The pleiotropic effects of tissue plasminogen activator in the brain:implications for stroke recovery

Tissue plasminogen activator(t PA)use in the treatment of ischemic stroke:t PA is a serine protease that catalyzes the breakdown of blood clots.Because of its thrombolytic properties,t PA is used to treat specific types of stroke,including ischemia,but is contraindicated for treatment of hemorrhagic stroke or head trauma.Although a life saving and powerful‘clot buster’,t PA has a

Sodium-glucose cotransporter 2 inhibitors’ mechanisms of action in heart failure

Three major cardiovascular outcome trials(CVOTs)with a new class of antidiabetic drugs-sodium-glucose cotransporter 2(SGLT2)inhibitors(EMPAREG OUTCOME trial with empagliflozin,CANVAS Program with canagliflozin,DECLARE-TIMI 58 with dapagliflozin)unexpectedly showed that cardiovascular outcomes could be improved possibly due to a reduction in heart failure risk,which seems to be the most sensitive outcome of SGLT2 inhibition.No other CVOT to date has shown any significant benefit on heart failure events.Even more impressive findings came recently from the DAPA-HF trial in patients with confirmed and well-treated heart failure:Dapagliflozin was shown to reduce heart failure risk for patients with heart failure with reduced ejection fraction regardless of diabetes status.Nevertheless,despite their possible wide clinical implications,there is much doubt about the mechanisms of action and a lot of questions to unravel,especially now when their benefits translated to nondiabetic patients,rising doubts about the validity of some current mechanistic assumptions.The time frame of their cardiovascular benefits excludes glucoselowering and antiatherosclerotic-mediated effects and multiple other mechanisms,direct cardiac as well as systemic,are suggested to explain their early cardiorenal benefits.These are:Anti-inflammatory,antifibrotic,antioxidative,antiapoptotic properties,then renoprotective and hemodynamic effects,attenuation of glucotoxicity,reduction of uric acid levels and epicardial adipose tissue,modification of neurohumoral system and cardiac fuel energetics,sodiumhydrogen exchange inhibition.The most logic explanation seems that SGLT2 inhibitors timely target various mechanisms underpinning heart failure pathogenesis.All the proposed mechanisms of their action could interfere with evolution of heart failure and are discussed separately within the main text.

A Capra hircus chromosome 19 locus linked to milk production influences mammary conformation

Background:Economically important milk production traits including milk volume,milk fat and protein yield vary considerably across dairy goats in New Zealand.A significant portion of the variation is attributable to genetic variation.Discovery of genetic markers linked to milk production traits can be utilised to drive selection of highperformance animals.A previously reported genome wide association study across dairy goats in New Zealand identified a quantitative trait locus(QTL)located on chromosome 19.The most significantly associated single nucleotide polymorphism(SNP)marker for this locus is located at position 26,610,610(SNP marker rs268292132).This locus is associated with multiple milk production traits including fat,protein and volume.The predicted effect of selection for the beneficial haplotype would result in an average production increase of 2.2 kg fat,1.9 kg protein and 73.6 kg milk yield.An outstanding question was whether selection for the beneficial allele would co-select for any negative pleiotropic effects.An adverse relationship between milk production and udder health traits has been reported at this locus.Therefore,a genome wide association study was undertaken looking for loci associated with udder traits.Results:The QTL and production associated marker rs268292132 was identified in this study to also be associated with several goat udder traits including udder depth(UD),fore udder attachment(FUA)and rear udder attachment(RUA).Our study replicates the negative relationship between production and udder traits with the high production allele at position 19:26,610,610(SNP marker rs268292132)associated with an adverse change in UD,FUA and RUA.Conclusions:Our study has confirmed the negative relationship between udder traits and production traits in the NZ goat population.We have found that the frequency of the high production allele is relatively high in the NZ goat population,indicating that its effect on udder conformation is not significantly detrimental on animal health.It will however be important to monitor udder conformation as the chromosome 19 locus is progressively implemented for marker assisted selection.It will also be of interest to determine if the gene underlying the production QTL has a direct effect on mammary gland morphology or whether the changes observed are a consequence of the increased milk volume.

Statins in risk-reduction and treatment of cancer

Statins,which are competitive inhibitors of 3-hydroxy-3-methyl-glutarylcoenzyme A reductase,reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications.In addition to this main activity,statins show pleiotropic effects such as antioxidant,anti-inflammatory and antiproliferative properties,with applications in many pathologies.Based on their antiproliferative properties,in vitro and in vivo studies have investigated their effects on various types of cancer(i.e.,breast cancer,prostate cancer,colorectal cancer,ovarian cancer,lung cancer)with different genetic and molecular characteristics.Many positive results were obtained,but they were highly dependent on the physiochemical properties of the statins,their dose and treatment period.Combined therapies of statins and cytotoxic drugs have also been tested,and synergistic or additive effects were observed.Moreover,observational studies performed on patients who used statins for different pathologies,revealed that statins reduced the risk of developing various cancers,and improved the outcomes for cancer patients.Currently,there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk.All these results are the foundation of new treatment directions in cancer therapy.

The domestication-associated L1 gene encodes a eucomic acid synthase pleiotropically modulating pod pigmentation and shattering in soybean

Pod coloration is a domestication-related trait in soybean,with modern cultivars typically displaying brown or tan pods,while their wild relative,Glycine soja,possesses black pods.However,the factors regulating this color variation remain unknown.In this study,we cloned and characterized L1,the classical locus responsible for black pods in soybean.By using map-based cloning and genetic analyses,we identified the causal gene of L1 and revealed that it encodes a hydroxymethylglutaryl-coenzyme A(CoA)lyase-like(HMGL-like)domain protein.Biochemical assays showed that L1 functions as a eucomic acid synthase and facilitates the synthesis of eucomic acid and piscidic acid,both of which contribute to coloration of pods and seed coats in soybean.Interestingly,we found that L1 plants are more prone to pod shattering under light exposure than l1 null mutants because dark pigmentation increases photothermal efficiency.Hence,pleiotropic effects of L1 on pod color and shattering,as well as seed pigmentation,likely contributed to the preference forl1 alleles during soybean domestication and improvement.Collectively,our study provides new insights into the mechanism of pod coloration and identifies a new target for future de novo domestication oflegume crops.

Nature’s marvels endowed in gaseous molecules Ⅰ:Carbon monoxide and its physiological and therapeutic roles

Nature has endowed gaseous molecules such as O_(2),CO_(2),CO,NO,H2 S,and N2 with critical and diverse roles in sustaining life,from supplying energy needed to power life and building blocks for life ’s physical structure to mediating and coordinating cellular functions.In this article,we give a brief introduction of the complex functions of the various gaseous molecules in life and then focus on carbon monoxide as a specific example of an endogenously produced signaling molecule to highlight the importance of this class of molecules.The past twenty years have seen much progress in understanding CO’s mechanism(s) of action and pharmacological effects as well as in developing delivery methods for easy administration.One remarkable trait of CO is its pleiotropic effects that have few parallels,except perhaps its sister gaseous signaling molecules such as nitric oxide and hydrogen sulfide.This review will delve into the sophistication of CO-mediated signaling as well as its validated pharmacological functions and possible therapeutic applications.