Placental SARS-CoV-2 Infection and Its Implications for Increased Risk of Adverse Pregnancy Outcomes.

OBJECTIVE: Pregnant women are at increased risk of coronavirus disease 2019 (COVID-19). This could be explained through the prism of physiologic and immunologic changes in pregnancy. In addition, certain immunological reactions originate in the placenta in response to viral infections.This study aimed to investigate whether severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can infect the human placenta and discuss its implications in the pathogenesis of adverse pregnancy outcomes. STUDY DESIGN: We conducted a retrospective cohort study in which we collected placental specimens from pregnant women who had a laboratory-confirmed SARS-CoV-2 infection. We performed RNA in situ hybridization assay on formalin-fixed paraffin-embedded tissues to establish the in vivo evidence for placental infectivity by this corona virus. In addition, we infected trophoblast isolated from uninfected term human placenta with SARS-CoV-2 variants to further provide in vitro evidence for such an infectivity. RESULTS: There was a total of 21 cases enrolled, which included 5 cases of spontaneous preterm birth (SPTB) and 2 intrauterine fetal demises (IUFDs). Positive staining of positive-sense strand of SARS-CoV-2 virions was detected in 15 placentas including 4 SPTB and both IUFDs. In vitro infection assay demonstrated that SARS-CoV-2 virions were highly capable of infecting both cytotrophoblast and syncytiotrophoblast. CONCLUSION: This study implies that placental SARS-CoV-2 infection may be associated with an increased risk of adverse obstetrical outcomes. KEY POINTS: · SARS-CoV-2 can effectively infect human placenta.. · Such infectivity is confirmed by in vitro experiments.. · Placental SARS-CoV-2 corelates with adverse obstetrical outcomes..

Tubulin Complexity in Cancer and Metastasis.

Tubulin plays a fundamental role in cellular function and as the subject for microtubule-active agents in the treatment of ovarian cancer. Microtubule-binding proteins (e.g., tau, MAP1/2/4, EB1, CLIP, TOG, survivin, stathmin) and posttranslational modifications (e.g., tyrosination, deglutamylation, acetylation, glycation, phosphorylation, polyamination) further diversify tubulin functionality and may permit additional opportunities to understand microtubule behavior in disease and to develop microtubule-modifying approaches to combat ovarian cancer. Tubulin-based structures that project from suspended ovarian cancer cells known as microtentacles may contribute to metastatic potential of ovarian cancer cells and could represent an exciting novel therapeutic target.

Small Molecule Activators of Mitochondrial Fusion Prevent Congenital Heart Defects Induced by Maternal Diabetes.

Most congenital heart defect (CHD) cases are attributed to nongenetic factors; however, the mechanisms underlying nongenetic factor-induced CHDs are elusive. Maternal diabetes is one of the nongenetic factors, and this study aimed to determine whether impaired mitochondrial fusion contributes to maternal diabetes-induced CHDs and if mitochondrial fusion activators, teriflunomide and echinacoside, could reduce CHD incidence in diabetic pregnancy. We demonstrated maternal diabetes-activated FoxO3a increases miR-140 and miR-195, which in turn represses Mfn1 and Mfn2, leading to mitochondrial fusion defects and CHDs. Two mitochondrial fusion activators are effective in preventing CHDs in diabetic pregnancy.

MicroRNA-322 overexpression reduces neural tube defects in diabetic pregnancies.

BACKGROUND: Hyperglycemia from pregestational diabetes mellitus induces neural tube defects in the developing fetus. Folate supplementation is the only effective way to prevent neural tube defects; however, some cases of neural tube defects are resistant to folate. Excess folate has been linked to higher maternal cancer risk and infant allergy. Therefore, additional interventions are needed. Understanding the mechanisms underlying maternal diabetes mellitus-induced neural tube defects can identify potential targets for preventing such defects. Despite not yet being in clinical use, growing evidence suggests that microRNAs are important intermediates in embryonic development and can serve as both biomarkers and drug targets for disease intervention. Our previous studies showed that maternal diabetes mellitus in vivo activates the inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) in the developing embryo and that a high glucose condition in vitro reduces microRNA-322 (miR-322) levels. IRE1α is an RNA endonuclease; however, it is unknown whether IRE1α targets and degrades miR-322 specifically or whether miR-322 degradation leads to neural tube defects via apoptosis. We hypothesize that IRE1α can inhibit miR-322 in maternal diabetes mellitus-induced neural tube defects and that restoring miR-322 expression in developing neuroepithelium ameliorates neural tube defects. OBJECTIVE: This study aimed to identify potential targets for preventing maternal diabetes mellitus-induced neural tube defects and to investigate the roles and relationship of a microRNA and an RNA endonuclease in mouse embryos exposed to maternal diabetes mellitus. STUDY DESIGN: To determine whether miR-322 reduction is necessary for neural tube defect formation in pregnancies complicated by diabetes mellitus, male mice carrying a transgene expressing miR-322 were mated with nondiabetic or diabetic wide-type female mice to generate embryos with or without miR-322 overexpression. At embryonic day 8.5 when the neural tube is not yet closed, embryos were harvested for the assessment of 3 miR-322 transcripts (primary, precursor, and mature miR-322), tumor necrosis factor receptor-associated factor 3 (TRAF3), and neuroepithelium cell survival. Neural tube defect incidences were determined in embryonic day 10.5 embryos when the neural tube should be closed if there is no neural tube defect formation. To identify which miR-322 transcript is affected by maternal diabetes mellitus and high glucose conditions, 3 miR-322 transcripts were assessed in embryos from dams with or without diabetes mellitus and in C17.2 mouse neural stem cells treated with different concentrations of glucose and at different time points. To determine whether the endonuclease IRE1α targets miR-322, small interfering RNA knockdown of IRE1α or overexpression of inositol-requiring transmembrane kinase/endoribonuclease 1α by DNA plasmid transfection was used to determine the effect of IRE1α deficiency or overexpression on miR-322 expression. RNA immunoprecipitation was performed to reveal the direct targets of inositol-requiring transmembrane kinase/endoribonuclease 1α. RESULTS: Maternal diabetes mellitus suppressed miR-322 expression in the developing neuroepithelium. Restoring miR-322 expression in the neuroepithelium blocked maternal diabetes mellitus-induced caspase-3 and caspase-8 cleavage and cell apoptosis, leading to a neural tube defect reduction. Reversal of maternal diabetes mellitus-inhibited miR-322 via transgenic overexpression prevented TRAF3 up-regulation in embryos exposed to maternal diabetes mellitus. Activated IRE1α acted as an endonuclease and degraded precursor miR-322, resulting in mature miR-322 reduction. CONCLUSION: This study supports the crucial role of the IRE1α-microRNA-TRAF3 circuit in the induction of neuroepithelial cell apoptosis and neural tube defect formation in pregnancies complicated by diabetes mellitus and identifies IRE1α and miR-322 as potential targets for preventing maternal diabetes mellitus-induced neural tube defects.

Reproductive Profile of Neuronal Androgen Receptor Knockout Female Mice With a Low Dose of DHT.

Hyperandrogenism and polycystic ovarian syndrome result from the imbalance or increase of androgen levels in females. Androgen receptor (AR) mediates the effects of androgens, and this study examines whether neuronal AR plays a role in reproduction under normal and increased androgen conditions in female mice. The neuron-specific AR knockout (KO) mouse (SynARKO) was generated from a female mouse (synapsin promoter driven Cre) and a male mouse (Ar fl/y). Puberty onset and the levels of reproductive hormones such as LH, FSH, testosterone, and estradiol were comparable between the control and the SynARKO mice. There were no differences in cyclicity and fertility between the control and SynARKO mice, with similar impairment in both groups on DHT treatment. Neuronal AR KO, as in this SynARKO mouse model, did not alleviate the infertility associated with DHT treatment. These studies suggest that neuronal AR KO neither altered reproductive function under physiological androgen levels, nor restored fertility under hyperandrogenic conditions.

Neuronal AR Regulates Glucose Homeostasis and Energy Expenditure in Lean Female Mice With Androgen Excess.

Hyperandrogenemia and polycystic ovary syndrome are a result of the imbalance of androgen levels in females. Androgen receptor (Ar) mediates the effect of androgen, and this study examines how neuronal Ar in the central nervous system mediates metabolism under normal and increased androgen conditions in female mice. The neuron-specific ARKO mouse (SynARKO) was created from female (Ar fl/wt; synapsin promoter driven Cre) and male (Ar fl/y) mice. A glucose tolerance test revealed impaired glucose tolerance that was partially alleviated in the SynARKO-dihydrotestosterone (DHT) mice compared with Con-DHT mice after 4 months of DHT treatment. Heat production and food intake was higher in Con-DHT mice than in Con-veh mice; these effects were not altered between SynARKO-veh and SynARKO-DHT mice, indicating that excess androgens may partially alter calorie intake and energy expenditure in females via the neuronal Ar. The pAkt/Akt activity was higher in the hypothalamus in Con-DHT mice than in Con-veh mice, and this effect was attenuated in SynARKO-DHT mice. Western blot studies show that markers of inflammation and microglia activation, such as NF-kB p-65 and IBA1, increased in the hypothalamus of Con-DHT mice compared with Con-veh. These studies suggest that neuronal Ar mediates the metabolic impacts of androgen excess in females.

Cordyceps cicadae NTTU 868 Mycelia Fermented with Deep Ocean Water Minerals Prevents D-Galactose-Induced Memory Deficits by Inhibiting Oxidative Inflammatory Factors and Aging-Related Risk Factors.

Cordyceps cicadae, a medicinal fungus that is abundant in bioactive compounds such as N6-(2-hydroxyethyl)-adenosine (HEA) and polysaccharides, possesses remarkable anti-inflammatory, antioxidant, and nerve damage recovery properties. Deep ocean water (DOW) contains minerals that can be absorbed and transformed into organic forms by fungi fermentation. Recent studies have shown that culturing C. cicadae in DOW can enhance its therapeutic benefits by increasing the levels of bioactive compounds and minerals' bioavailibility. In this study, we investigated the effects of DOW-cultured C. cicadae (DCC) on brain damage and memory impairment induced by D-galactose in rats. Our results indicate that DCC and its metabolite HEA can improve memory ability and exhibit potent antioxidant activity and free radical scavenging in D-galactose-induced aging rats (p < 0.05). Additionally, DCC can mitigate the expression of inflammatory factors, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), thereby preventing brain aging. Furthermore, DCC showed a significant decrease in the expression of the aging-related proteins glial fibrillary acidic protein (GFAP) and presenilin 1 (PS1). By reducing brain oxidation and aging-related factors, DOW-cultured C. cicadae demonstrate enhanced anti-inflammatory, antioxidant, and neuroprotective effects, making it a promising therapeutic agent for preventing and treating age-related brain damage and cognitive impairment.

Single-atom Pt-CeO2/Co3O4 catalyst with ultra-low Pt loading and high performance for toluene removal.

The design and manufacture of high activity and thermal stability catalysts with minimal precious metal loading is essential for deep degradation of volatile organic compounds (VOCs). In this paper, a novel single-atom Pt-CeO2/Co3O4 catalyst with ultra-low Pt loading capacity (0.06 wt%, denoted as 0.06Pt-SA) was fabricated via one-step co-precipitation method. The 0.06Pt-SA exhibited excellent toluene degradation activity of T90 = 169 °C, matched with the nanoparticle Pt-supported CeO2/Co3O4 catalyst with more than six times higher Pt loading (0.41 wt%, denoted as 0.41Pt-NP). Moreover, the ultra-long durability (toluene conversion remains 99% after 120 h stability test) and excellent toluene degradation ability in a wide space speed range of 0.06Pt-SA were superior to that of 0.41Pt-NP catalyst. The excellent performance was derived from the strong metal-support interaction (SMSI) between the single atomic Pt and the carrier, which induced more Pt0 and Ce3+ for oxygen activation and more Co3+ for toluene removal. The in situdiffuse reflectance infrared spectroscopy (DRIFTS) experiments confirmed that the conversion of intermediates was accelerated in the reaction process, thereby promoting the toluene degradation. Our results should inspire the exploitation of noble single-atomic modification strategy for developing the low cost and high performance VOCs catalyst.

Anatomical features of plantar fasciitis in various age cohorts: Based on magnetic resonance imaging.

BACKGROUND: Due to the lack of further studies on the influence of age factors on plantar fasciitis, this study evaluates the characteristic observation points of magnetic resonance imaging in various age cohorts of patients with plantar fasciitis to help diagnosis. METHODS: A retrospective analysis of 160 cases of plantar fasciitis patients and normal subjects (who have the disease unrelated to plantar fasciitis) who have undergone an MRI examination in our institution. The two groups were separately divided into young adult subjects (36 to 44 years old), middle age adult subjects (45 to 59 years old), and older adult subjects (60 to 79 years old). Data was gathered regarding plantar fascia thickness, the coronal length of the plantar fascia at the calcaneal origin, the signal intensity of plantar fascia and surrounding structures, and the presence or absence of plantar calcaneal spurs, all of which were assessed objectively by the investigators. RESULTS: There were statistical differences in the thickness of plantar fascia between two groups of three age cohorts (Older adult patients: 0.59 ± 0.09 cm; Middle age adult patients: 0.49 ± 0.09 cm; Young adult patients: 0.47 ± 0.05 cm) (all p < 0.001). In addition, there were also statistical differences in the high signal intensity changes of the plantar fascia and surrounding soft tissues between two groups of three age cohorts (all p < 0.001). In older adult plantar fasciitis patients, with regard to plantar calcaneal spur discovery, there was a statistical difference between the two groups (Chi-square = 12.799. df = 1. p < 0.001). CONCLUSION: In plantar fasciitis cases where a diagnosis is difficult, abnormalities in the soft tissue surrounding the plantar fascia in patients of low age are noteworthy. In older adult patients, the discovery of plantar calcaneal spurs with abnormal thickening of plantar fascia deserves attention, and abnormal MRI findings are more manifest. But the final diagnosis should be based on the medical history. LEVEL OF EVIDENCE: Level 3.

In situ electrochemical construction of Co/CoP crystalline-amorphous hetero-phase catalysts for highly efficient electrocatalytic hydrogen evolution.

Herein we develop a facile, one-step electrochemical approach for the in situ construction of a Co/CoP crystalline-amorphous hetero-phase catalyst towards the hydrogen evolution reaction (HER). The unique catalyst demonstrates a low overpotential of 83 mV at 10 mA cm-2 with a small Tafel slope of 55.3 mV dec-1 in 1.0 M KOH. The Co/CoP crystalline-amorphous hetero-phase is highly conducive to regulating the Co-P electronic structure and weakening the H atom adsorption, thus markedly boosting the HER performance. This work offers an innovative strategy to develop a highly efficient transition metal phosphide electrocatalyst with a novel structure.

Manipulating the surface states of BiVO4 through electrochemical reduction for enhanced PEC water oxidation.

Bismuth vanadate (BiVO4) is a prospective candidate for photoelectrochemical (PEC) water oxidation, but its commercial application is limited due to the serious surface charge recombination. In this work, we propose a novel and effective electrochemical reduction strategy combined with co-catalyst modification to manipulate the surface states of the BiVO4 photoanode. Specifically, an ultrathin amorphous structure is formed on the surface of BiVO4 after electrochemical reduction ascribed to the breaking of the surface metal-O bonds. Photoelectrochemical measurements and first-principles calculation show that the electrochemical reduction treatment can effectively reduce the surface energy, thereby passivating the recombined surface states (r-ss) and increasing the mobility of photogenerated holes. In addition, the FeOOH co-catalyst layer further increases the intermediate surface states (i-ss) of BiVO4, stabilizes the surface structure and enhances its PEC performance. Benefiting from the superior charge transfer efficiency and the excellent water oxidation kinetics, the -0.8/BVO/Fe photoanode achieves 2.02 mA cm-2 photocurrent at 1.23 VRHE (2.4 times that of the original BiVO4); meanwhile, the onset potential shifts 90 mV to the cathode. These results provide a new surface engineering tactic to modify the surface states of semiconductor photoanodes for high-efficiency PEC water oxidation.

Exosomes mediated fibrogenesis in dilated cardiomyopathy through a MicroRNA pathway.

Cardiac fibrosis is a hallmark in late-stage familial dilated cardiomyopathy (DCM) patients, although the underlying mechanism remains elusive. Cardiac exosomes (Exos) have been reported relating to fibrosis in ischemic cardiomyopathy. Thus, we investigated whether Exos secreted from the familial DCM cardiomyocytes could promote fibrogenesis. Using human iPSCs differentiated cardiomyocytes we isolated Exos of angiotensin II stimulation conditioned media from either DCM or control (CTL) cardiomyocytes. Of interest, cultured cardiac fibroblasts had increased fibrogenesis following exposure to DCM-Exos rather than CTL-Exos. Meanwhile, injecting DCM-Exos into mouse hearts enhanced cardiac fibrosis and impaired cardiac function. Mechanistically, we identified the upregulation of miRNA-218-5p in the DCM-Exos as a critical contributor to fibrogenesis. MiRNA-218-5p activated TGF-ß signaling via suppression of TNFAIP3, a master inflammation inhibitor. In conclusion, our results illustrate a profibrotic effect of cardiomyocytes-derived Exos that highlights an additional pathogenesis pathway for cardiac fibrosis in DCM.

Obesity impacts placental function through activation of p-IRE1a-XBP1s signaling.

Maternal obesity is associated with a variety of obstetrical outcomes including stillbirth, preeclampsia, and gestational diabetes, and increases the risk of fetuses for congenital heart defects. Obesity during pregnancy represents a major contribution to metabolic dysregulation, which not only plays a key role in the pathogenesis of adverse outcome but also can potently induce endoplasmic reticulum (ER) stress. However, the mechanism associating such an obesogenic metabolic environment and adverse pregnancy outcomes has remained poorly understood. In this study, we aimed to determine whether the ER stress pathways (also named unfolded protein response (UPR)) were activated in the placenta by obesity. We collected placenta from the obese pregnancy (n = 12) and non-obese pregnancy (n = 12) following delivery by Caesarean-section at term. The specimens were assessed with immunocytochemistry staining and RT-QPCR. Our results revealed that in the obese placenta, p-IRE1α and XBP1s were significantly increased, CHOP and nine UPR chaperone genes were upregulated, including GRP95, PDIA6, Calnexin, p58IPK, SIL-1, EDEM, Herp, GRP58 and Calreticulin. However, Perk and BiP are not activated in the obese placenta. Our data suggest that upregulated p-IRE1α and XBP1s signaling, and UPR chaperone genes may play an important role in maternal obesity-induced placental pathology. In conclusion, this is the first report on ER stress and UPR activation in the placenta of maternal obesity. Our findings represent the first step in the understanding of one of the key ER signaling pathways, also referred to IRE1α-XBP1, in placental pathophysiology affected by obesity, which may be an important mechanism accounting for the observed higher maternal and perinatal risks.

SARS-CoV-2 infection induces activation of ferroptosis in human placenta.

Ferroptosis, a regulated non-apoptotic form of cell death, has been implicated in the response to varied types of infectious agents including virus. In this study, we sought to determine whether SARS-CoV-2 infection can induce activation of ferroptosis in the human placenta. We collected placentas from 23 pregnant females with laboratory-confirmed SARS-CoV-2 following delivery and then used RNA in situ hybridization assay for detection of viral positive-sense strand (PSS) to confirm that these placentas have been infected. We also used immunohistochemistry assay to assess expression levels of acyl-CoA synthetase long-chain family member 4 (ACSL4), an essential executioner of ferroptosis in the same specimens. Our results showed that ACSL4 expression was significantly increased in the group with positive positive-sense strand staining compared to their negative counterparts (p = 0.00022). Furthermore, we found that there was a positive trend for increased PSS staining along with increased ACSL4 expression. Our study supports that ferroptosis is activated in the response to SARS-CoV-2 infection in the human placenta, highlighting a molecular mechanism potentially linking this coronavirus infection and pathogenesis of adverse pregnancy outcomes.

Fe-Co controlled super-hygroscopic hydrogels toward efficient atmospheric water harvesting.

Extracting atmospheric moisture for freshwater production is an appealing way to mitigate the global water crisis. However, the low moisture sorption capacity and high desorption temperature are the major bottlenecks for efficient atmospheric water harvesting. Herein, we develop a transition metal super-hygroscopic hydrogel by an economical strategy, which is constructed through a facile coordination between metal salts and ethanolamine. When the empty electron orbital of the metal ion is coordinated with the lone electron pair of nitrogen or oxygen atom, the water active sorption site is formed. A single water layer is bonded on the sites by a coordination effect, followed by physical interaction with water to form multi-layer structures. The Fe and Co ions in the hydrogel function as dual sorption sites to capture moisture, which can harvest additional water by the synergistic effect of bimetals. As a result, the bimetal hydrogel contributes to a high water uptake of 5.22 g g-1 at 95% RH, triggering the desorption process by one solar intensity due to its low desorption temperature (≤50 °C).

Oxidative Stress Kinase Activation and Impaired Insulin Receptor Signaling Precede Overt Alzheimer's Disease Neuropathology.

BACKGROUND: The cascade of events that lead to Alzheimer's disease (AD) consists of several possible underlying signal transduction pathways. Apoptosis signal-regulating kinase 1 (ASK1) and insulin receptor (IR) signaling are implicated in AD. OBJECTIVE: We aimed to determine whether ASK1 activation and IR signaling impairment occurred prior to and during overt AD. METHODS: Immunostaining, immunoblotting, and quantitative PCR were used to assess the levels of ASK1 and IR signaling intermediates. Glucose uptake was determined in AD-patient derived inducible pluripotent stem cells (iPSCs). RESULTS: ASK1 signaling was activated in postmortem brain tissues acquired from APOE4 carriers, a causative heritable factor, and in brain tissues of AD subjects in comparison with those harboring the normal APOE3 variant, which was manifested with an increased phosphorylated ASK1 (p-ASK1) and reduced thioredoxin 1 (TRX1). ASK1 downstream signaling effectors were also significantly elevated in these APOE4 carriers and AD brain tissues. Increased insulin receptor substrate 1 (IRS1) phosphorylation at serine residues, and decreased p-AKT1, p-IRß, and GLUT3 expression were present in all APOE4 carriers and AD samples, suggesting impaired IR signaling leading to insulin resistance. ASK1 activation, IR signaling impairment, and GLUT3 reduction were also present in young AD transgenic mice prior to AD syndromes, AD mice at AD neuropathology onset, and AD iPSCs and their derived neurons prior to p-Tau aggregation. CONCLUSION: We conclude that the activation of oxidative stress-responsive kinases and reduced IR signaling precede and are persistent in AD pathogenesis. Our data further suggest possible crosstalk between ASK1 signaling and insulin resistance in AD etiology.

SARS-CoV-2 Nsp6 damages Drosophila heart and mouse cardiomyocytes through MGA/MAX complex-mediated increased glycolysis.

SARS-CoV-2 infection causes COVID-19, a severe acute respiratory disease associated with cardiovascular complications including long-term outcomes. The presence of virus in cardiac tissue of patients with COVID-19 suggests this is a direct, rather than secondary, effect of infection. Here, by expressing individual SARS-CoV-2 proteins in the Drosophila heart, we demonstrate interaction of virus Nsp6 with host proteins of the MGA/MAX complex (MGA, PCGF6 and TFDP1). Complementing transcriptomic data from the fly heart reveal that this interaction blocks the antagonistic MGA/MAX complex, which shifts the balance towards MYC/MAX and activates glycolysis-with similar findings in mouse cardiomyocytes. Further, the Nsp6-induced glycolysis disrupts cardiac mitochondrial function, known to increase reactive oxygen species (ROS) in heart failure; this could explain COVID-19-associated cardiac pathology. Inhibiting the glycolysis pathway by 2-deoxy-D-glucose (2DG) treatment attenuates the Nsp6-induced cardiac phenotype in flies and mice. These findings point to glycolysis as a potential pharmacological target for treating COVID-19-associated heart failure.

RNA Hypomethylation and Unchanged DNA Methylation Levels in the Cortex of ApoE4 Carriers and Alzheimer's Disease Subjects.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and ApoE4 variants are significant risk factors for AD. Epigenetic modifications are involved in AD pathology. However, it is unclear whether DNA/RNA methylation plays a role in AD pathology, and dysregulation of DNA/RNA methylation occurs in ApoE4 carriers. OBJECTIVE: The present study aimed to determine whether dysregulation of DNA/RNA methylation is present in the brains of ApoE4 carriers and AD patients. METHODS: In this study, postmortem brain tissues from carriers of ApoE4 and ApoE3, from AD and non- AD controls, were used in the analysis of DNA/RNA methylation, methyltransferases, and their demethylases. RESULTS: Immunofluorescence staining indicates that RNA methylation is suppressed in ApoE4 carriers. Further analysis shows that the expression of RNA methyltransferases and an RNA methylation reader is suppressed in ApoE4 carriers, whereas RNA demethylase expression is increased. RNA hypomethylation occurs in NeuN+ neurons in ApoE4 carriers and AD patients. Furthermore, in ApoE4 carriers, both DNA methyltransferases and demethylases are downregulated, and overall DNA methylation levels are unchanged. CONCLUSION: Our finding indicates that RNA methylation decreased in ApoE4 carriers before AD pathology and AD individuals. The expression of RNA methyltransferases and RNA methylation reader is inhibited, and RNA demethylase is upregulated in ApoE4 carriers, which leads to suppression of RNA methylation, and the suppression precedes the AD pathogenesis and persists through AD pathology.

8-Hydroxyquinoline-modified ruthenium(II) polypyridyl complexes for JMJD inhibition and photodynamic antitumor therapy.

As an ideal scaffold for metal ion chelation, 8-hydroxyquinoline (8HQ) can chelate different metal ions, such as Fe2+, Cu2+, Zn2+, etc. Here, by integrating 8HQ with a ruthenium(II) polypyridyl moiety, two Ru(II)-8HQ complexes (Ru1 and Ru2), [Ru(N-N)2L](PF6)2 (L = 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)quinolin-8-ol; N-N: 2,2'-bipyridine (bpy, in Ru1), 1,10-phenanthroline (phen, in Ru2)) were designed and synthesized. In both complexes, ligand L is an 8HQ derivative designed to chelate the cofactor Fe2+ of jumonji C domain-containing demethylase (JMJD). As expected, Ru1 and Ru2 could inhibit the activity of JMJD by chelating the key cofactor Fe2+ of JMJD, resulting in the upregulation of histone-methylation levels in human lung cancer (A549) cells, and the upregulation was more pronounced under light conditions. In addition, MTT data showed that Ru1 and Ru2 exhibited lower dark toxicity, and light irradiation could significantly enhance their antitumor activity. The marked photodynamic activities of Ru1 and Ru2 could induce the elevation of reactive oxygen species (ROS), depolarization of mitochondrial membrane potential (MMP), and activation of caspases. These mechanistic studies indicated that Ru1 and Ru2 could induce apoptosis through the combination of JMJD inhibitory and PDT activities, thereby achieving dual antitumor effects.

Comparative efficacy and mechanism of action of cardiac progenitor cells after cardiac injury.

Successful cell therapy requires cells to resist the hostile ischemic myocardium, be retained to continue secreting cardioprotective growth factors/exosomes, and resist immunological host responses. Clinically relevant stem/progenitor cells in a rodent model of acute myocardial infarction (MI) demonstrated that neonatal cardiac mesenchymal stromal cells (nMSCs) provide the most robust cardiac functional recovery. Transplanted nMSCs significantly increased the number of tissue reparative macrophages and regulatory T-cells and decreased monocyte-derived inflammatory macrophages and neutrophils in the host myocardium. mRNA microarray and single-cell analyses combined with targeted depletion studies established CD47 in nMSCs as a key molecule responsible for cell retention in the myocardium through an antiphagocytic mechanism regulated by miR34a-5p. Gain and loss-of-function studies demonstrated that miR34a-5p also regulated the production of exosomes and cardioprotective paracrine factors in the nMSC secretome. In conclusion, miR34a-5p and CD47 play an important role in determining the composition of nMSCs' secretome and immune evasion, respectively.