Animal models of heart failure with preserved ejection fraction (HFpEF): from metabolic pathobiology to drug discovery.

Heart failure (HF) with preserved ejection fraction (HFpEF) is currently a preeminent challenge for cardiovascular medicine. It has a poor prognosis, increasing mortality, and is escalating in prevalence worldwide. Despite accounting for over 50% of all HF patients, the mechanistic underpinnings driving HFpEF are poorly understood, thus impeding the discovery and development of mechanism-based therapies. HFpEF is a disease syndrome driven by diverse comorbidities, including hypertension, diabetes and obesity, pulmonary hypertension, aging, and atrial fibrillation. There is a lack of high-fidelity animal models that faithfully recapitulate the HFpEF phenotype, owing primarily to the disease heterogeneity, which has hampered our understanding of the complex pathophysiology of HFpEF. This review provides an updated overview of the currently available animal models of HFpEF and discusses their characteristics from the perspective of energy metabolism. Interventional strategies for efficiently utilizing energy substrates in preclinical HFpEF models are also discussed.

Urolithin A ameliorates obesity-induced metabolic cardiomyopathy in mice via mitophagy activation.

Metabolic cardiomyopathy (MC) is characterized by intracellular lipid accumulation and utilizing fatty acids as a foremost energy source, thereby leading to excess oxidative stress and mitochondrial dysfunction. There is no effective therapy available yet. In this study we investigated whether defective mitophagy contributed to MC and whether urolithin A (UA), a naturally occurring microflora-derived metabolite, could protect against MC in experimental obese mice. Mice were fed high fat diet for 20 weeks to establish a diet-induced obese model. We showed that mitochondrial autophagy or mitophagy was significantly downregulated in the heart of experimental obese mice. UA (50 mg·kg-1·d-1, for 4 weeks) markedly activated mitophagy and ameliorated MC in obese mice by gavage. In PA-challenged H9C2 cardiomyocytes, UA (5 µM) significantly increased autophagosomes and decreased autolysosomes. Furthermore, UA administration rescued PINK1/Parkin-dependent mitophagy and relieved mitochondrial defects in the heart of obese mice, which led to improving cardiac diastolic function and ameliorating cardiac remodelling. In PA-challenged primarily isolated cardiomyocytes, both application of mitophagy inhibitor Mdivi-1 (15 µM) and silencing of mitophagy gene Parkin blunted the myocardial protective effect of UA. In summary, our data suggest that restoration of mitophagy with UA ameliorates symptoms of MC, which highlights a therapeutic potential of UA in the treatment of MC.

COVID-19-related post-traumatic growth in the general public: a cross-sectional study from Yunnan, China.

To investigate post-traumatic growth induced by COVID-19 pandemic in certain Yunnan residents and to analyze its influencing factors. A total of 581 permanent residents of Yunnan province completed the electronic questionnaire from 18 April 2020 to 26 April 2020. Logistic regression analysis showed that the educational levels, self-perceived health status, family history of infectious diseases, family history of infectious diseases, personality and frequency of going through COVID-19 related news were influencing factors of PTG (P < 0.05). As a traumatic event, the threat of COVID-19 may enable some people to gain positive psychological development in adversity. This will provide reference for public psychological crisis intervention following the COVID-19 pandemic.

[Advances in Treatment of Human Epidermal Growth Factor Receptor 2-Positve Gastric Cancer].

Gastric cancer ranks as the fifth most common malignant tumor worldwide and the fourth leading cause of cancer-related deaths.Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer is a special type of gastric adenocarcinoma,the prognosis of which can be improved by trastuzumab plus cytotoxic chemotherapy such as cisplatin and fluorouracil.Pembrolizumab on the basis of Tmabplus chemotherapy can further improve the overall response rate,which has become the first-line standardized therapy against HER2-positive gastric cancer.However,there are still some obstacles such as the innate resistance to Tmab in specific populations.The research on HER2-targeted therapy provides clues for clinical decision-making.This review documents the current neoadjuvant and adjuvant therapies against late-stage HER2-positive gastric cancer,as well as the progress in novel HER2 pathway-targeted drugs.

Does the additional use of clomiphene citrate or letrozole for in vitro fertilization deserve more attention?

BACKGROUND: Adding clomiphene citrate (CC) and/or letrozole (LE) to in vitro fertilization (IVF) cycles for mild ovarian stimulation is a general approach. Although lots of researches have demonstrated partial benefits of the strategy, all-around effects of oral medications remained deficient. This paper aims to assess whether an addition of oral medication will result in considerable outcomes on T-Gn (total dose of gonadotropin), Gn days, total retrieved ova, high quality embryos, blastocyst number, ovarian hyperstimulation syndrome (OHSS) rate, clinical pregnancy rate and cumulative pregnancy rate, even if it was not conventional mild/minimal stimulations. RESULTS: Participants were categorized to three diverse populations as high responders, normal responders and poor responders according to basal antral follicle count. T-Gn in patients treated with CC/LE distinctly decreased from 2496.96 IU/d to 1827.68 IU/d, from 2860.28 IU/d to 2119.99 IU/d, and from 3182.15 IU/d to 1802.84 IU/d, respectively. For high ovary responders and normal responders, the OHSS incidence rate also declined from 29.2 to 4.3% (P < 0.001) and from 1.1 to 0.0% (P = 0.090). Other, there was no statistical difference with respect to the T-retrieved ova (total retrieved ova), high quality embryos, cultured blastocyst and blastocyst number in high responders. For normal responders and poor ovary responders, T-Gn, Gn days, T-retrieved ova, high quality embryos, cultured blastocyst and blastocysts number in oral medications group all apparently decreased. Clinical pregnancy rate per fresh cycle of poor responders with prior oral medications was significantly decreased (25.7% vs. 50.8%, P = 0.005), and no significant differences in high responders and normal responders were expressed (52.5% vs. 44.2%, P = 0.310; 51.9% vs. 42.4%, P = 0.163) between two groups of participants. The numbers of cumulative pregnancy rates were lower in the conventional group compared to the add group for high (75.90% versus 81.03%, P = 0.279), normal (62.69% versus 71.36%, P = 0.016) and poor (39.74% versus 68.21%, P < 0.001) responders. CONCLUSIONS: The addition of CC/LE to the ovulation induction during IVF has certain efficacy in terms of low cost, low OHSS incidence. CC/LE deserves more recommendations as a responsible strategy in high responders due to advantageous pregnancy outcomes. For normal responders, the strategy needs to be considered with more comprehensive factors.

Chemical Constituents and Biological Activity Profiles on Pleione (Orchidaceae).

Pleione (Orchidaceae) is not only famous for the ornamental value in Europe because of its special color, but also endemic in Southern Asia for its use in traditional medicine. A great deal of research about its secondary metabolites and biological activities has been done on only three of 30 species of Pleione. Up to now, 183 chemical compounds, such as phenanthrenes, bibenzyls, glucosyloxybenzyl succinate derivatives, flavonoids, lignans, terpenoids, etc., have been obtained from Pleione. These compounds have been demonstrated to play a significant role in anti-tumor, anti-neurodegenerative and anti-inflammatory biological activities and improve immunity. In order to further develop the drugs and utilize the plants, the chemical structural analysis and biological activities of Pleione are summarized in this review.

Leptin Attenuates the Contractile Function of Adult Rat Cardiomyocytes Involved in Oxidative Stress and Autophagy.

BACKGROUND: Leptin has been identified as an important protein involved in obesity. As a chronic metabolic disorder, obesity is associated with a high risk of developing cardiovascular and metabolic diseases, including heart failure. The aim of this paper was to investigate the effects and the mechanism of leptin on the contractile function of cardiomyocytes in the adult rat. METHODS: Isolated adult rat cardiomyocytes were exposed to leptin (1, 10, and 100 nmol/L) for 1 hour. The calcium transients and the contraction of adult rat cardiomyocytes were recorded with SoftEdge MyoCam system. Apocynin, tempol and rapamycin were added respectively, and Western blotting was employed to evaluate the expression of LC3B and Beclin-1. RESULTS: The peak shortening and maximal velocity of shortening/relengthening (± dL/dtmax) of cell shortening were significantly decreased, and the time to 50% relengthening was prolonged with leptin perfusion. Leptin also significantly reduced the baseline, peak and time to 50% baseline of calcium transient. Leptin attenuated autophagy as indicated by decreased LC3-II and Beclin-1. All of the abnormalities were significantly attenuated by apocynin, tempol or rapamycin. CONCLUSIONS: Our results indicated that leptin depressed the intracellular free calcium and myocardial systolic function via increasing oxidative stress and inhibiting autophagy.

EGCG Blocked Phenylephrin-Induced Hypertrophy in H9C2 Cardiomyocytes, by Activating AMPK-Dependent Pathway.

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism. Previous studies have shown that activation of AMPK results in suppression of cardiac myocyte hypertrophy via inhibition of the p70S6 kinase (p70S6K) and eukaryotic elongation factor-2 (eEF2) signaling pathways. Epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, possesses multiple protective effects on the cardiovascular system including cardiac hypertrophy. However, the molecular mechanisms has not been well investigated. In this study, we found that EGCG could significantly reduce natriuretic peptides type A (Nppa), brain natriuretic polypeptide (BNP) mRNA expression and decrease cell surface area in H9C2 cardiomyocytes stimulated with phenylephrine (PE). Moreover, we showed that AMPK is activated in H9C2 cardiomyocytes by EGCG, and AMPK-dependent pathway participates in the inhibitory effects of EGCG on cardiac hypertrophy. Taken together, our findings provide the first evidence that the effect of EGCG against cardiac hypertrophy may be attributed to its activation on AMPK-dependent signaling pathway, suggesting the therapeutic potential of EGCG on the prevention of cardiac remodeling in patients with pressure overload hypertrophy.

Metals/bisulfite system involved generation of 24-sulfonic-25-ene ginsenoside Rg1, a potential quality control marker for sulfur-fumigated ginseng.

Ginseng is a most popular health-promoting food with ginsenosides as its main bioactive ingredients. Illegal sulfur-fumigation causes ginsenosides convert to toxic sulfur-containing derivatives, and reduced the efficacy/safety of ginseng. 24-sulfo-25-ene ginsenoside Rg1 (25-ene SRg1), one of the sulfur-containing derivatives, is a potential quality control marker of fumigated ginseng, but with low accessibility owing to its unknown generation mechanism. In this study, metals/bisulfite system involved generation mechanism was investigated and verified. The generation of 25-ene SRg1 in sulfur-fumigated ginseng is that SO2, formed during sulfur-fumigation, reacted with water and ionized into HSO3-. On the one hand, under the metals/bisulfite system, HSO3- generates HSO5- and free radicals which converted ginsenoside Rg1 to 24,25-epoxide Rg1; on the other hand, as a nucleophilic group, HSO3- reacted with 24,25-epoxide Rg1 and further dehydrated to 25-ene SRg1. This study provided a technical support for the promotion of 25-ene SRg1 as the characteristic quality control marker of sulfur-fumigated ginseng.

Two pairs of new isobenzofuranone enantiomers from a soil-derived fungus Penicillium canescens DWS225.

Two pairs of new isobenzofuranone derivative enantiomers, (±)-penicifurans E (1) and (±)-penicifurans F (2), together with four know compounds (3-6) were isolated from the solid fermentation of Penicillium canescens DWS225. The structures of these enantiomers were elucidated by extensive NMR spectroscopic data, and their absolute configurations were assigned by the experimental and calculated ECD data. The neuroprotective effects of all the isolates against oxygen-glucose deprivation/reperfusion injury in pheochromocytoma-12 cells (PC12) were investigated.

Liver-cell protective pyridones from the fungi Tolypocladium album dws120.

Five previously undescribed pyridone derivatives, tolypyridones I-M, were identified from the solid rice medium fermented by Tolypocladium album dws120, along with two known compounds tolypyridone A (or trichodin A) and pyridoxatin. Their planar structures and partial relative configurations have been determined by careful interpretation of their spectroscopic data. The full assignment of the relative and absolute configurations of tolypyridones I-M was achieved by gauge-independent atomic orbital 13C NMR calculation, quantitative nuclear Overhauser effects based interatomic distance calculation, and electronic circular dichroism calculation. In addition, we have fully determined the configuration of tolypyridone A by X-ray diffraction analysis. In bioassay, tolypyridones I was able to restore cell viability and inhibit the release of alanine aminotransferase and aspartate aminotransferase for ethanol-induced LO2 cells, suggesting its potential as a liver protective agent.

Cognition of the warning symptoms and risk factors for cancer among Chinese college students: a cross-sectional study based on a summer social practice activity.

BACKGROUND: To investigate the cognition of cancer warning symptoms and cancer risk factors among Chinese college students, analyze the influencing factors, and explain the correlations between cancer cognition and cancer symptom discrimination, cancer fear and psychological distress. METHODS: Chinese college students were recruited in this cross-sectional study funded by a summer social practice activity in Yunnan Province, China. Cognition rates of cancer warning symptoms and cancer risk factors were evaluated using Cancer Warning symptoms Cognition Questionnaire (CWSCQ) and Cancer Risk Factors Cognition Questionnaire (CRFCQ), respectively. Factors associated with cognition of cancer warning symptoms, and factors associated with cognition of cancer risk factors were evaluated using multiple linear regression analysis. Interactions between cancer cognition, cancer symptom discrimination, psychological distress, and cancer fear were evaluated by structural equation modeling. RESULTS: There were 846 effective samples, with an effective rate of 80.9%. The cognition rates of cancer warning symptoms were from 47.9% to 84.4%, which were affected by cancer symptom discrimination, education, attitudes towards cancer screening, living expenses, drinking history, and ways to obtain cancer knowledge (p < 0.05). The cognition rates of cancer risk factors were from 46.3% to 91.3% in participants, which were affected by education, cancer symptom discrimination, psychological distress, attitudes towards cancer screening, life satisfaction, cancer history in relatives and friends, ways to obtain cancer knowledge, smoking history, and nursing history for cancer patients (p < 0.05). Cancer cognition and cancer symptom discrimination showed intermediary effects on psychological distress and cancer fear (p < 0.001). CONCLUSIONS: The overall cancer cognition situation among Chinese college students is not optimistic, which highlights the necessity of improving the cancer health literacy among Chinese college students. With the increasing morbidity and mortality rates of cancer, it is necessary to raise awareness of early detection, and early treatment of cancer among the general public. Health education interventions are helpful to improve cancer health literacy.

Endogenous glucocorticoids inhibit myocardial inflammation induced by lipopolysaccharide: involvement of regulation of histone deacetylation.

Emerging evidence indicates that myocardial inflammation plays a key role in the pathogenesis of cardiac diseases. But the exact mechanisms for this chronic inflammatory disorder have not been elucidated. Glucocorticoids (GCs) are the most effective anti-inflammatory treatments available for many inflammatory diseases. However, it is unknown whether endogenous GCs are able to exert anti-inflammatory effect on myocardial inflammation. In this study, the potential role of endogenous GCs in the regulation of myocardial inflammation was investigated. We showed that the reduction of endogenous GC level by adrenalectomy promoted the production of basal and lipopolysaccharide (LPS)-induced proinflammatory cytokines, which could be partly reversed by supplementing with exogenous physiological level of hydrocortisone. Inhibition of GC receptor (GR) signaling pathway with GR antagonist mifepristone (RU486) or histone deacetylase inhibitor trichostatin A (TSA) also increased the levels of basal and LPS-induced proinflammatory cytokines. Moreover, blockade of GC-GR signaling pathway by adrenalectomy, RU486 or TSA enhanced LPS-induced myocardial nuclear factor-κB activation and histone acetylation but inhibited myocardial histone deacetylase expression and activity. Cardiac function studies demonstrated that blockade of the GC-GR signaling pathway aggravated inflammation-induced cardiac dysfunction. These findings indicate that endogenous GCs are able to inhibit myocardial inflammation induced by LPS. Endogenous GCs represent an important endogenous anti-inflammatory mechanism for myocardium in rats and such mechanism injury may be an important factor for pathogenesis of cardiac diseases.

Inhibition of Liver Cancer HepG2 Cell Proliferation by Enzymatically Prepared Low-molecular Citrus Pectin.

BACKGROUND: Low-molecular citrus pectin (LCP) is a pectin polysaccharide with low molec-ular weight, low degree of crux, and no branching. It is obtained by degrading natural citrus pectin (CP) through physical, chemical and enzymatic methods. LCP has received considerable attention in recent years due to its potential applications in the medical and biological fields. METHODS: In our previous study, LCP was prepared from CP by using recombinant Bacillus subtilis pectate lyase B. Monosaccharide comparative analysis revealed that the galacturonic acid content of LCP was higher than that of CP. The cell viability effect of LCP was elucidated by using HepG2 cells and the Cell Counting Kit-8 (CCK-8) assay. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, Annexin V-FITC/PI staining, and flow cytometer propidium iodide stain-ing were performed to detect the effects of LCP on apoptosis and cell cycle arrest in HepG2 cells. Mi-tochondrial membrane potential (MMP) was observed through 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine assay. RESULTS & DISCUSSION: The Mw of the prepared LCP was 7.6 kDa, which was significantly lower than that of CP (140 kDa). Cell viability decreased with the increase in the concentration of LCP. The half-inhibitory concentration of 1.46 ± 0.02 mg/mL was determined. Treatment with 1.6 mg/mL LCP in-duced the apoptosis of HepG2 cells with the inhibition rate of 83.10% ± 4.72%, and the cell cycle was arrested in the S phase. Furthermore, the MMP of HepG2 cells decreased with the increase in LCP concentration. CONCLUSION: The enzymatically prepared LCP could inhibit the proliferation of HepG2 cells. This study provided a partial experimental basis and reference for LCP to become a potential functional food for anti-liver cancer.

Reassignment of the structures of pestalopyrones A-D.

Pestalopyrones A-D are four unusual tricyclic pyrone derivatives with flexible chiral structures, isolated from the endophytic fungus Pestalotiopsis neglecta S3. The full elucidation of their structures was a challenging task, and remained unsolved in the original article. Herein, the relative configurations of pestalopyrones A and pestalopyrones B were unambiguously assigned by detailed analyses on spectroscopic data and GIAO 13C NMR calculation method with sorted training sets (STS). The planar structures of pestalopyrones C and pestalopyrones D were revised by reinterpretation of their reported spectroscopic data, and then their relative configurations were deduced by STS GIAO 13C NMR calculation and NOE analysis. The absolute configurations of all the mentioned compounds were determined by the comparison of their experimental and calculated ECD curves.

Development and reliability and validity test of the Fear of Cancer Scale (FOCS).

OBJECTIVE: To develop a Fear of Cancer Scale (FOCS) for non-cancer populations. METHODS: FOCS was developed by classical measurement theory. A total of 15 college students were invited to conduct semi-structured interviews. Seven experts were invited for expert consultation. A total of 2012 Chinese college students who had completed the electronic questionnaire on WJX.cn platform was included. The reliability and validity of FOCS were verified. Multiple linear regression analysis was adopted to explore the influencing factors of cancer fear among college students and further verify the validity of FOCS. RESULTS: There were 17 items in the FOCS, including two subscales - direct fear (8 items), and indirect fear (9 items). FOCS had good validity and reliability. Multiple linear regression showed that GAD-7 score, CSDS score, negative coping score, positive coping score, guardian's highest education, gender, life satisfaction, nationality and major were the influencing factors of cancer fear (p < .05). CONCLUSIONS: The 17-item FOCS was a reliable and valid measure to examine the level of cancer fear in non-cancer populations.

Effect of indole-3-carbinol on ethanol-induced liver injury and acetaldehyde-stimulated hepatic stellate cells activation using precision-cut rat liver slices.

1. Indole-3-carbinol (I3C), a major indole compound found in high levels in cruciferous vegetables, shows a broad spectrum of biological activities. However, few studies have reported the effect of I3C on alcoholic liver injury. In the present study, we investigated the protective effect of I3C on acute ethanol-induced hepatotoxicity and acetaldehyde-stimulated hepatic stellate cells (HSC) activation using precision-cut liver slices (PCLS). 2. Rat PCLS were incubated with 50 mmol/L ethanol or 350 µmol/L acetaldehyde, and different concentrations (100-400 µmol/L) of I3C were added into the culture system of these two liver injury models, respectively. Hepatotoxicity was assessed by measuring enzyme leakage and malondialdehyde (MDA) content in tissue. Activities of alcoholic enzymes were also determined. α-Smooth muscle actin (α-SMA), transforming growth factor (TGF-ß(1) ) and hydroxyproline (HYP) were used as indices to evaluate the activation of HSC. In addition, matrix metalloproteinase-1 (MMP-1) and the tissue inhibitor of metalloproteinase (TIMP-1) were observed to estimate collagen degradation. 3. I3C significantly reduced the enzyme leakage in ethanol-treated slices. In I3C groups, cytochrome P450 (CYP) 2E1 activities were inhibited by 40.9-51.8%, whereas alcohol dehydrogenase (ADH) activity was enhanced 1.6-fold compared with the ethanol-treated group. I3C also showed an inhibitory effect against HSC activation and collagen production stimulated by acetaldehyde. After being incubated with I3C (400 µmol/L), the expression of MMP-1 was markedly enhanced, whereas TIMP-1 was decreased. 4. These results showed that I3C protected PCLS against alcoholic liver injury, which might be associated with the regulation of ethanol metabolic enzymes, attenuation of oxidative injury and acceleration of collagen degradation.

Psychological distress in the shadow of the COVID-19 pandemic: Preliminary development of an assessment scale.

COVID-19 is now spreading worldwide, and poses some public mental health problems which requires close attention. This study aims to develop a scale of COVID-19 related psychological distress in healthy public (CORPD) to assess the severity of psychological distress in uninfected healthy populations. We compiled a 14-item scale which contains two dimensions- Anxiety & fear and Suspicion -using the classical measurement theory. 652 Chinese citizens consented and completed a survey through an online questionnaire APP. The reliability test showed that the scale had good internal consistency reliability and Split-Half reliability, and the validity test showed that it had good structure validity, content validity and criterion correlation validity. This scale can be used to assess the psychological distress of people in China and in other COVID-19-hit regions and countries. It also provides a reference for future studies on COVID-19 or other respiratory infectious diseases related public mental health.

Next-generation sequencing yields the complete chloroplast genome of Pleione forrestii (Orchidaceae).

Pleione forrestii is an endangered terrestrial orchid with significant ornamental values. Here, we report the first complete chloroplast genome of P. forrestii. The circular genome was 158,759 bp in length and consisted of a pair of inverted repeats (IR 26,429 bp), which were separated by a large single-copy region (LSC 87,236 bp) and a small single copy-region (SSC 18,665 bp). It contained 135 genes (115 unique), including 87 protein-coding genes, 38 tRNAs, and 8 rRNAs. The maximum likelihood phylogenetic analysis indicated that P. forrestii was sister to P. bulbocodioides and P. formosana.