Development of Small-Molecule Anti-HIV-1 Agents Targeting HIV-1 Capsid Proteins.

The capsid of human immunodeficiency virus type 1 (HIV-1) forms a conical structure by assembling oligomers of capsid (CA) proteins and is a virion shell that encapsulates viral RNA. The inhibition of the CA function could be an appropriate target for suppression of HIV-1 replication because the CA proteins are highly conserved among many strains of HIV-1, and the drug targeting CA, lenacapavir, has been clinically developed by Gilead Sciences, Inc. Interface hydrophobic interactions between two CA molecules via the Trp184 and Met185 residues in the CA sequence are indispensable for conformational stabilization of the CA multimer. Our continuous studies found two types of small molecules with different scaffolds, MKN-1 and MKN-3, designed by in silico screening as a dipeptide mimic of Trp184 and Met185 have significant anti-HIV-1 activity. In the present study, MKN-1 derivatives have been designed and synthesized. Their structure-activity relationship studies found some compounds having potent anti-HIV activity. The present results should be useful in the design of novel CA-targeting molecules with anti-HIV activity.

The electrophysiological index can effectively predict subsequent coronary artery aneurysm in children with Kawasaki disease.

Objectives: The Gunma score is used to predict the severity of Kawasaki disease (KD), including coronary artery aneurysm (CAA) as a cardiac complication, in Japan. Additionally, the characteristic ratio of ventricular repolarization (T-peak to T-end interval to QT interval [Tp-e/QT]) on a surface electrocardiogram reflects myocardial inflammation. This study aimed to determine whether the Tp-e/QT can be used to predict CAA in children with KD. Methods: We analyzed chest surface electrocardiograms of 112 children with KD before receiving intravenous immunoglobulin therapy using available software (QTD; Fukuda Denshi, Tokyo, Japan). Results: The Tp-e/QT (lead V5) was positively correlated with the Gunma score (r=0.352, p<0.001). The Tp-e/QT was larger in patients with CAA (residual CAA at 1 month after onset) than in those without CAA (0.314±0.026 versus 0.253±0.044, p=0.003). A receiver operating characteristic curve analysis was performed to assess whether the Gunma score and Tp-e/QT could predict subsequent CAA. The area under the curve of the Gunma score was 0.719 with the cutoff set at 5 points. The area under the curve of the Tp-e/QT was 0.892 with a cutoff value of 0.299. The fit of the prediction models to the observed probability was tested by the Hosmer-Lemeshow test with calibration plots using Locally weighted scatterplot smoothing (LOESS) fit. The Gunma score (p=0.95) and Tp-e/QT (p=0.95) showed a good fit. Conclusions: The Tp-e/QT is a useful biomarker in predicting coronary aneurysm complications in KD.

Temporal and spatial dynamics of immune cells in spontaneous liver transplant tolerance.

The liver has long been deemed a tolerogenic organ. We employed high-dimensional mass cytometry and immunohistochemistry to depict the temporal and spatial dynamics of immune cells in the spleen and liver in a murine model of spontaneous liver allograft acceptance. We depicted the immune landscape of spontaneous liver tolerance throughout the rejection and acceptance stages after liver transplantation and highlighted several points of importance. Of note, the CD4+/CD8+ T cell ratio remained low, even in the tolerance phase. Furthermore, a PhenoGraph clustering analysis revealed that exhausted CD8+ T cells were the most dominant metacluster in graft-infiltrating lymphocytes (GILs), which highly expressed the costimulatory molecule CD86. The temporal and spatial dynamics of immune cells revealed by high-dimensional analyses enable a fine-grained analysis of GIL subsets, contribute to new insights for the discovery of immunological mechanisms of liver tolerance, and provide potential ways to achieve clinical operational tolerance after liver transplantation.

Dexmedetomidine versus fentanyl for sedation in extremely preterm infants.

BACKGROUND: Few studies have compared the efficacy and complications of dexmedetomidine (DEX) and fentanyl (FEN) in extremely preterm infants. METHODS: We conducted a single-institution, retrospective controlled before and after study of preterm infants before 28 weeks of gestation admitted between April 2010 and December 2018 to compare the complications and efficacy of DEX and FEN for preterm infants. Patients were administered FEN prior to 2015 and DEX after 2015 as the first-line sedative. A composite outcome of death during hospitalization and developmental quotient (DQ) < 70 at a corrected age of 3 years was compared as the primary outcome. Secondary outcomes including postmenstrual weeks at extubation, days of age when full enteral feeding was achieved and additional sedation by phenobarbital (PB) were compared. RESULTS: Sixty-six infants were enrolled into the study. The only perinatal factor that differed between the FEN (n = 33) and DEX (n = 33) groups was weeks of gestation. The composite outcome of death and DQ < 70 at a corrected age of 3 years were not significantly different. Postmenstrual weeks at extubation did not significantly differ between groups after adjustment for weeks of gestation and being small for gestational age. On the other hand, full feeding was significantly prolonged by DEX (p = 0.031). Additional sedation was less common in the DEX group (p = 0.044). CONCLUSION: The composite outcome of death and DQ < 70 at a corrected age of 3 years were not significantly different by DEX or FEN for primary sedation. Prospective randomized controlled trials should examine the long-term effects on development.

Coral calcium carried hydrogen ameliorates the severity of non-alcoholic steatohepatitis induced by a choline deficient high carbohydrate fat-free diet in elderly rats.

Hydrogen has been reported to act as an antioxidant, anti-apoptosis and anti-inflammatory agent. Coral calcium carried hydrogen (G2-SUISO) is a safer and more convenient form of hydrogen agent than others. The mechanism underlying the hepatoprotective effects of G2-SUISO using an elderly non-alcoholic steatohepatitis (NASH) rat model was investigated. Two days after fasting, six-month-old elderly male F344/NSlc rats were given a choline deficient high carbohydrate fat-free (CDHCFF) diet from day 0 to day 3 as CDHCFF control group, and then switched to a normal diet from days 4 to 7 with or without 300 mg/kg G2-SUISO. Rats in each group were finally being sacrificed on day 3 or day 7. In the CDHCFF diet group, G2-SUISO decreased the liver weight-to-body weight ratio, the serum AST, ALT, total cholesterol levels, inflammatory infiltration, pro-inflammatory cytokine expression and lipid droplets with inhibiting lipogenic pathways by reducing sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase and fatty acid synthase gene expression compared with the CDHCFF diet alone. G2-SUISO had beneficial effects of anti-apoptosis as well the down-regulation of pro-apoptotic molecules including NF-κB, caspase-3, caspase-9 and Bax. These findings suggest that G2-SUISO treatment exerts a significant hepatoprotective effect against steatosis, inflammation and apoptosis in elderly NASH rats.

Combined phospholipids adjuvant augments anti-tumor immune responses through activated tumor-associated dendritic cells.

Dendritic cells (DCs) can initiate both naïve and memory T cell activation, as the most potent antigen-presenting cells. For efficient anti-tumor immunity, it is essential to enhance the anti-tumoral activity of tumor-associated DCs (TADCs) or to potently restrain TADCs so that they remain immuno-stimulating cells. Combined phospholipids (cPLs) adjuvant may act through the activation of DCs. This study demonstrated the potential mechanism of tumor growth inhibition of cPLs adjuvant, and confirmed that cPLs adjuvant could induce the maturation and activation (upregulation of MHC-II, CD80, CD40, IL-1ß, IL-12, IL-6 expression) of BMDCs in vitro. Then we isolated tumor infiltrating lymphocytes (TILs) from solid tumor and analyzed the phenotype and cytokines of TILs. The examination of the TILs revealed that cPLs adjuvant upregulated the expression of co-stimulatory molecules (MHC-II, CD86), phosphatidylserine (PS) receptor (TIM-4) on TADCs and enhanced the cytotoxic effect (CD107a), as well as pro-inflammatory cytokine production (IFN-γ, TNF-α, IL-2) by the tumor-resident T cells. Taken together, cPLs adjuvant may be an immune-potentiating adjuvant for cancer immunotherapy. This reagent may lead to the development of new approaches in DC-targeted cancer immunotherapy.

Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins.

The HIV-1 capsid is a shell that encapsulates viral RNA, and forms a conical structure by assembling oligomers of capsid (CA) proteins. Since the CA proteins are highly conserved among many strains of HIV-1, the inhibition of the CA function could be an appropriate goal for suppression of HIV-1 replication, but to date, no drug targeting CA has been developed. Hydrophobic interactions between two CA molecules through Trp184 and Met185 in the protein are known to be indispensable for conformational stabilization of the CA multimer. In our previous study, a small molecule designed by in silico screening as a dipeptide mimic of Trp184 and Met185 in the interaction site was synthesized and found to have significant anti-HIV-1 activity. In the present study, molecules with different scaffolds based on a dipeptide mimic of Trp184 and Met185 have been designed and synthesized. Their significant anti-HIV activity and their advantages compared to the previous compounds were examined. The present results should be useful in the design of novel CA-targeting anti-HIV agents.

PD-L1 antibody enhanced ß-glucan antitumor effects via blockade of the immune checkpoints in a melanoma model.

In the tumor microenvironment (TME), one of the major functions of tumor-recruited CD11b+ cells are the suppression of the T-cell-mediated anti-tumor immune response. ß-glucan could convert the phenotype of tumor-recruited CD11b+ cells from the suppressive to the promotive, and enhanced their anti-tumor effects. However, ß-glucan could enhance the PD-1/PD-L1 expression on CD11b+ cells, while PD-1 could inhibit macrophage phagocytosis and PD-L1 could induce a co-inhibitory signal in T-cells and lead to T-cell apoptosis and anergy. These protumor effects may be reversed by PD-1/PD-L1 block therapy. In the present study, we focused on the efficacy of ß-glucan anti-tumor therapy combined with anti-PD-L1 mAb treatment, and the mechanism of their synergistic effects could be fully verified. We verified the effect of ß-glucan (i.e., inflammatory cytokine secretion of TNF-α, IL-12, IL-6, IL-1ß and the expression of immune checkpoint PD-1/PD-L1) in naïve mouse peritoneal exudate CD11b+ cells. In our mouse melanoma model, treatment with a PD-L1 blocking antibody with ß-glucan synergized tumor regression. After treatment with ß-glucan and anti-PD-L1 mAb antibody, tumor infiltrating leukocyte (TILs) not only showed a competent T-cell function (CD107a, perforin, IL-2, IFN-γ and Ki67) and CTL population, but also showed enhanced tumor-recruited CD11b+ cell activity (IL-12, IL-6, IL-1ß and PD-1). This effect was also verified in the peritoneal exudate CD11b+ cells of tumor-bearing mice. PD-1/PD-L1 blockade therapy enhanced the ß-glucan antitumor effects via the blockade of tumor-recruited CD11b+ cell immune checkpoints in the melanoma model.

Nephritis-Associated Plasmin Receptor (NAPlr): An Essential Inducer of C3-Dominant Glomerular Injury and a Potential Key Diagnostic Biomarker of Infection-Related Glomerulonephritis (IRGN).

Nephritis-associated plasmin receptor (NAPlr) was originally isolated from the cytoplasmic fraction of group A Streptococci, and was found to be the same molecule as streptococcal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and plasmin receptor (Plr) on the basis of nucleotide and amino acid sequence homology. Its main functions include GAPDH activity, plasmin-binding capacity, and direct activation of the complement alternative pathway (A-P). Plasmin trapped by deposited NAPlr triggers the degradation of extracellular matrix proteins, such as glomerular basement membranes and mesangial matrix, and the accumulation of macrophages and neutrophils, leading to the induction of plasmin-related endocapillary glomerular inflammation. Deposited NAPlr at glomerular endocapillary site directly activates the complement A-P, and the endocapillary release of complement-related anaphylatoxins, C3a and C5a, amplify the in situ endocapillary glomerular inflammation. Subsequently, circulating and in situ-formed immune complexes participate in the glomerular injury resulting in NAPlr-mediated glomerulonephritis. The disease framework of infection-related glomerulonephritis (IRGN) has been further expanded. GAPDH of various bacteria other than Streptococci have been found to react with anti-NAPlr antibodies and to possess plasmin-binding activities, allowing glomerular NAPlr and plasmin activity to be utilized as key biomarkers of IRGN.

Effect of Hypothermia on Myocardial Depolarization and Repolarization in Neonates with Hypoxic-Ischemic Encephalopathy Due to Asphyxia.

Therapeutic hypothermia (TH) is effective for neonatal hypoxic-ischemic encephalopathy (HIE). The combination of abnormal myocardial repolarization and fatal arrhythmia in patients with accidental hypothermia has prompted clinical validation of the proarrhythmic potential of TH. However, to our knowledge, there have been few clinical studies on myocardial depolarization and repolarization abnormalities caused by TH in neonates. Therefore, we investigated the effects of TH on neonatal myocardial depolarization and repolarization by capturing the waveform changes in electrocardiograms (ECGs) associated with body temperature (BT) before and after TH. We included three neonates with HIE diagnosed at birth who were treated with TH in our hospital. The heart rate, RR interval, P wave duration, PR interval, QRS duration, QT interval, corrected QT (QTc) interval by Fridericia's formula, J point-T end (JT) interval, corrected JT (JTc) interval by Fridericia's formula, T peak-T end (Tpe) interval, Tpe/QT, and QRS/QTc were calculated retrospectively using an ECG. The correlations of ECG parameters recorded concurrently with 33 samples in which BT measurements were confirmed were performed. BT and heart rate were positively correlated (R: 0.589, p = 0.0003). BT was negatively correlated with Tpe/QT (R: - 0.470, p = 0.0058), the QTc interval (R: - 0.680, p < 0.0001), and the corrected JT interval (R: - 0.697, p < 0.0001). TH does not affect atrial or ventricular depolarization but prolongs the ventricular repolarization process in a temperature-dependent manner.

The effects of oral administration of Aureobasidium pullulans-cultured fluid containing ß-glucan on concanavalin A injected mice.

A black yeast, Aureobasidium pullulans, extracellularly produces ß-(1,3), (1,6)-D-glucan (ß-glucan) under certain conditions. The ß-glucan is known to be an immunomodulatory agent, and ß-glucan enriched A. pullulans cultured fluid (AP-CF) is used in supplements to maintain human health. Concanavalin A (ConA) is a lectin, and when injected it is known to cause T cell mediated autoimmune hepatitis in mice. The present study investigated the effects of oral administration of AP-CF on ConA injection in mice. The results demonstrated that increases in serum alanine transaminase (ALT) levels after ConA injection were significantly suppressed in an AP-CF administered group of mice. To understand the mechanism of the ALT lowering effects of AP-CF, we used Foxp3 (forkhead box P3) knock-in mice which express the green fluorescent protein (GFP) in Foxp3 induced cells, and the effects of AP-CF on the regulatory T cell (Treg) populations were investigated. The results show that the basal level of Foxp3+ Treg populations in peripheral blood lymphocytes, liver infiltrating lymphocytes, and splenocytes was decreased after 7 days of administration of AP-CF. These findings suggest that oral administration of AP-CF suppresses the basal level of inflammation, and that it may be postulated to be involved in the ALT lowering effects of AP-CF.

Small-Molecule Anti-HIV-1 Agents Based on HIV-1 Capsid Proteins.

The capsid of human immunodeficiency virus type 1 (HIV-1) is a shell that encloses viral RNA and is highly conserved among many strains of the virus. It forms a conical structure by assembling oligomers of capsid (CA) proteins. CA dysfunction is expected to be an important target of suppression of HIV-1 replication, and it is important to understand a new mechanism that could lead to the CA dysfunction. A drug targeting CA however, has not been developed to date. Hydrophobic interactions between two CA molecules via Trp184/Met185 in CA were recently reported to be important for stabilization of the multimeric structure of CA. In the present study, a small molecule designed by in silico screening as a dipeptide mimic of Trp184 and Met185 in the interaction site, was synthesized and its significant anti-HIV-1 activity was confirmed. Structure activity relationship (SAR) studies of its derivatives were performed and provided results that are expected to be useful in the future design and development of novel anti-HIV agents targeting CA.

Corrigendum to "Hydrogen Gas Attenuates Hypoxic-Ischemic Brain Injury via Regulation of the MAPK/HO-1/PGC-1a Pathway in Neonatal Rats".

[This corrects the article DOI: 10.1155/2020/6978784.].

Hydrogen-rich water protects against liver injury in nonalcoholic steatohepatitis through HO-1 enhancement via IL-10 and Sirt 1 signaling.

Nonalcoholic steatohepatitis (NASH) could progress to hepatic fibrosis in the absence of effective control. The purpose of our experiment was to investigate the protective effect of drinking water with a high concentration of hydrogen, namely, hydrogen-rich water (HRW), on mice with nonalcoholic fatty liver disease to elucidate the mechanism underlying the therapeutic action of molecular hydrogen. The choline-supplemented, l-amino acid-defined (CSAA) or the choline-deficient, l-amino acid-defined (CDAA) diet for 20 wk was used to induce NASH and fibrosis in the mice model and simultaneously treated with the high-concentration 7-ppm HRW for different periods (4 wk, 8 wk, and 20 wk). Primary hepatocytes were stimulated by palmitate to mimic liver lipid metabolism during fatty liver formation. Primary hepatocytes were cultured in a closed vessel filled with 21% O2 + 5% CO2 + 3.8% H2 and N2 as the base gas to verify the response of primary hepatocytes in a high concentration of hydrogen gas in vitro. Mice in the CSAA + HRW group had lower serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and milder histological damage. The inflammatory cytokines were expressed at lower levels in the HRW group than in the CSAA group. Importantly, HRW reversed hepatocyte fatty acid oxidation and lipogenesis as well as hepatic inflammation and fibrosis in preexisting hepatic fibrosis specimens. Molecular hydrogen inhibits the lipopolysaccharide-induced production of inflammation cytokines through increasing heme oxygenase-1 (HO-1) expression. Furthermore, HRW improved hepatic steatosis in the CSAA + HRW group. Sirtuin 1 (Sirt1) induction by molecular hydrogen via the HO-1/adenosine monophosphate activated protein kinase (AMPK)/peroxisome proliferator-activated receptor α (PPARα)/peroxisome proliferator-activated receptor γ (PPAR-γ) pathway suppresses palmitate-mediated abnormal fat metabolism. Orally administered HRW suppressed steatosis induced by CSAA and attenuated fibrosis induced by CDAA, possibly by reducing oxidative stress and the inflammation response.NEW & NOTEWORTHY The mRNA expression of inflammatory cytokines in the HRW group was lower than in the CSAA group. HRW reversed hepatocyte apoptosis as well as hepatic inflammation and fibrosis in NASH specimens. Molecular hydrogen inhibits LPS-induced inflammation via an HO-1/interleukin 10 (IL-10)-independent pathway. HRW improved hepatic steatosis in the CSAA + HRW group. Sirt1 induction by molecular hydrogen via the HO-1/AMPK/PPARα/PPARγ pathway suppresses palmitate-mediated abnormal fat metabolism.

Potent leads based on CA-19L, an anti-HIV active HIV-1 capsid fragment.

Several anti-HIV-1 peptides have previously been found among overlapping fragment peptide libraries that contain an octa-arginyl moiety and cover the whole sequence of an HIV-1 capsid (CA) protein. Several derivatives based on a potent CA fragment peptide CA-19L have been synthesized. CA-19L overlaps with the Helix 9 region of the CA protein, which could be important for oligomerization of the CA proteins. Derivatives of CA-19L in which several amino acid residues were added to the N- and C-termini according to the natural CA sequence, were synthesized and their anti-HIV activity was evaluated. Some potent compounds were found, and these potential new anti-HIV agents are expected to be useful as new tools for elucidation of CA functions.

Bivalent HIV-1 fusion inhibitors based on peptidomimetics.

Membrane fusion is a valid target for inhibition of HIV-1 replication. A 34-mer fragment peptide (C34), which is contained in the HIV-1 envelope protein gp41, has significant anti-HIV activity. Previously, a dimeric derivative of C34 linked by a disulfide bridge at its C-terminus was found to have more potent anti-HIV activity than the C34 peptide monomer. To date, several peptidomimetic small inhibitors have been reported, but most have lower potency than peptide derivatives related to C34. In the present study we applied this dimerization concept to these peptidomimetic small inhibitors and designed several bivalent peptidomimetic HIV-1 fusion inhibitors. The importance of the length of linkers crosslinking two peptidomimetic compounds was demonstrated and several potent bivalent inhibitors containing tethered peptidomimetics were produced.

Protective Immune Responses Elicited by Deglycosylated Live-Attenuated Simian Immunodeficiency Virus Vaccine Are Associated with IL-15 Effector Functions.

Deglycosylated, live-attenuated SIV vaccines elicited protective immune responses against heterologous SIVsmE543-3, which differs from the vaccine strain SIVmac239 to levels similar to those across HIV-1 clades. Two thirds of the vaccinees contained the chronic SIVsmE543-3 infection (controllers), whereas one third did not (noncontrollers). In this study, we investigated immune correlates of heterologous challenge control in rhesus macaques of Burmese origin. Because depletion of CD8+ cells in the controllers by administration of anti-CD8α Ab abrogated the control of viral replication, CD8+ cells were required for the protective immune response. However, classical SIV-specific CD8+ T cells did not account for the protective immune response in all controllers. Instead, IL-15-responding CD8α+ cells, including CD8+ T and NK cells, were significantly higher in the controllers than those in the noncontrollers, before and after vaccination with deglycosylated SIV. It is well established that IL-15 signal transduction occurs through "trans-presentation" in which IL-15 complexed with IL-15Rα on monocytes, macrophages, and dendritic cells binds to IL-15 Rß/γ expressed on CD8+ T and NK cells. Accordingly, levels of IL-15 stimulation were strongly affected by the depletion of monocytes from PBMCs, implying key roles of innate immune cells. These results suggest that intrinsic IL-15 responsiveness may dictate the outcome of protective responses and may lead to optimized formulations of future broadly protective HIV vaccines.

Exploratory studies on CA-15L, an anti-HIV active HIV-1 capsid fragment.

Utilizing overlapping fragment peptide libraries covering the whole sequence of an HIV-1 capsid (CA) protein with the addition of an octa-arginyl moiety, we had previously found several peptides with anti-HIV-1 activity. Herein, among these potent CA fragment peptides, CA-15L was examined because this peptide sequence overlaps with Helix 7, a helix region of the CA protein, which may be important for oligomerization of the CA proteins. A CA-15L surrogate with hydrophilic residues, and its derivatives, in which amino acid sequences are shifted toward the C-terminus by one or more residues, were synthesized and their anti-HIV activity was evaluated. In addition, its derivatives with substitution for the Ser149 residue were synthesized and their anti-HIV activity was evaluated because Ser149 might be phosphorylated in the step of degradation of CA protein oligomers. Several active compounds were found and might become new anti-HIV agents and new tools for elucidation of CA functions.

Hydrogen Gas Attenuates Hypoxic-Ischemic Brain Injury via Regulation of the MAPK/HO-1/PGC-1a Pathway in Neonatal Rats.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of death in neonates with no effective treatments. Recent advancements in hydrogen (H2) gas offer a promising therapeutic approach for ischemia reperfusion injury; however, the impact of this approach for HIE remains a subject of debate. We assessed the therapeutic effects of H2 gas on HIE and the underlying molecular mechanisms in a rat model of neonatal hypoxic-ischemic brain injury (HIBI). H2 inhalation significantly attenuated neuronal injury and effectively improved early neurological outcomes in neonatal HIBI rats as well as learning and memory in adults. This protective effect was associated with initiation time and duration of sustained H2 inhalation. Furthermore, H2 inhalation reduced the expression of Bcl-2-associated X protein (BAX) and caspase-3 while promoting the expression of Bcl-2, nuclear factor erythroid-2-related factor 2, and heme oxygenase-1 (HO-1). H2 activated extracellular signal-regulated kinase and c-Jun N-terminal protein kinase and dephosphorylated p38 mitogen-activated protein kinase (MAPK) in oxygen-glucose deprivation/reperfusion (OGD/R) nerve growth factor-differentiated PC12 cells. Inhibitors of MAPKs blocked H2-induced HO-1 expression. HO-1 small interfering RNA decreased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and sirtuin 1 (SIRT1) and reversed the protectivity of H2 against OGD/R-induced cell death. These findings suggest that H2 augments cellular antioxidant defense capacity through activation of MAPK signaling pathways, leading to HO-1 expression and subsequent upregulation of PGC-1α and SIRT-1 expression. Thus, upregulation protects NGF-differentiated PC12 cells from OGD/R-induced oxidative cytotoxicity. In conclusion, H2 inhalation exerted protective effects on neonatal rats with HIBI. Early initiation and prolonged H2 inhalation had better protective effects on HIBI. These effects of H2 may be related to antioxidant, antiapoptotic, and anti-inflammatory responses. HO-1 plays an important role in H2-mediated protection through the MAPK/HO-1/PGC-1α pathway. Our results support further assessment of H2 as a potential therapeutic for neurological conditions in which oxidative stress and apoptosis are implicated.

Immunomodulatory effects of Salvianolic acid B in a spontaneous abortion mouse model.

Pregnancy is a kind of natural immune tolerance. Immune factors play an important role in recurrent spontaneous abortion and repeated implantation failure. Salvianolic acid B (SalB) has anti-tumor, anti-inflammatory, anti-oxidation and immunomodulatory functions. However, there are few reports on the relationship between SalB and maternal-fetal immune tolerance. In this study, CBA/J × DBA/2 J mice as a spontaneous abortion mouse model were given SalB. The results showed that the abortion rate was significantly decreased after SalB treatment. The populations of Nkp46 and cytotoxic CD8+ T cells in the placenta of female mice treated with SalB were significantly decreased. The qRT-PCR showed that SalB was able to significantly reduce the expression of pro-inflammatory factors and Toll-like Receptor in the placenta. In addition, SalB was able to increase the area of the labyrinth in the placenta. In conclusion, these findings suggest that SalB is beneficial for the immune-modulation at the maternal-fetal interface in a spontaneous abortion mouse model, resulting in a decrease in the abortion rate. This may encourage new ideas for the treatment of patients with repeated implantation failure.