In Vitro Anti-viral Activities and Structureactivity Relationship Studies of Flavones and Dihydroflavone Derivatives as Influenza Virus Potential Neuraminidase Inhibitors

From the bioassay tests, 14 neuraminidase inhibitors （NIs） flavones and dihydroflavones derivatives from natural plants displayed different degree of inhibitory activities. Further- more, compounds No. 8 and 14 showed good inhibitory activity against influenza A virus with IC50 = 835.4 and 860.6 μg/mL. Then, to investigate interactions between NIs and neuraminidase （NA）, molecular docking was performed. Docking results indicated that Arg118, Asp151, Arg292 and Arg371 were the key residues in the active pocket of 2ht8. Main influencing factors of interactions between NIs and NA were hydrogen bond and electrostatic, then hydrophobic factor. Moreover, experimental activities of NIs were consistent with total scores of the docking. In order to understand the chemical-biological interactions governing their activities toward NA, QSAR models of 14 NIs were developed. The obtained HQSAR （hologram quantitative structure activity relationship）, PLS （partial least squares） and SRA （stepwise regression analysis） models were robust and had good exterior predictive capabilities. Moreover, squared multiple correlation coefficients （R2） and squared cross-validated correlation coefficients （Q2） of HQSAR and PLS models based on descriptors by Gaussian and Sarchitect were 0.832 and 0.721, 0.925 and 0.688, 0.892 and 0.692, respectively. R2 and SE （standard error） of SRA model based on descriptors by Gaussian were 0.922 and 0.072. Therefore, these models may be further used to design and evaluate the bioactivity of new compounds.

Mutation-induced spatial differences in neuraminidase structure and sensitivity to neuraminidase inhibitors

Neuraminidase （NA）, a major surface glycoprotein of influenza virus with well-defined active sites, is an ideal plat- form for the development of antiviral drugs. However, a growing number of NA mutations have drug resistance to today＇s inhibitors. Numerous efforts are made to explore the resistance mechanisms through understanding the structural changes in mutated NA proteins and the associated different binding profiles of inhibitors, via x-ray, nuclear magnetic resonance, electron microscopy, and molecular dynamics methods. This review presents the architectural features of mutated NA proteins, as well as the respective inhibitor sensitivities arising from these spatial differences. Finally, we summarize the resistance mechanisms of today＇s neuraminidase inhibitors and the outlook tbr the development of novel inhibitors.

Molecular docking investigation for Indonesian H274Y mutant neuraminidase type 1 with neuraminidase inhibitors

The aim of this study is to get insight the interaction between Indonesian H274Y mutant neuraminidase with four inhibitors. Not only to seek preferable inhibitor to be used, but also to investigate the interaction occurred, especially hydrogen bonds formed. Hydrogen bonds analysis and its interaction energies calculation showed that zanamivir is the most preferable inhibitor with 13 hydrogen bonds formed and –439.96 kcal/mol. Laninamivir would be an alternative inhibitor since it has 10 hydrogen bonds and –307.19 kcal/mol. The investigation of ΔSAS showed almost all active site residues buried when interacted with inhibitors. Only a few residues have an increases ΔSAS. Lipinski rule analysis showed that zanamivir and laninamivir would be best taken by injection or inhalation.

QSAR Studies on Influenza Neuraminidase Inhibitors——Acylthiourea Analogue

The quantitative structure-activity relationship （QSAR） of 30 acylthiourea analogues was studied by using a three-dimensional holographic vector of atomic interaction field （3D-HoVAIF） to describe their chemical structures. The descriptors obtained were screened by stepwise multiple regression （SMR） and a partial least-squares （PLS） regression model was built. The correlation coefficient r^2 of the established model and Leave-One-Out （LOO） Cross-Validation （CV） correlation coefficient q^2 are 0.624 and 0.409, respectively. The model has favorable stability and good prediction capability, and further QSAR analysis showed that hydrophobic interaction has the most important effect on the activity of acylthiourea analogue and 3D-HoVAIF was applicable to the molecular structural characterization and biologicalactivity prediction.

New Neuraminidase Inhibitory Alkaloids from the Mangrove Soil-Derived Fungus Arthrinium sp.SCSIO 41305

New alkaloid,(E)-2-(hydroxyimino)-4-methylpentanamide(1)and a new cyclopentano[b]pyridine,4-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-one(2),together with ten known compounds(3–12)were isolated from the mangrove soil-derived fungus Arthrinium sp.SCSIO 41305.Extensive spectroscopic analysis and X-Ray crystallographic analysis were used to elucidate the structure of(E)-2-(hydroxyimino)-4-methylpentanamide(1),including its absolute configuration.All the isolated compounds(1–12)were evaluated for their antimicrobial and enzyme inhibitory activities against acetylcholinesterase(ACh E),neuraminidase(NAs),and phosphatidylinositol 3-kinase(PI3K).Among them,compounds 1 and 3 exhibited strong neuraminidase inhibitory activity with IC_(50)values of 12.04,1.92μmol L^(-1)(IC_(50)20μmol L^(-1)for oseltamivir acid),while compounds 5,6,8,and 10showed moderate neuraminidase inhibitory activity,and compounds 6–10 displayed weak enzyme inhibitory activities against PI3K.

Evidence of Synergistic Activity of Medicinal Plant Extracts against Neuraminidase Inhibitor Resistant Strains of Influenza Viruses

The frequent emergence of drug resistant influenza viral strains emphasizes the urgent and continual need to develop new antiviral drugs. Given the encouraging findings of previous studies on antiviral compounds from plant sources, this study focused on medicinal plants from Borneo that were traditionally used to treat symptoms of influenza infection. Following the promising results of earlier investigations, four plant extracts that demonstrated multiple modes of viral inhibition were studied against wild-type and neuraminidase (NA) inhibitor-resistant strains of Types A and B influenza viruses. The extracts exhibited more pronounced activities against the wild-type viruses than the NA inhibitor-resistant strains. Variations in the antiviral potential of the extracts collected from different parts of the same plant were also evidenced in the in vitro micro-inhibition assays. Even though all plant extracts affected NA activity of all viruses, only two extracts demonstrated hemagglutination inhibitory (HI) activities against Type A pandemic H1N1 and Type B viruses. Furthermore, Receptor Destroying Enzyme (RDE) treatments of extracts exhibiting HI activities indicated the presence of sialic acid (SA)-like component(s) that may be responsible for HI activity. Since the antiviral potential of extracts was not completely suppressed by RDE, the possibility of non SA-like antiviral components cannot be ruled out. Therefore, synergistic activity between SA-like and non SA-like components contained in the plant extracts may be responsible for the demonstrated antiviral potential. The results also indicated the presence of non SA-like components that may act against other viral proteins apart from hemagglutinin (HA) and NA. Hence, this study supports the presence of multiple antiviral components that act against different viral proteins or interfere with different stages of viral replication. Our results suggest that these plant extracts have the potential to be developed as therapeutic agents for the treatment of influenza and could be a solution to the global occurrence of viral strains resistant to NA inhibitors.

Assessing the corrosion protection property of coatings loaded with corrosion inhibitors using the real-time atmospheric corrosion monitoring technique

The atmospheric corrosion monitoring(ACM)technique has been widely employed to track the real-time corrosion behavior of metal materials.However,limited studies have applied ACM to the corrosion protection properties of organic coatings.This study compared a bare epoxy coating with one containing zinc phosphate corrosion inhibitors,both applied on ACM sensors,to observe their corrosion protection properties over time.Coatings with artificial damage via scratches were exposed to immersion and alternating dry and wet environments,which allowed for monitoring galvanic corrosion currents in real-time.Throughout the corrosion tests,the ACM currents of the zinc phosphate/epoxy coating were considerably lower than those of the blank epoxy coating.The trend in ACM current variations closely matched the results obtained from regular electrochemical tests and surface analysis.This alignment highlights the potential of the ACM technique in evaluating the corrosion protection capabilities of organic coatings.Compared with the blank epoxy coating,the zinc phosphate/epoxy coating showed much-decreased ACM current values that confirmed the effective inhibition of zinc phosphate against steel corrosion beneath the damaged coating.

Programmed cell death 1 inhibitor sintilimab plus S-1 and gemcitabine for liver metastatic pancreatic ductal adenocarcinoma

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive cancer with poor prognosis.When it metastasizes to the liver,treatment options become particularly limited and challenging.Current treatment options for liver metastatic PDAC are limited,and chemotherapy alone often proves insufficient.Immunotherapy,particularly programmed cell death 1(PD-1)inhibitors like sintilimab,shows potential efficacy for various cancers but has limited reports on PDAC.This study compares the efficacy and safety of sintilimab plus S-1 and gemcitabine vs S-1 and gemcitabine alone in liver metastatic PDAC.AIM To explore the feasibility and effectiveness of combined PD-1 inhibitor sintilimab and S-1 and gemcitabine(combination group)vs S-1 and gemcitabine used alone(chemotherapy group)for treating liver metastatic pancreatic adenocarcinoma.METHODS Eligible patients were those with only liver metastatic PDAC,an Eastern Cooperative Oncology Group performance status of 0-1,adequate organ and marrow functions,and no prior anticancer therapy.Participants in the combination group received intravenous sintilimab 200 mg every 3 weeks,oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle,and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles or until disease progression,death,or unacceptable toxicity.Participants in the chemotherapy group received oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles.Between June 2020 and December 2021,66 participants were enrolled,with 32 receiving the combination treatment and 34 receiving chemotherapy alone.RESULTS The group receiving the combined therapy exhibited a markedly prolonged median overall survival(18.8 months compared to 10.3 months,P<0.05)and progression-free survival(9.6 months vs 5.4 months,P<0.05).compared to the chemotherapy group.The incidence of severe adverse events did not differ significantly between the two groups(P>0.05).CONCLUSION The combination of PD-1 inhibitor sintilimab with S-1 and gemcitabine demonstrated effectiveness and safety for treating liver metastatic PDAC,meriting further investigation.

Proton pump inhibitors and all-cause mortality risk among cancer patients

BACKGROUND Proton pump inhibitors(PPIs)are widely used,including among cancer patients,to manage gastroesophageal reflux and other gastric acid-related disorders.Recent evidence suggests associations between long-term PPI use and higher risks for various adverse health outcomes,including greater mortality.AIM To investigate the association between PPI use and all-cause mortality among cancer patients by a comprehensive analysis after adjustment for various confounders and a robust methodological approach to minimize bias.METHODS This retrospective cohort study used data from the TriNetX research network,with electronic health records from multiple healthcare organizations.The study employed a new-user,active comparator design,which compared newly treated PPI users with non-users and newly treated histamine2 receptor antagonists(H2RA)users among adult cancer patients.Newly prescribed PPIs(esomeprazole,lansoprazole,omeprazole,pantoprazole,or rabeprazole)users were compared to non-users or newly prescribed H2RAs(cimetidine,famotidine,nizatidine,or ranitidine)users.The primary outcome was all-cause mortality.Each patient in the main group was matched to a patient in the control group using 1:1 propensity score matching to reduce confounding effects.Multivariable Cox regression models were used to estimate hazard ratios(HRs)and 95% confidence interval(CI).RESULTS During the follow-up period(median 5.4±1.8 years for PPI users and 6.5±1.0 years for non-users),PPI users demonstrated a higher all-cause mortality rate than non-users after 1 year,2 years,and at the end of follow up(HRs:2.34-2.72).Compared with H2RA users,PPI users demonstrated a higher rate of all-cause mortality HR:1.51(95%CI:1.41-1.69).Similar results were observed across sensitivity analyses by excluding deaths from the first 9 months and 1-year post-exposure,confirming the robustness of these findings.In a sensitivity analysis,we analyzed all-cause mortality outcomes between former PPI users and individuals who have never used PPIs,providing insights into the long-term effects of past PPI use.In addition,at 1-year follow-up,the analysis revealed a significant difference in mortality rates between former PPI users and non-users(HR:1.84;95%CI:1.82-1.96).CONCLUSION PPI use among cancer patients was associated with a higher risk of all-cause mortality compared to non-users or H2RA users.These findings emphasize the need for cautious use of PPIs in cancer patients and suggest that alternative treatments should be considered when clinically feasible.However,further studies are needed to corroborate our findings,given the significant adverse outcomes in cancer patients.

Production and application of recombinant haemagglutinin neuraminidase of Newcastle disease virus

Objective:To discuss the possibility of expressing the haemagglutinin-neuraminidase（HN） protein in prokaryotic system such as Escherichia coli（E.coli） cells by cloning the full length HN gene.Methods:The full length HN gene of Newcastle Disease Virus（NDV） of size 1 734 bp was preciously isolated by RT-PCR.The sequence was assessed and submitted to Nucleic Acid Databank（NCBI） and the gene ID was EU215390.1 after cloning and sequencing.Now the assessed HN gene was subcloned into pET 32 a+ expression vector for production the HN protein in E.coli, BL21（DE3） PLYSS cells following standard protocols.The crude lysate protein from the induced positive clone was size assessed by sodium dodecyl sulfale-polyacrylamide gel electrophoresis （SDS-PAGE） and their haemagglutination（HA） property against chicken RBC was assessed by standard micro HA test.Results:The molecular size of the full HN gene of NDV as assessed by cloning and digesting the positive clone to release the insert was 1.7 kb.The expressed protein in both crude and pure form was assessed to be 63 kDa and 81 kDa,respectively.The HA activity of the crude protein of the positive clone was 1 in 40.Conclusions:This finding indicates that the fusion protein retains the biological activity of native protein in the crude form and therefore could be used as a diagnostic reagent for antibody detection and for routine assessment of immune status in commercial layer forms.

Analysis of correlated mutations, stalk motifs, and phylogenetic relationship of the 2009 influenza A virus neuraminidase sequences

The 2009 H1N1 influenza pandemic has attracted worldwide attention. The new virus first emerged in Mexico in April, 2009 was identified as a unique combination of a triple- reassortant swine influenza A virus, composed of genetic information from pigs, hu- mans, birds, and a Eurasian swine influenza virus. Several recent studies on the 2009 H1N1 virus util-ized small datasets to conduct analysis. With new sequences available up to date, we were able to extend the previous research in three areas. The first was finding two networks of co-mutations that may po-tentially affect the current flu-drug binding sites on neuraminidase (NA), one of the two surface proteins of flu virus. The second was discovering a special stalk motif, which was dominant in the H5N1 strains in the past, in the 2009 H1N1 strains for the first time. Due to the high virulence of this motif, the second finding is significant in our current research on 2009 H1N1. The third was updating the phylogenetic an- alysis of current NA sequences of 2009 H1N1 and H5N1, which demonstrated that, in clear contrast to previous findings, the N1 sequences in 2009 are di-verse enough to cover different major branches of the phylogenetic tree of those in previous years. As the novel influenza A H1N1 virus continues to spread globally, our results highlighted the importance of performing timely analysis on the 2009 H1N1 virus.

Compound heterozygous mutations in the neuraminidase 1 gene in type 1 sialidosis: A case report and review of literature

BACKGROUND Type 1 sialidosis,also known as cherry-red spot-myoclonus syndrome,is a rare autosomal recessive lysosomal storage disorder presenting in the second decade of life.The most common symptoms are myoclonus,ataxia and seizure.It is rarely encountered in the Chinese mainland.CASE SUMMARY A 22-year-old male presented with complaints of progressive myoclonus,ataxia and slurred speech,without visual symptoms;the presenting symptoms began at the age of 15-year-old.Whole exome sequencing revealed two pathogenic heterozygous missense variants[c.239C>T(p.P80L)and c.544A>G(p.S182G)in the neuraminidase 1(NEU1)gene],both of which have been identified previously in Asian patients with type 1 sialidosis.All three patients identified in China's Mainland come from three unrelated families,but all three show the NEU1 mutations p.S182G and p.P80L pathogenic variants.Increasing sialidase activity through chaperones is a promising therapeutic target in sialidosis.CONCLUSION Through retrospective analysis and summarizing the clinical and genetic characteristics of type 1 sialidosis,we hope to raise awareness of lysosomal storage disorders among clinicians and minimize the delay in diagnosis.

Pathogenicity and amino acid sequences of hemagglutinin cleavage site and neuraminidase stalk of differently passaged H9N2-avian influenza virus in broilers

Low pathogenic Avian Influenza (AI) virus has the ability to evolve to high pathogenic viruses resulting in significant economic losses in the poultry sector. This study aims at assessing the impact of H9N2 viral passaging in broilers and its relatedness to pathogenicity and amino acid (a.a) sequences of the hemagglutinin (HA) cleavage site and neuraminidase (NA) stalk. The original H9N2 AI virus (P0) was used to challenge ten-21 days old broilers. Individual recovery of H9N2 virus from homogenates of trachea, lungs and airsacs was attempted in 9 days old chicken embryos, as a conclusion of the first passage (P1). Tracheal isolates of H9N2 were passaged for a second (P2) and a third (P3) time in broilers, followed by a similar embryonic recovery procedure. The a.a. sequence of a part of HA1 cleavage site and Neuraminidase stalk were compared among the differently passaged viruses;an assessement of the relatedness of the determined a.a. sequences to the pathogenicity in broilers, based on frequency of mortality, morbidity signs, gross and microscopic lesions at 3 days post challenge with the P1, P2, and P3-H9N2, is concluded. An increase in certain morbidity signs and specific lesions was observed in P2- and P3-H9N2 challenged broilers compared to birds challenged with P1-H9N2. A conserved R-S-S-R amino acid sequence at the HA1 cleavage site was observed in the differently passaged H9N2, associated with a variability in the NA stalk-a.a sequences. The passaging of the low pathogenic H9N2 virus in broilers leads to a trend of increase in pathogenicity, manifested in higher frequency of morbidity signs, and of specific gross and microscopic lesions of the examined organs. This passaging was associated with a conserved a.a. sequence of the hemaglutinin cleavage site and a variability in the sequence of the neuraminidase stalk. A detailed study of the potential of the detected variability in the neuraminidase stalk of H9N2 in induction of a higher pathogenicity in broilers will be the subject of future investigations.

Indonesian avian influenza H274Y mutant neuraminidase homology models assessment

Five models of Indonesian H274Y mutant neuralminidase type 1 (N1) were generated from the template 3CKZ by homology modeling. The template has the best similarity percentage 97% with the model sequence. The models was evaluated to search the best model with DOPE, 3D-profiles and PROCHECK in a good rank. The results show model 3 as a potential model to be used in the simulation with the lowest DOPE score, highest verify-3D score and from Ramachandran plots we inferred that it also shared the 1st rank with model 4 based on the 99.4% of the residues found, without Glycine and Proline, at the most favoured and additionally allowed region of both model structures.

Activity of T Cells Stimulated by Hemagglutinin-neuraminidase of Newcastle Disease Virus in vivo

To investigate the stimulated activity of T cells and the anti-tumor properties of hemagglutinin-neuraminidase（HN） of Newcastle disease virus（NDV） strain Changchun（NDVcc）, the expression of HN gene in hepatoma cells（human HepG-2 and mouse H22 cells） infected with the recombinant adenovirus（Ad-HN） was identified by Western blot analysis and flow cytometry. Sialidase activity of NDVcc HN expressed by Ad-HN was assayed by the periodate-resorcinol method. The in vivo anti-tumor effects of NDVcc HN were evaluated in the H22 solid tumor model. Regional lymph nodes of the mouse model treated with Ad-HN were removed to harvest T lymphocytes and evaluating the specific cytotoxicity of cytotoxic T lymphocyte（CTL） and natural killer（NK） cells by an L-lactate dehydrogenase（LDH） assay, in the mean time, the secretion of cytokines was analyzed by enzyme linked immunosorbent assays（ELISA）. The results show that NDVcc HN was effectively expressed by Ad-HN in HepG-2 and H22 cells. The sialidase activity assay showed that Ad-HN significantly reduced sialic acid level of the hepatoma cells compared with the cells infected the empty adenovirus vector（Ad-mock）. When treated with Ad-HN, the growth of subcutaneous H22 primary tumors in C57BL/6 mice was suppressed, and the mean mice survival increased. In addition, the treatment of Ad-HN elicited strong NK and CTL responses, and high levels of Th1 cytokines, such as IL-2 and IFN-γ. In conclusion, NDVcc HN effectively elicits T cell-mediate anti-tumor cytotoxicity via sialidase activity and may be a novel strategy for cancer immunotherapy.

Sheng Jiang San, traditional multi-herb formulation, exerts anti-influenza effects in vitro and in vivo via neuraminidaseinhibition and immune regulation

OBJECTIVE Sheng Jiang San(SJS),a multi-herb formulation,is used in treating high fever,thirsty and anxiety in ancient China and it is sometimes used to treat seasonal influenza in modern.However,there is no evidencebased investigation and mechanism research to support SJS′s anti-influenza efficacy.This study aims to investigate the anti-influenza effect of SJS and its possible mechanisms.METHODS In this study,we examined the inhibitory effect of SJS against different influenza viruses on Madin-Darby canine kidney cells.Influenza virus infected BALB/c mice were employed as in vivo model to evaluate the efficacy.Mice challenged with A/PR/8/34(H1N1)were orally administrated SJS 1 g·kg^-1 daily for seven days and monitored for 14 d.The survival rate,body mass changes,lung index,lung viral load,histopathologic changes and immune-regulation of the mice were measured.The underlying anti-influenza virus mechanisms were studied by a series of biological assays in vitro to determine if hemagglutinin,ribonucleoprotein complex or nerauminidase were targets of SJS.RESULTS SJS exerted a broad spectrum of inhibitory effects on multiple influenza strains in a dose-dependent manner.And IC50 of SJS against A/WSN/33(H1N1)was lower than 35 mg·L^-1.SJS also protected 50%of mice from influenza virus PR8 infection.The lung index and the lung viral load of SJS treated mice were signifi⁃cantly decrease compared with untreated mice.SJS 2 g·L^-1 inhibited 80%of neuraminidase enzymatic activity.SJS also up-regulated TNF-αand IFN-αand down-regulated IL-2 of influenza virus induced mice.CONCLUSION SJS is a useful formulation for treating influenza virus infection.

Risk of hepatitis B virus reactivation in oncological patients treated with tyrosine kinase inhibitors:A case report and literature analysis

Hepatitis B virus(HBV)reactivation(HBVr)represents a severe and potentially life-threatening condition,and preventive measures are available through blood test screening or prophylactic therapy administration.The assessment of HBVr traditionally considers factors such as HBV profile,including hepatitis B surface antigen(HBsAg)and antibody to hepatitis B core antigen,along with type of medication(chemotherapy;immunomodulants).Nevertheless,consideration of possible patient’s underlying tumor and the specific malignancy type(solid or hematologic)plays a crucial role and needs to be assessed for decision-making process.

Substrate specificity of avian influenza H5N1 neuraminidase

AIM: To characterise neuraminidase(NA) substrate specificity of avian influenza H5N1 strains from humans and birds comparing to seasonal influenza virus.METHODS: Avian influenza H5N1 strains from humans and birds were recruited for characterising their NA substrate specificity by using a modified commercial fluorescence Amplex Red assay. This method can identify the preference of α2,6-linked sialic acid or α2,3-linked sialic acid. Moreover, to avoid the bias of input virus, reverse genetic virus using NA gene from human isolated H5N1 were generated and used to compare with the seasonal influenza virus. Lastly, the substrate specificity profile was further confirmed by high-performance liquid chromatography(HPLC) analysis of the enzymatic product. RESULTS: The H5N1 NA showed higher activity on α2,3-linked sialic acid than α2,6-linked(P < 0.0001). To compare the NA activity between the H5N1 and seasonal influenza viruses, reverse genetic viruses carrying the NA of H5N1 viruses and NA from a seasonal H3N2 virus was generated. In these reverse genetic viruses, the NA activity of the H5N1 showed markedly higher activity against α2,3-linked sialic acid than that of the H3N2 virus, whereas the activities on α2,6-linkage were comparable. Interestingly, NA from an H5N1 human isolate that was previously shown to have heamagglutinin(HA) with dual specificity showed reduced activity on α2,3-linkage. To confirm the substrate specificity profile, HPLC analytic of enzymatic product was performed. Similar to Amplex red assay, H5N1 virus showed abundant preference on α2,3-linked sialic acid.CONCLUSION: H5N1 virus maintains the avian specific NA and NA changes may be needed to accompany changes in HA receptor preference for the viral adaptation to humans.

Sodium-dependent glucose transporter 2 inhibitors effects on myocardial function in patients with type 2 diabetes and asymptomatic heart failure

BACKGROUND Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have shown efficacy in reducing heart failure(HF)burden in a very heterogeneous groups of patients,raising doubts about some contemporary assumptions of their mechanism of action.We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy.Two groups of patients were included in the study:the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control.AIM To evaluate the outcomes regarding natriuretic peptide,oxidative stress,inflammation,blood pressure,heart rate,cardiac function,and body weight.METHODS The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain(GLS),N-terminal pro-brain natriuretic peptide,myeloperoxidase(MPO),high-sensitivity C-reactive protein(hsCRP),and systolic and diastolic blood pressure.To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up,a rise in stroke volume index,body mass index(BMI)decrease,and lack of heart rate increase,linear regression analysis was performed.RESULTS There was a greater reduction of MPO,hsCRP,GLS,and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up.Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI,while the predictor of stroke volume index increase was SGLT2i therapy itself.CONCLUSION SGLT2i affect body composition,reduce cardiac load,improve diastolic/systolic function,and attenuate the sympathetic response.Glycemic control contributes to the improvement of heart function,blood pressure control,oxidative stress,and reduction in inflammation.

Analysis of Oseltamivir Resistance Substitutions in Influenza Virus Glycoprotein Neuraminidase using a Lentivirus-Based Surrogate Assay System

Influenza A virus poses a great threat to global health, and oseltamivir (trade marked as Tamiflu), which targets influenza surface glycoprotein neuraminidase (NA), is used clinically as a major anti-influenza treatment. However, certain substitutions in NA can render an influenza virus resistant to this drug. In this study, using a lentiviral pseudotyping system, which alleviates the safety concerns of studying highly pathogenic influenza viruses such as avian influenza H5N1, that utilizes influenza surface glycoproteins (hemagglutinin or HA, and NA) and an HIV-core combined with a luciferase reporter gene as a surrogate assay, we first assessed the functionality of NA by measuring pseudovirion release in the absence or presence of oseltamivir. We demonstrated that oseltamivir displays a dose-dependent inhibition on NA activity. In contrast, a mutant NA (H274Y) is more resistant to oseltamivir treatment. In addition, the effects of several previously reported substitution NA mutants were examined as well. Our results demonstrate that this lentivirus-based pseudotyping system provides a quick, safe, and effective way to assess resistance to neuraminidase inhibitors. And we believe that as new mutations appear in influenza isolates, their impact on the effectiveness of current and future anti-NA can be quickly and reliably evaluated by this assay.