and differentiate into proliferative and contractile myofibroblasts are recognized as the main drivers of fibrosis. Obesity-related adipocytokine dysregulation is known to accelerate liver fibrosis progression, but the direct fibrogenic effect of mature adipocytes on HSCs has been rarely reported. Therefore, the purpose of this study was to explore the fibrogenic effect of adipocyte 3T3-L1 cells on hepatic stellate LX-2 cells. The results showed that incubating LX-2 cells with the supernatant of 3T3-L1 adipocytes triggered the expression of ECM related proteins, such as α-smooth muscle actin (α-SMA), type I collagen (CO-I), and activated TGF β/Smad2/3 signaling pathway in LX-2 cells. In addition, 3T3-L1 cells inhibited insulin sensitivity, activated endoplasmic reticulum stress and autophagy to promote the development of fibrosis. These results supported the notion that mature adipocytes can directly activate hepatic stellate cells, and the establishment of an in vitro model of adipocytes on HSCs provides an insight into screening of drugs for liver diseases, such as nonalcoholic fatty liver disease.

Review Progress of 3D Organoid Technology for Preclinical Investigations: Towards Human In Vitro Models Yingjuan Liu *, Honglin Xu, Sabu Abraham, Xin Wang, and Bernard D. Keavney* Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, M13 9PT, UK. * Correspondence: yingjuan.liu@manchester.ac.uk (Yingjuan Liu); bernard.keavney@manchester.ac.uk (Bernard D. Keavney) Received: 1 November 2022 Accepted: 24 November 2022 Published: 21 December 2022 Abstract: Currently, with an increased requirement for new therapeutic strategies, preclinical drug testing or screening platforms have rapidly evolved in recent years. In comparison to traditional 2D cell cultures, 3D organoids or spheroids with or without scaffolds improve the microenvironment of in vitro cultures, advancing the in vitro biological observation and enabling mechanistic studies of drug reactions in the human tissue-like environment. 3D organoids and spheroids are straightforward to produce, and relatively uniform in size and shape. This helps to facilitate high throughput screening requirements. Spheroids and organoids have been applied in anti-cancer drug testing, toxicity evaluations, as well as mechanism studies for variable organ systems, including the intestine, liver, pancreas, brain, and heart. Among 3D cultures of spheroids and organoids, ‘tumour spheroids’ formed by dissociated tumour tissues or cancer cell lines are relatively simple in composition and commonly applied to anticancer drug screening. The ‘healthy organoids’ differentiated from hiPSCs/hESCs are more complex in cell composition, distribution, structure and function with higher similarity to in vivo organs, and have found applications in toxicity tests, personalised medicine, and therapeutic and mechanistic studies. In most cases, the multicellular 3D organoids are more resistant and stable in reaction to stimulations or chemicals in vitro , suggesting more accurate modelling of in vivo responses. Here, we review recent progress in human-origin organoid/spheroid systems and their applications in preclinical studies.

The water-soluble polysaccharide, SF-2, obtained from starfish (Asterias rollestoni), belongs to the group of polysaccharides known as mannoglucan sulfate. It is composed of mannose as well as glucose and contains 13.85% SO42-. We aimed to detect the immunoenhancement effects of SF-2 in macrophages and cyclophosphamide (CYP)-induced immunosuppression mouse models. RAW 264.7 macrophage cells were treated with SF-2 for different periods of time (0 h, 0.5 h, 1 h, 3 h, 6 h, and 9 h) and the results showed that SF-2 promoted the production of nitric oxide and up-regulated the levels of pro-inflammatory cytokines and related proteins, such as TNF-α, IL-1β, IL-6, COX-2, MMP-9, and iNOS in a time-dependent manner. In addition, SF-2 activated NLRP3 inflammasome and the MAPK/NF-κB signaling pathway, thus promoting its immunoenhancement effects. Moreover, we co-cultured the primary peritoneal macrophages with SF-2 for 6 h and found that SF-2 enhanced the expression of NLRP3 inflammasome and the release of cytokines. Furthermore, SF-2 significantly increased the body weight, spleen index, thymus index, and inflammatory cell counts in CYP-induced immunosuppression mouse models. These results indicate that SF-2 is a potential immunoenhancement mediator that acts by activating the NLRP3 inflammasome and MAPK/NF-κB pathway.

Xiaolin Wu,1,2 Yingjuan Liu,2 Lin Zhu,2 Yue Wang,2 Yuqian Ren,2 Baohe Cheng,3 Leiming Ren,4 Keli Ge,2 Hongyun Li1 1Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, People’s Republic of China; 2Institute of Integrative Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong, 266021, People’s Republic of China; 3Shandong Haoyun Guoji Stem Cells Hospital, Jinan, Shandong, 250001, People’s Republic of China; 4Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of ChinaCorrespondence: Hongyun LiDepartment of Neurology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, Shandong, People’s Republic of ChinaEmail 18661808653@163.comKeli GeInstitute of Integrative Medicine, School of Basic Medicine, Qingdao University, No. 38, Dengzhou Road, Shibei District, Qingdao, Shandong, People’s Republic of ChinaEmail ntfadu@163.comIntroduction: Vascular dementia (VaD), one of the brain injuries, is difficult to be cured, so it is important to take active neuroprotective treatment after its occurrence. Many studies have shown that apoptosis serves an important role in VaD occurrence; therefore, inhibition of apoptosis may contribute to the recovery of neurological function after VaD occurrence. Cerebroprotein hydrolysate-I (CH-I), a neuropeptide preparation which consists of several amino acids and small molecular peptides as the main active constituent, is extracted using a method similar to cerebrolysin (CBL) which has neuroprotective and neurotrophic effects.Methods: In the present study, a VaD model which was constructed using bilateral common carotid artery occlusion (BCCAO) in Kunming mice was applied to examine the neuroprotective effects of CH-I.Results: The results show that CH-I treatment could attenuate the decrease of learning and memory ability, cell apoptosis in the hippocampal CA1 region and inhibit the activation of caspase-3 and caspase-9 in VaD mice. Furthermore, CH-I treatment could also upregulate Bcl-2 protein levels and activate PI3K and Akt.Discussion: We speculate that CH-I may induce a neuroprotective effect activating PI3K/Akt signaling pathway in VaD mice.Keywords: vascular dementia, cerebroprotein hydrolysate-I, apoptosis, PI3K/Akt

Studies have found that salidroside, isolated from Rhodiola rosea L, has various pharmacological activities, but there have been no studies on the effects of salidroside on brain hippocampal senescence. The purpose of this study was to investigate the mechanistic role of salidroside in hippocampal neuron senescence and injury. In this study, long-term cultured primary rat hippocampal neurons and naturally aged C57 mice were treated with salidroside. The results showed that salidroside increased the viability and MAP2 expression, reduced β-galactosidase (β-gal) levels of rat primary hippocampal neurons. Salidroside also improved cognition dysfunction in ageing mice and alleviated neuronal degeneration in the ageing mice CA1 region. Moreover, salidroside decreased the levels of oxidative stress and p21, p16 protein expressions of hippocampal neurons and ageing mice. Salidroside promoted telomerase reverse transcriptase (TERT) protein expression via the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway. In conclusion, our findings suggest that salidroside has the potential to be used as a therapeutic strategy for anti-ageing and ageing-related disease treatment.

Cancer pain is a common problem in clinical cancer therapy. Opioid analgesia is one of the most effective drugs for pain relief with satisfying performance besides the side effect of opioid-induced constipation (OIC). Acupuncture, as a Chinese traditional non-invasive intervention, has been applied to clinical cancer pain management and functional constipation therapy. However, only a few studies have adopted this treatment for OIC patients. Due to limited numbers of investigated subjects and variability of application methods, including treatment apparatus, acupoints, durations, and sessions, the interpretation of acupuncture’s therapy effects from single-site randomized clinical trials (RCT) is limited. Therefore, we conducted a meta-analysis by collecting published data from Pubmed, Embase, Cochrane library, and Web of Science. Five RCTs focusing on the application of acupuncture with or without medication in OIC patients were included. An overall remission rate of 86.8% in the acupuncture-treated group was achieved, higher than the control group (78.9%; RR, 1.10, 95% CI [1.03, 1.18]). The symptom scores, reporting on defecation frequency, defecation straining, abdominal pain, defection time, and stool property, in acupuncture groups were lower than control groups with a standardized mean difference (SMD) of −2.21 [−4.15, −0.27]. The quality of life (QOL) for patients in the acupuncture treated group increased compared to the control group with reduced PAC-QOL scores (SMD, −1.02 [−1.78, −0.26]). Referring to the effects from pure acupuncture treatment (SMD, −0.43 [−0.83, −0.03]), the co-intervention of acupuncture and drugs (SMD, −1.77 [−2.51, −1.02]) improved the life quality of patients more remarkably (P < 0.05). Overall, our data confirmed the therapeutic effects of acupuncture in the treatment of OIC. The co-intervention of acupuncture with drugs improves the outcomes of OIC patients better than a single strategy. Combined therapy with both medicine and acupuncture has insightful potential for future clinical cancer patient management on constipation problems.

Parkinson&rsquo, s disease (PD), one of the most common neurodegenerative disorders, is caused by dopamine depletion in the striatum and dopaminergic neuron degeneration in the substantia nigra. In our previous study, we hydrolyzed the fucoidan from Saccharina japonica, obtaining three glucuronomannan oligosaccharides (GMn, GM1, GM2, and GM3) and found that GMn ameliorated behavioral deficits in Parkinsonism mice and downregulated the apoptotic signaling pathway, especially with GM2 showing a more effective role in neuroprotection. However, the neuroprotective mechanism is unclear. Therefore, in this study, we aimed to assess the neuroprotective effects of GM2 in vivo and in vitro. We applied GM2 in 1-methyl-4-phenylpyridinium (MPP+)-treated PC12 cells, and the results showed that GM2 markedly improved the cell viability and mitochondrial membrane potential, inhibited MPP+-induced apoptosis, and enhanced autophagy. Furthermore, GM2 contributed to reducing the loss of dopaminergic neurons in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice through enhancing autophagy. These data indicate that a possible protection of mitochondria and upregulation of autophagy might underlie the observed neuroprotective effects, suggesting that GM2 has potential as a promising multifunctional lead disease-modifying therapy for PD. These findings might pave the way for additional treatment strategies utilizing carbohydrate drugs in PD.

Parkinson&rsquo, s disease (PD), characterized by dopaminergic neuron degeneration in the substantia nigra and dopamine depletion in the striatum, affects up to 1% of the global population over 50 years of age. Our previous study found that a heteropolysaccharide from Saccharina japonica exhibits neuroprotective effects through antioxidative stress. In view of its high molecular weight and complex structure, we degraded the polysaccharide and subsequently obtained four oligosaccharides. In this study, we aimed to further detect the neuroprotective mechanism of the oligosaccharides. We applied MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to induce PD, and glucuronomannan oligosaccharides (GMn) was subsequently administered. Results showed that GMn ameliorated behavioral deficits in Parkinsonism mice. Furthermore, we observed that glucuronomannan oligosaccharides contributed to down-regulating the apoptotic signaling pathway through enhancing the expression of tyrosine hydroxylase (TH) in dopaminergic neurons. These results suggest that glucuronomannan oligosaccharides protect dopaminergic neurons from apoptosis in PD mice.

Previous genome-wide association studies (GWAS) have identified a region of chromosome 4p16 associated with the risk of Atrial Septal Defect (ASD), which is among the commonest Congenital Heart Disease (CHD) phenotypes. Here, we identify the responsible gene in the region and elucidate disease mechanisms. Linkage disequilibrium in the region, eQTL analyses in human atrial tissues, and spatio-temporal gene expression studies in human embryonic hearts concordantly suggested the long noncoding RNA (lncRNA) STX18-AS1 as the causative gene in the region. Using CRISPR/Cas9 knockdown in HepG2 cells, STX18-AS1 was shown to regulate the expression of the key cardiac transcription factor NKX2-5 via a trans-acting effect on promoter histone methylation. Furthermore, STX18-AS1 knockdown depleted the potential of human embryonic stem cells (H9) to differentiate into cardiomyocytes, without affecting their viability and pluripotency, providing a mechanistic explanation for the clinical association.

Porphyran, derived from the marine red algae Porphyra and Pyropia, is a type of polysaccharide. Oligo-porphyran (OP) was prepared from porphyran (isolated from Pyropia yezoensis) through the acidolysis reaction containing a linear backbone of alternating 3-linked β-d-galactose and 4-linked α-l-galactose-6-sulfate. Our previous studies have shown that oligo-porphyran could attenuate MPTP-induced behavioral deficits in mice by inhibiting the tyrosine hydroxylase (TH) loss. In the present study, we further investigated how OP protects the dopamine neurons from loss in PC12 cells. OP significantly attenuated LDH release and the production of reactive oxygen species (ROS) lesioned by 6-OHDA. Moreover, OP alleviated the mitochondrial membrane potential (MMP) loss, the ratio of Bax/Bcl-2, and upregulated the PI3K/ Akt/PKC pathway, the level of tyrosine hydroxylase (TH), and dopamine transporter (DAT). Furthermore, OP decreased the production of proinflammatory cytokines. Terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) staining further indicated that OP treatment inhibited apoptosis. These results might contribute to the overall understanding of the potential health benefits of OP for food and drug applications.

A heteropolysaccharide (SHP) with a strong immunomodulatory effect on RAW 264.7 cells was prepared from Saccharina japonica. Chemical analysis demonstrated that SHP was primarily composed of mannose, glucuronic acid, glucose, fucose, galactose, xylose and rahmnose with a molar ratio of 1.00:0.85:0.84:0.58:0.30:0.37:0.15. ESI-MS showed that depolymerized SHP produced oligo-glucuronan, oligo-glucuronomannan, sulfated fuco-oligosaccharides and other hetero-oligosaccharides. The in vitro immunomodulatory results showed that SHP could increase NO production and up-regulate the expression of many immune effectors, including iNOS, COX-2 and TNF-α, displaying an apparent immune enhancement activities. Western blot analysis proved that SHP activated the expression levels of many key components involved in NF-κB, MAPK and Akt signaling pathways. Our results together indicated that SHP has the potential to be developed as a novel immunomodulator for activating immune system.

Additional file 1. Review protocol and supplementary tables for inclusion and exclusion criteria and classification of severe CHDs.

Polysaccharides have been proven to be involved in the immune response in both anti-inflammation and pro-inflammation due to their distinct pharmacological properties. Recent studies showed that polysaccharides from Grateloupia livida (Harv.) Yamada possessed several biological activities, including anti-oxidant, anti-angiogenic, anti-cancer and antiviral. Our previous work has elucidated the structural features of the polysaccharides (named WGW) by combining ESI-MS with NMR and infrared (IR) spectroscopic analyses. The polysaccharides were mainly composed of galactose linked with sulfate ester, concluding to be μ-carrageenan and κ-carrageenan. The purpose of this study was to investigate the immunoregulation effects of WGW on macrophage RAW 264.7 cell. The cells were treated with WGW for different times, then Griess reagent was applied to detect the production of NO. The results presented that WGW induced the release of NO in large quantities (ranging from 2 µg/mL to 256 µg/mL) and improved the phagocytosis of macrophage RAW264.7 cells. Furthermore, WGW have a predominant role in the improvement of proinflammatory mediators, such TNF-α, IL-1β, iNOS, MMP-9 and COX2. Moreover, WGW activated NLRP3 inflammasome, in which MAPK/NF-κB signaling pathway played an important role. These results indicated WGW might be a potential immuno-stimulation drug to promote inflammation.

Objectives A number of risk variants have been identified from Genome-wide association studies (GWAS) of Congenital Heart Disease (CHD). However, none of them has been functionally confirmed as yet. We sought to identify the gene and mechanism responsible for the GWAS signal (OR=1.46; p=2.61×10–10) which we previously identified at chromosome 4p16 for atrial septal defect (ASD). Methods and results Exploration of the linkage disequilibrium pattern between SNPs in the region indicated association was restricted to the interval spanning the long noncoding RNA STX18-AS1. Since no homolog of STX18-AS1 is found beyond primates, all experiments were conducted in human tissues and cell lines. With RNA from 108 Right Atrial Appendages and corresponding blood DNA, we confirmed the risk SNPs (rs870142 and rs16835979) were eQTLs for STX18-AS1 in human cardiac tissues. In RNA expression analyses using qPCR on embryonic heart samples, the transcription of STX18-AS1 was detected to be the highest at CS14-CS18, the critical time for atrial septation during human heart development. With in situ hybridization on whole embryonic hearts of CS17-CS19, the expression of STX18-AS1 was also determined in the myocardium of Atrial Septum. We next identified STX18-AS1 as a regulator of the key cardiac transcriptional factor NKX2-5 using CRISPR/Cas9 knockdown of STX18-AS1 in HepG2 cells. Mutations in NKX2-5 cause septal defects in humans. Reduced STX18-AS1 transcription inhibited the expression of NKX2-5 accompanied by decreased H3K4me3 at its promoter region. We demonstrated the interaction between STX18-AS1 RNA and WDR5 protein, which supported the epigenetic regulation effects of STX18-AS1. Using in vitro cardiomyocyte differentiation from human embryonic stem cells, we demonstrated that the knockdown of STX18-AS1 depleted the potential of human embryonic stem cells in differentiating into beating cardiomyocytes without changes in cell viability and pluripotency. Conclusion STX18-AS1 is the first long noncoding RNA influencing CHD risk identified from GWAS. The mechanism involves downregulation of the NKX2-5 gene through epigenetic mechanisms. Conflict of interest No

Chlormequat chloride is the most widely used plant growth regulator in agriculture to promote sturdier growth of grain crops by avoidance of lodging. Therefore, human exposure to chlormequat chloride is very common, but its developmental toxicity has not been studied. Thus, we investigated the developmental toxicity of chlormequat chloride by applying rat whole embryo culture (WEC) model, limb bud micromass culture and 3T3 fibroblast cytotoxicity test. Chlormequat chloride at 150μg/ml (0.93mM) retarded the rat embryo growth without causing significant morphological malformations and at 500μg/ml (3.1mM) caused both retardation and morphological malformation of the embryos. However, the proliferation and differentiation of limb bud cells were not affected by chlormequat chloride at as high as up to 1000μg/ml (6.2mM) applied. This concentration of chlormequat chloride did not affect the cell viability as examined by 3T3 fibroblast cytotoxicity test either, suggesting that cellular toxicity may not play a role in chlormequat induced inhibition of rat embryo growth. Collectively, our results demonstrated that chlormequat chloride may affect embryo growth and development without inhibiting cell viability.

Summary MicroRNAs (miRNAs) play crucial roles in cancer development and progression. The purposes of this study were to explore the role of miR-376c in cervical cancer and to clarify the regulation of BMI1 by miR-376c. Quantitative RT-PCR was used to measure miR-376c expression in cervical cancer tissues and cell lines. The cell proliferation, cell cycle and Transwell invasion assays were performed. A luciferase reporter assay was conducted to confirm the target gene of miR-376c, and the results were validated in cervical cancer cell lines and tissues. MiR-376c was significantly downregulated in cervical cancer cell lines and clinical tissues. Upregulation of miR-376c impaired cell proliferation, blocked G1/S checkpoint of cell cycle and suppressed cell invasion in vitro. BMI1 was verified as a direct target of miR-376c, which was further confirmed by the inverse expression of miR-376c and BMI1 in patient specimens. The newly identified miR-376c/BMI1 pathway provides an insight into cervical cancer progression and may represent a novel therapeutic target.

Background Globally, access to healthcare and diagnostic technologies are known to substantially impact the reported birth prevalence of congenital heart disease (CHD). Previous studies have shown marked heterogeneity between different regions, with a suggestion that CHD prevalence is rising globally, but the degree to which this reflects differences due to environmental or genetic risk factors, as opposed to improved detection, is uncertain. We performed an updated systematic review to address these issues. Methods Studies reporting the birth prevalence of CHD between the years 1970–2017 were identified from searches of PubMed, EMBASE, Web of Science and Google Scholar. Data on the prevalence of total CHD and 27 anatomical subtypes of CHD were collected. Data were combined using random-effect models. Subgroup and meta-regression analyses were conducted, focused on geographical regions and levels of national income. Results Two hundred and sixty studies met the inclusion criteria, encompassing 130 758 851 live births. The birth prevalence of CHD from 1970–2017 progressively increased to a maximum in the period 2010–17 of 9.410/1000 [95% CI (confidence interval) 8.602–10.253]. This represented a significant increase over the fifteen prior years (P = 0.031). The change in prevalence of mild CHD lesions (ventricular septal defect, atrial septal defect and patent ductus arteriosus) together explained 93.4% of the increased overall prevalence, consistent with a major role of improved postnatal detection of less severe lesions. In contrast the prevalence of lesions grouped together as left ventricular outflow tract obstruction (which includes hypoplastic left heart syndrome) decreased from 0.689/1000 (95% CI 0.607–0.776) in 1995–99, to 0.475/1000 (95% CI 0.392–0.565; P = 0.004) in 2010–17, which would be consistent with improved prenatal detection and consequent termination of pregnancy when these very severe lesions are discovered. There was marked heterogeneity among geographical regions, with Africa reporting the lowest prevalence [2.315/1000 (95% CI 0.429–5.696)] and Asia the highest [9.342/1000 (95% CI 8.072–10.704)]. Conclusions The reported prevalence of CHD globally continues to increase, with evidence of severe unmet diagnostic need in Africa. The recent prevalence of CHD in Asia for the first time appears higher than in Europe and America, where disease ascertainment is likely to be near-complete, suggesting higher genetic or environmental susceptibility to CHD among Asian people.

A variety of biologically active products have been isolated from Gracilariopsis lemaneiformis. In the present study, two novel angiotensin-converting enzyme (ACE) inhibitory peptides, FQIN [M(O)] CILR, and TGAPCR, were screened and identified from G. lemaneiformis protein hydrolysates by LC-MS/MS. The IC50 values of FQIN [M(O)] CILR and TGAPCR were 9.64 &plusmn, 0.36 &mu, M and 23.94 &plusmn, 0.82 &mu, M, respectively. In the stability study, both peptides showed stabilities of pH, temperature, simulated gastrointestinal digestion, and ACE hydrolysis. The Lineweaver&ndash, Burk plot showed that the two peptides were noncompetitive inhibitors of ACE. Molecular docking simulated the intermolecular interactions of two peptides and ACE, and the two peptides formed hydrogen bonds with the active pockets of ACE. However, FQIN [M(O)] CILR was more closely linked to the active pockets of ACE, thereby exerting better ACE inhibition. Spontaneously hypertensive rats (SHRs) were studied with an oral dose of 10 mg/kg body weight. Both peptides reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP) in SHRs, of which FQIN [M(O)] CILR was able to reduce the systolic blood pressure by 34 mmHg (SBP) (p &lt, 0.05). Therefore, FQIN [M(O)] CILR was an excellent ACE inhibitory peptide.

Parkinson’s disease (PD) is a neurodegenerative movement disorder that is caused by a selective loss of dopaminergic neurons. Current PD treatments provide symptomatic relief but do not prevent or decelerate disease progression. Previous studies have suggested that acetylated and phosphorylated porphyran, derived from Porphyra, produces a neuroprotective effect against 6-OHDA-induced damage. Due to its antioxidant and neuroprotective potential, this study evaluates whether oligo-porphyran (OP) could be beneficial in an experimental model of PD in mice. The drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was intraperitoneally injected (20 mg/kg body weight) for seven days to simulate PD, followed by OP administration. We found that the behavioral deficits in spontaneous motor activity, latency to descend in a pole test, and suspension in a traction test were ameliorated, and excessive dopamine (DA) metabolism was suppressed after OP treatment. Additionally, we found that OP protected dopaminergic neurons by preventing MPTP-induced decreases in dopaminergic transporter and tyrosine hydroxylase protein levels. We speculated whether OP regulates a signaling pathway that affects the behavioral changes seen in PD mice. In this study, the PI3K/Akt/Bcl-2 pathway was detected. Our results demonstrate that OP increased the phosphorylation of PI3K/Akt/GSK-3β and inhibited the activation of caspase-3 and poly (ADP-ribose) polymerase, with changes in the Bax/Bcl-2 ratio. These results showed that OP might promote DA neuron survival in vivo by regulating the PI3K/Akt/Bcl-2 pathway, thereby ameliorating the neurobehavioral deficits in a PD mouse model and suggesting OP as a neuroprotective treatment for PD.

We investigated the protective effects of curcumin on liver-damaged Cyprinus carpio var. Jian (Jian carp). The carp were fed 0.1%, 0.5%, or 1.0% curcumin for 60 days, then injected intraperitoneally with 30% carbon tetrachloride solution. Liver and blood samples were collected to measure the liver index, serum- and liver-associated enzymes, liver histology, nuclear factor-κB (NF-κB)/c-Rel, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-12 mRNA expression, and the level of NF-κB/c-Rel protein in the liver, and for a comet assay. We found that 0.5% and 1.0% curcumin significantly reduced the CCl(4)-induced increase in the liver index. The comet assay showed that the tail moment, olive tail moment, tail length, and tail DNA% improved in fish pretreated with 0.5 or 1.0% curcumin. CCl(4)-induced histological changes, including extensive hepatocyte degeneration, indistinct cell borders, nuclear condensation, and karyolysis were clearly reduced after treatment with 0.5% and 1.0% curcumin. Moreover, 0.5% and 1.0% curcumin significantly inhibited the CCl(4)-induced increase in serum glutamic oxaloacetic transaminase and promoted the restoration of superoxide dismutase in the liver; 1.0% curcumin significantly reduced serum glutamic pyruvic transaminase and lactate dehydrogenase and hepatic malondialdehyde, but significantly increased the total antioxidant capacity and glutathione levels in the liver. The CCl(4)-induced upregulation of NF-κB/c-Rel, IL-1β, and TNF-α mRNAs and NF-κB/c-Rel protein levels was inhibited by 0.5% and 1.0% curcumin, and IL-12 mRNA was reduced by all three doses of curcumin. The effects of curcumin on the liver index, enzymes, histological changes, and cytokines were dose-dependent. Our results indicate that curcumin reduces CCl(4)-induced liver damage in Jian carp by upregulating antioxidative activities and inhibiting NF-κB, IL-1β, TNF-α, and IL-12 expression.

The aim of the present study was to investigate the protective effects and possible mechanism of phyllanthin against carbon tetrachloride (CCl4)-induced hepatic damage in common carp. Fish were fed diet containing four doses of phyllanthin (0, 100, 300, and 600 mg/kg diet) for 60 days, and then given an intraperitoneal injection of CCl4 (30 % in arachis oil) at a dose of 0.5 ml/kg body weight. At 72 h after CCl4 injection, blood and liver samples were collected for the analyses of serum biochemical parameters, peroxidation product, glutathione, and antioxidant enzyme activities. The results showed that administration of phyllanthin at the doses of 300 and 600 mg/kg in the diet prior to CCl4 intoxication considerably inhibited the adverse alterations caused by CCl4 in serum and liver tissue, including glutamate pyruvate transaminase, glutamate oxalate transaminase, lactate dehydrogenase, total protein, albumin, superoxide dismutase, glutathione peroxidase, catalase, glutathione, total antioxidant capacity and malondialdehyde. Furthermore, the positive effects of phyllanthin were confirmed in histopathologic examination. Overall results proved the hepatoprotection of phyllanthin, and it is suggested that phyllanthin may be used as a hepatoprotective agent to prevent liver diseases in fish.

Long-range chromosomal interactions bring distal regulatory elements and promoters together to regulate gene expression in biological processes. By performing promoter capture Hi-C (PCHi-C) on human embryonic stem cell-derived cardiomyocytes (hESC-CMs), we show that such promoter interactions are a key mechanism by which enhancers contact their target genes after hESC-CM differentiation from hESCs. We also show that the promoter interactome of hESC-CMs is associated with expression quantitative trait loci (eQTLs) in cardiac left ventricular tissue; captures the dynamic process of genome reorganisation after hESC-CM differentiation; overlaps genome-wide association study (GWAS) regions associated with heart rate; and identifies new candidate genes in such regions. These findings indicate that regulatory elements in hESC-CMs identified by our approach control gene expression involved in ventricular conduction and rhythm of the heart. The study of promoter interactions in other hESC-derived cell types may be of utility in functional investigation of GWAS-associated regions.

A water-soluble substance was extracted from the Chinese herb, Alternanthera philoxcroides with hot water and alcohol. Aliquots of this initial extract were further fractionated by treatment with ether, ethyl acetate and alcohol respectively. The four extracts were assayed for anti-viral activity against three serum, Hantaan virus 114 (HV114), HV435 and A9 strains. Results show that the four extracts are capable of inhibiting Hantaan virus propagation, of which extract No.1 has the best efficiency. The three dosage of extract No.1, which are used upon three Hantaan virus serum IC50, are 153, 157, 154 μg/mL. New-born mice were made to be infected with HV114 and then fed in vivo with extract No.1 on the 3rd, 10th and 14th days after being infected by the virus. The treatment continued for 8 days with a dosage of 2.5 g/kg. Result shows that survival rates of mice were 75%, 50% and 0, respectively. The median time to death (MTDs) of the three groups were 37, 30, 23 days.