Alkaloids as potential antivirals.A comprehensive review

Alkaloids are a diverse group of natural phytochemicals.These phytochemicals in plants provide them protection against pests,and herbivorous organisms and also control their development.Numerous of these alkaloids have a variety of biological effects,and some have even been developed into medications with different medicinal properties.This review aims to provide a broad overview of the numerous naturally occurring alkaloids(isolated from both terrestrial and aquatic species)along with synthetically produced alkaloid compounds having prominent antiviral properties.Previous reviews on this subject have focused on the biological actions of both natural and synthetic alkaloids,but they have not gone into comprehensive detail about their antiviral properties.We reviewed here several antiviral alkaloids that have been described in the literature in different investigational environments i.e.(in-vivo,in-ovo,in-vitro,and in-silico),and found that these alkaloid compounds have significant antiviral properties against several infectious viruses.These alkaloids repressed and targeted various important stages of viral infection at non-toxic doses while some of the alkaloids reported here also exhibited comparable inhibitory activities to commercially used drugs.Overall,these anti-viral effects of alkaloids point to a high degree of specificity,implying that they could serve as effective and safe antiviral medicines if further pursued in medicinal and pharmacological investigations.

Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition via p-FAK/ p-paxillin/YAP signaling

Carcinoma-associated fibroblasts(CAFs)are the main cellular components of the tumor microenvironment and promote cancer progression by modifying the extracellular matrix(ECM).The tumor-associated ECM is characterized by collagen crosslinking catalyzed by lysyl oxidase(LOX).Small extracellular vesicles(sEVs)mediate cell-cell communication.However,the interactions between sEVs and the ECM remain unclear.Here,we demonstrated that sEVs released from oral squamous cell carcinoma(OSCC)-derived CAFs induce collagen crosslinking,thereby promoting epithelial-mesenchymal transition(EMT).CAF sEVs preferably bound to the ECM rather than being taken up by fibroblasts and induced collagen crosslinking,and a LOX inhibitor or blocking antibody suppressed this effect.Active LOX(αLOX),but not the LOX precursor,was enriched in CAF sEVs and interacted with periostin,fibronectin,and bone morphogenetic protein-1 on the surface of sEVs.CAF sEV-associated integrinα2β1 mediated the binding of CAF sEVs to collagen I,and blocking integrinα2β1 inhibited collagen crosslinking by interfering with CAF sEV binding to collagen I.CAF sEV-induced collagen crosslinking promoted the EMT of OSCC through FAK/paxillin/YAP pathway.Taken together,these findings reveal a novel role of CAF sEVs in tumor ECM remodeling,suggesting a critical mechanism for CAF-induced EMT of cancer cells.

Untargeted metabolomics analysis of four date palm(Phoenix dactylifera L.)cultivars using MS and NMR

Since ancient times,the inhabitants of dry areas have depended on the date palm(Phoenix dactylifera L.)as a staple food and means of economic security.For example,dates have been a staple diet for the inhabitants of the Arabian Peninsula and Sahara Desert in North Africa for millennia and the local culture is rich in knowledge and experience with the benefits of dates,suggesting that dates contain many substances essential for the human body.Madinah dates are considered one of the most important types of dates in the Arabian Peninsula,with Ajwa being one of the most famous types and grown only in Madinah,Saudi Arabia.Date seeds are traditionally used for animal feed,seed oil production,cosmetics,and as a coffee substitute.Phytochemical compounds that have been detected in date fruits and date seeds include phenolic acids,carotenoids,and flavonoids.Phenolic acids are the most prevalent bioactive constituents that contribute to the antioxidant activity of date fruits.The bioactive properties of these phytochemicals are believed to promote human health by reducing the risk of diseases such as chronic inflammation.Ajwa dates especially are thought to have superior bioactivity properties.To investigate these claims,in this study,we compare the metabolic profiles of Ajwa with different types of dates collected from Saudi Arabia and Tunisia.We show by UHPLC-MS that date seeds contain several classes of flavonoids,phenolic acids,and amino acid derivatives,including citric acid,malic acid,lactic acid,and hydroxyadipic acid.Additionally,GC-MS profiling showed that date seeds are richer in metabolite classes,such as hydrocinnamic acids(caffeic,ferulic and sinapic acids),than flesh samples.Deglet N fruit extract(minimum inhibitory concentration:27 MIC/μM)and Sukkari fruit extract(IC_(50):479±0.58μg/mL)have higher levels of antibacterial and antioxidative activity than Ajwa fruits.However,the seed analysis showed that seed extracts have better bioactivity effects than fruit extracts.Specifically,Ajwa extract showed the best MIC and strongest ABTS radical-scavenging activity among examined seed extracts(minimum inhibitory concentration:20μM;IC_(50):54±3.61μg/mL).Our assays are a starting point for more advanced in vitro antibacterial models and investigation into the specific molecules that are responsible for the antioxidative and anti-bacterial activities of dates.

Metabolomic alterations and chromosomal instability status in gastric cancer

AIM To explore the correlation of metabolomics profiles ofgastric cancer(GC) with its chromosomal instability(CIN) status.METHODS Nineteen GC patients were classified as CIN and nonCIN type by The Cancer Genome Atlas Research Group system, based on 409 oncogenes and tumor suppressor genes sequenced. The aqueous metabolites of the GC tumor and its surrounding adjacent healthy tissues were identified through liquid chromatographymass spectrometry. Groups were compared by defining variable importance in projection score of > 1.2, a fold change value or its reciprocal of > 1.2, and a P value of < 0.05 as a significant difference.RESULTS In total,twelve men and seven women were enrolled, with a median age of 66 years(range, 47-87 years). The numbers of gene alterations in the CIN GC group were significantly higher than those in the non-CIN GC(32-218 vs 2-17; P < 0.0005). Compared with the adjacent healthy tissues, GC tumors demonstrated significantly higher aspartic acid, citicoline, glutamic acid, oxidized glutathione, succinyladenosine, and uridine diphosphate-Nacetylglucosamine levels, but significantly lower butyrylcarnitine, glutathione hydroxyhexanoycarnitine, inosinic acid, isovalerylcarnitine, and threonine levels(all P < 0.05). CIN tumors contained significantly higher phosphocholine and uridine 5'-monophosphate levels but significantly lower beta-citryl-L-glutamic acid levels than did non-CIN tumors(all P < 0.05). CIN GC tumors demonstrated additional altered pathways involving alanine, aspartate, and glutamate metabolism, glyoxylate and dicarboxylate metabolism, histidine metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis.CONCLUSION Metabolomic profiles of GC tumors and the adjacent healthy tissue are distinct, and the CIN status is associated with downstream metabolic alterations in GC.

Differential impact of aging and gender on lipid and lipoprotein profiles in a cohort of healthy Chinese Singaporeans

Aim： To evaluate the impact of age and gender on lipid and lipoprotein profiles and the burden of dyslipidemia in a cohort of healthy Chinese Singaporean. Methods： A total of 1 775 healthy Chinese, 536 men and 1 239 women aged between 30 and 70 years old were involved in the present study. Results： Gender differences in all lipid and lipoprotein levels were clearly evident. Singaporean Chinese men have significantly higher levels of total cholesterol （TC）, triglyceride （TG）, low density lipoprotein-cholesterol （LDL-C） and total cholesterol/high density lipoprotein-cholesterol （TC/HDL-C）, and lower levels of HDL-C than women. Although lipid and lipoprotein levels in men did not change in the different age groups, those in women, especially TC, LDL-C and TC/HDL-C, were significantly higher in older women （〉 50 years old） than corresponding levels in younger women （30-46 years old）. Furthermore, TG was significantly correlated with lipids and lipoproteins differently in men and women. If 100 mg/dL of LDL-C were to be adopted as the therapeutic cut-off level, then the burden of care will be huge as approximately 90% of both Chinese men and women have LDL-C greater than 100 mg/dL. Condusion： In light of the findings of the present study, we suggest that preventive measures to promote the reduction in risk of coronary heart disease （CHD） must address the high proportion of men and women with high LDL-C, and that these measures should take into account both the gender and age factors. For men, reduction of high cholesterol must start early in life, whereas for women, steps must be taken earlier to mitigate the anticipated sharp increase in risk, especially after menopause.

New tools for optimizing fluid resuscitation in acute pancreatitis

Acute pancreatitis(AP)is a frequent disease with degrees of increasing severity responsible for high morbidity.Despite continuous improvement in care,mortality remains significant.Because hypovolemia,together with microcirculatory dysfunction lead to poor outcome,fluid therapy remains a cornerstone of the supportive treatment.However,poor clinical evidence actually support the aggressive fluid therapy recommended in recent guidelines since available data are controversial.Fluid management remains unclear and leads to current heterogeneous practice.Different strategies may help to improve fluid resuscitation in AP.On one hand,integration of fluid therapy in a global hemodynamic resuscitation has been demonstrated to improve outcomein surgical or septic patients.Tailored fluid administration after early identification of patients with high-risk of poor outcome presenting inadequate tissue oxygenation is a major part of this strategy.On the other hand,new decision parameters have been developed recently to improve safety and efficiency of fluid therapy in critically ill patients.In this review,we propose a personalized strategy integrating these new concepts in the early fluid management of AP.This new approach paves the way to a wide range of clinical studies in the field of AP.

Interactions among age, adiposity, bodyweight, lifestyle factors and sex steroid hormones in healthy Singaporean Chinese men

Aim： To examine the inter-relationships among age, lifestyle factors, anthropometric parameters, percent body fat and steroid hormone parameters in 531 healthy Singaporean Chinese men aged between 29 and 72 years old. Methods： Various lifestyle parameters were quantified through a survey, and testosterone （T）, estradiol （E2）, dehydroepiandrosterone sulphate （DHEAS） and sex hormone binding globulin （SHBG） were measured using established methods. Anthropometric parameters were collected and computed, and percent body fat （Siri） was measured using the DEXA scanner. Results： SHBG, DHEAS, bioavailable-T （Bio-T）, E2, Siri, Ht, W/H, W/Ht and work stress were independently correlated with age. Using multivariate analyses and adjusting for age and other related factors, exercise, smoking and alcohol consumption have positive impacts on androgen levels and body composition. However, black and green tea consumption was associated with negative effects on body composition and with higher levels of E2 and Free Estradiol Index （FEI）. Men with shorter sleep duration had significantly lower T levels as compared to those with 6 h or more of nightly sleep. Higher T levels were associated with lower levels of adiposity and other indices of adiposity, whereas higher E2 levels were related to higher levels of adiposity. Men with higher DHEAS were significantly taller and heavier than those with low DHEAS levels. Conclusion： The study showed the close interactions among the gonadal/adrenal and metabolic compartments, with age being a key determinant in their interactions. Lifestyle factors such as exercise, smoking, sleeping and alcohol and tea consumption might play significantly roles in determining the status of health in men.

Glycerophospholipids pathways and chromosomal instability in gastric cancer: Global lipidomics analysis

BACKGROUND Based on the breakthrough of genomics analysis, The Cancer Genome Atlas Research Group recently proposed an integrative genomic analysis, dividing gastric cancer(GC) into four subtypes, characterized by the chromosomal instability(CIN) status. However, the CIN status of GC is still vaguely characterized and lacking the valuable easy-to-use CIN markers to diagnosis in molecular and histological detection.AIM To explore the associations of CIN with downstream lipidomics profiles.METHODS We collected cancerous and noncancerous tissue samples from 18 patients with GC; the samples were divided into CIN and non-CIN types based on the system of The Cancer Genome Atlas Research Group and 409 sequenced oncogenes and tumor suppressor genes. We identified the lipidomics profiles of the GC samples and samples of their adjacent noncancerous tissues by using liquid chromatography–mass spectrometry. Furthermore, we selected leading metabolites based on variable importance in projection scores of > 1.0 and P <0.05.RESULTS Twelve men and six women participated in this study; the participants had a median age of 67.5 years(range, 52–87 years) and were divided into CIN(n = 9)and non-CIN(n = 9) groups. The GC samples exhibited distinct profiles of lysophosphocholine, phosphocholine, phosphatidylethanolamine,phosphatidylinositol, phosphoserine, sphingomyelin, ceramide, and triglycerides compared with their adjacent noncancerous tissues. The glycerophospholipid levels(phosphocholine, phosphatidylethanolamine, and phosphatidylinositol)were 1.4-to 2.3-times higher in the CIN group compared with the non-CIN group(P < 0.05). Alterations in the glycerolipid and glycerophospholipid pathways indicated progression of GC toward CIN.CONCLUSION The lipidomics profiles of GC samples were distinct from those of their adjacent noncancerous tissues. CIN status of GC is primarily associated with downstream lipidomics in the glycerophospholipid pathway.

“No Need to Get Salty” Or Is There? Sodium Functionality as a Consideration in Nutrition Public Health Policy

Aim: Public health professionals focus on both downstream (individual) and upstream (population-level) interventions to reduce sodium consumption and prevent sodium-related chronic diseases. Effective upstream interventions specifically aimed at reducing dietary sodium intake include the implementation of comprehensive nutrition standards that restrict the amount of sodium contained in foods available for purchase. The aim of this work was to identify sought-after foods that did not meet the Philadelphia Nutrition Standards’ sodium limits and reformulate those foods to be standards-compliant and consumer-acceptable. Subject and Methods: Two foods were reformulated for compliancy with the Philadelphia Nutrition Standards’ sodium limits and consumer acceptability: the hoagie roll and soft pretzel. Reformulation included sensory testing and engaging potential manufacturing partners to investigate products’ commercial potential. Results: While hoagie roll reformulation led to a local company manufacturing and selling the reformulated product, soft pretzel reformulation stalled due to lack of consumer acceptability of the reformulated product. Salt contributes desirable characteristics in the texture, taste, and appearance of the soft pretzel, the absence of which consumers found unacceptable. Conclusion: Product reformulation holds great potential to create lower-sodium foods that otherwise have all of the characteristics of the higher-sodium “original” products but requires an understanding of the role of salt in product recipes. Reducing salt without considering its multiple functions in food may result in a product that is unacceptable or even unsafe. A simple four-step tool can help public health practitioners evaluate the extent to which products are suitable for reformulation.

Prediction of pore volume compressibility by a new non-linear equation in carbonate reservoirs

Pore volume compressibility is an essential parameter in reservoir studies,as it plays a major role in recovery mechanisms.Over the past decades,many attempts have been made to establish a link between the pore compressibility and the porosity and other mechanical properties of the rock.Some scholars introduced analytical correlations between pore compressibility and rock mechanical properties,while others developed empirical formulas for estimating pore compressibility based on a porosity calculated by comparing nonlinear models to laboratory data.In this study,pore volume compressibility is measured on 55 carbonate samples and then applied to derive an empirical relationship between pore compressibility and porosity at each stress step,which is useful for predicting pore compressibility based on initial porosity.We take the net stress effect into account and derive an empirical correlation based on net effective stress and initial porosity to predict pore compressibility.In the end,we compare the measured pore compressibility with that predicted by the derived correlation and other non-leaner models,which indicates that the newly proposed non-linear equation outperforms those available in literature。

Nitrogen Reduction to Ammonia by a Phosphorus-Nitrogen PN^(3) P-Mo(V)Nitride Complex:Significant Enhancement via Ligand Postmodification

Efforts to develop organometallic complexes for catalytic nitrogen reduction have seen significant progress in recent years.However,the strategies for improving the activity of the homogenous catalysts have mainly focused on alternating ligands and metals.Herein,we report that the activity and stability of a PN_(P-Mo pincer complex(2)toward dinitrogen(N_(2))reduction were greatly enhanced through postmodification of the PN^(3)P pincer framework of its parent complex(1).A high ratio of NH_(3)/Mo(3525)was achieved in the presence of SmI_(2)as a reductant.In sharp contrast,1 only afforded an NH_(3)/Mo ratio of 21.Moreover,when supported by an anionic pincer ligand,2 furnished a high oxidation state Mo(V)-nitride complex via N_(2)cleavage as a plausible key intermediate in the catalytic process,suggesting a catalytic cycle that may involve different oxidation states(Ⅱ/Ⅴ)from those with 10-πelectron configuration in the literature.

Incremental value of contrast echocardiography in the diagnosis of left ventricular noncompaction

Contrast echocardiography with left ventricular opacification （LVO） improves the definition of endocardium in two-dimensional echocardiography （2DE）. This study was aimed to determine whether LVO offered added diagnostic value in noncompaetion of left ventricular myocardium （NCVM）. A total of 85 patients （40± 20 years, 54 males） with suspected NCVM were subjected to transthoracic 2DE and LVO, and 40 healthy volunteers were examined with 2DE and assigned as control subjects. The location of NCVM, the thickness ratio of noncompacted to compacted myocardium （NCR）, and the cavity size and ejection fraction of LV were quantified. Results revealed that NCVM was mainly located in the LV medium （53.2%）, apical （46.2%） segments, and lateral wall （39.8%）. The NCR obtained through LVO was greater than that detected through 2DE （4.2 ±1.3 vs. 3.3 ±1.2, P 〈 0.001）, and higher inter-correlations and less intra- and inter-observer variabilities were determined in the former than in the latter. The NCVM detection rates were also increased from 63.5% via 2DE to 83.5% via LVO and 89.4% via 2DE combined with LVO （2DE ＋ LVO） （P = 0.0004）. The LV cavity size was greater and the LV ejection fraction （LVEF） was lower in the NCVM patients than in the control group （P 〈 0.01）. In the NCVM group, the LV cavity size was higher and the LVEF was lower in LVO than in 2DE （P 〈 0.01）. In conclusion, contrast echocardiography contributes significant sensitivity and reproducibility to routine transthoraeic echoeardiography in NCVM diagnosis. Therefore, this technique should be clinically performed to diagnose suspected NCVM.

Posterior shoulder fracture-dislocation:A systematic review of the literature and current aspects of management

Purpose Posterior fracture-dislocation of shoulder is an infrequent traumatic event;however,most orthopaedic surgeons may face the challenge of treating it.The aim of this study is to review and summarise systematically the current principles of the management of this complex injury,and create a treatment algorithm.Methods Both PubMed and Scopus Databases were systematically searched for the terms“posterior shoulder fracture-dislocation”or“posterior glenohumeral fracture-dislocation”or“posterior glenoid fracture-dislocation”for articles written in English and published in the last decade.Results A total of 900 articles were identified,of which 13 were retained for analysis.A total of 153 patients(161 shoulders)were identified.These patients were treated either with open reduction and internal fixation,modified McLaughlin procedure,allograft/autograft humeral head reconstruction or shoulder arthroplasty.The mean age was 40.15 years.The mean postoperative Constant score in cases treated by open reduction and internal fixation was 86.45,whereas by bone graft was 84.18.Further,the mean postoperative Constant score was between 79.6 and 67.1 in those that were managed by modified McLaughlin and arthroplasty procedure,respectively.Conclusion The management of posterior shoulder fracture-dislocation may be challenging,and the best surgical option depends on many variables such as the chronicity of the injury,the presence of a fracture at the level of the surgical neck or tuberosities and the extend of the Hill-Sachs lesion if any.A treatment algorithm is proposed,based on the current literature in an effort to create a consensus for these injuries.For the acute shoulder fracture-dislocations,an open reduction should be performed.For the chronic fracture/dislocations in the elderly low-demand patients,conservative treatment should be performed.For the rest of the patients,depending on the severity of the Hill-Sachs lesion different surgical options are available such as the McLaughlin technique,the use of an allograft,osteotomy or arthroplasty.

Tungsten Blue Oxide as a Reusable Electrocatalyst for Acidic Water Oxidation by Plasma-Induced Vacancy Engineering

In contrast to alkaline water electrolysis,acidic water electrolysis remains an elusive goal due to the lack of earth-abundant,efficient,and acid-stable water oxidation electrocatalysts.Here,we show that materials with intrinsically poor electrocatalytic activity can be turned into active electrocatalysts that drive the acidic oxygen evolution reaction(OER)effectively.This development is achieved through ultrafast plasma sputtering,which introduces abundant oxygen vacancies that reconstruct the surface electronic structures,and thus,regulated the surface interactions of electrocatalysts and the OER intermediates.Using tungsten oxide(WO_(3))as an example,we present a broad spectrum of theoretical and experimental characterizations that show an improved energetics of OER originating from surface oxygen vacancies and resulting in a significantly boosted OER performance,compared with pristine WO_(3).Our result suggests the efficacy of using defect chemistry to modify electronic properties and hence to improve the OER performance of known materials with poor activity,providing a new direction for the discovery of acid-stable OER catalysts.

Flexible and biocompatible high-performance solid-state micro-battery for implantable orthodontic system

To augment the quality of our life,fully compliant personalized advanced health-care electronic system is pivotal.One of the major requirements to implement such systems is a physically flexible high-performance biocompatible energy storage(battery).However,the status-quo options do not match all of these attributes simultaneously and we also lack in an effective integration strategy to integrate them in complex architecture such as orthodontic domain in human body.Here we show,a physically complaint lithium-ion micro-battery(236μg)with an unprecedented volumetric energy(the ratio of energy to device geometrical size)of 200 mWh/cm^(3) after 120 cycles of continuous operation.Our results of 90%viability test confirmed the battery’s biocompatibility.We also show seamless integration of the developed battery in an optoelectronic system embedded in a threedimensional printed smart dental brace.We foresee the resultant orthodontic system as a personalized advanced health-care application,which could serve in faster bone regeneration and enhanced enamel health-care protection and subsequently reducing the overall health-care cost.

The evolution of surgical and medical treatment of aortic root aneurysm

Since first report of aortic root replacement in 1968, the surgical risk and long term outcome of patients with aortic root aneurysm have been continuously improving. In the last 30 years, the surgical approach is also evolving towards more valve conservation with prophylactical intervention at an earlier clinical stage. Translational research has also led to emerging surgical innovation and new drug therapy. Their efficacies are currently under vigorous clinical trials and evaluations.

Mechanistic elucidation of the role of metal oxidation states in nickel mediated electrocatalytic coupling of benzyl halides

We present the mechanistic understanding of an electrochemically-driven nickel-catalyzed coupling reaction.Computational analysis reveals that the spin density is mostly residing on the nickel(Ni)center when Ni^(II) is reduced to NiI.Ni-mediated halogen atom abstraction through outer-sphere electron-transfer pathway to yield coupling products under mild conditions is demonstrated.Importantly,we have elucidated the role of Ni^(I) and Ni^(0) for successive coupling of benzyl bromide and benzyl chloride derivatives,respectively,to corresponding bibenzyl products.The Ni-catalyst bearing a PN^(3) P-ligand is an effective catalyst,producing a strong ligand effect on the reactivity and selectivity for the homocoupling reactions.