The intrinsic ability of peripheral nerves to regenerate after injury is extremely limited,especially in case of severe injury.This often leads to poor motor function and permanent disability.Existing approaches for t...The intrinsic ability of peripheral nerves to regenerate after injury is extremely limited,especially in case of severe injury.This often leads to poor motor function and permanent disability.Existing approaches for the treatment of injured nerves do not provide appropriate conditions to support survival and growth of nerve cells.This drawback can be compensated by the use of gene therapy and cell therapy-based drugs that locally provide an increase in the key regulators of nerve growth,including neurotrophic factors and extracellular matrix proteins.Each growth factor plays its own specific angiotrophic or neurotrophic role.Currently,growth factors are widely studied as accelerators of nerve regeneration.Particularly noteworthy is synergy between various growth factors,that is essential for both angiogenesis and neurogenesis.Fibroblast growth factor 2 and vascular endothelial growth factor are widely known for their proangiogenic effects.At the same time,fibroblast growth factor 2 and vascular endothelial growth factor stimulate neural cell growth and play an important role in neurodegenerative diseases of the peripheral nervous system.Taken together,their neurotrophic and angiogenic properties have positive effect on the regeneration process.In this review we provide an in-depth overview of the role of fibroblast growth factor 2 and vascular endothelial growth factor in the regeneration of peripheral nerves,thus demonstrating their neurotherapeutic efficacy in improving neuron survival in the peripheral nervous system.展开更多
Knee osteoarthritis is a chronic, indolent disease that will affect an ever increasing number of patients, especially the elderly and the obese. It is characterized by degeneration of the cartilage substance inside th...Knee osteoarthritis is a chronic, indolent disease that will affect an ever increasing number of patients, especially the elderly and the obese. It is characterized by degeneration of the cartilage substance inside the knee which leads to pain, stiffness and tenderness. By some estimations in 2030, only in the United States, this medical condition will burden 67 million people. While conventional treatments like physiotherapy or drugs offer temporary relief of clinical symptoms, restoration of normal cartilage function has been difficult to achieve. Moreover, in severe cases of knee osteoarthritis total knee replacement may be required. Total knee replacements come together with high effort and costs and are not always successful. The aim of this review is to outline the latest advances in stem cell therapy for knee osteoarthritis as well as highlight some of the advantages of stem cell therapy over traditional approaches aimed at restoration of cartilage function in the knee. In addition to the latest advances in the field, challenges associated with stem cell therapy regarding knee cartilage regeneration and chondrogenesis in vitro and in vivo are also outlined and analyzed. Furthermore, based on their critical assessment of the present academic literature the authors of this review share their vision about the future of stem cell applications in the treatment of knee osteoarthritis.展开更多
Background: Physical activity(PA) and diet are 2 lifestyle factors that affect cardiometabolic risk. However, data on how a high-fat highcarbohydrate(HFHC) diet influences the effect of different intensities of PA on ...Background: Physical activity(PA) and diet are 2 lifestyle factors that affect cardiometabolic risk. However, data on how a high-fat highcarbohydrate(HFHC) diet influences the effect of different intensities of PA on cardiometabolic health and cardiovascular function in a controlled setting are yet to be fully established. This study investigated the effect of sedentary behavior, light-intensity training(LIT), and high-intensity interval training(HIIT) on cardiometabolic markers and vascular and cardiac function in HFHC-fed adult rats.Methods: Twelve-week-old Wistar rats were randomly allocated to 4 groups(12 rats/group): control(CTL), sedentary(SED), LIT, and HIIT.Biometric indices, glucose and lipid control, inflammatory and oxidative stress markers, vascular reactivity, and cardiac electrophysiology of the experimental groups were examined after 12 weeks of HFHC-diet feeding and PA interventions.Results: The SED group had slower cardiac conduction(p = 0.0426) and greater thoracic aortic contractile responses(p < 0.05) compared with the CTL group. The LIT group showed improved cardiac conduction compared with the SED group(p = 0.0003), and the HIIT group showed decreased mesenteric artery contractile responses compared with all other groups and improved endothelium-dependent mesenteric artery relaxation compared with the LIT group(both p < 0.05). The LIT and HIIT groups had lower visceral(p = 0.0057 for LIT, p = 0.0120 for HIIT)and epididymal fat(p < 0.0001 for LIT, p = 0.0002 for HIIT) compared with the CTL group.Conclusion: LIT induced positive adaptations on fat accumulation and cardiac conduction, and HIIT induced a positive effect on fat accumulation,mesenteric artery contraction, and endothelium-dependent relaxation. No other differences were observed between groups. These findings suggest that few positive health effects can be achieved through LIT and HIIT when consuming a chronic and sustained HFHC diet.展开更多
AIM: To assess the effects of ischemic preconditioning(IPC, 10-min ischemia/10-min reperfusion) on steatotic liver mitochondrial function after normothermic ischemia-reperfusion injury(IRI).METHODS: Sixty male Sprague...AIM: To assess the effects of ischemic preconditioning(IPC, 10-min ischemia/10-min reperfusion) on steatotic liver mitochondrial function after normothermic ischemia-reperfusion injury(IRI).METHODS: Sixty male Sprague-Dawley rats were fed8-wk with either control chow or high-fat/high-sucrose diet inducing > 60% mixed steatosis. Three groups(n = 10/group) for each dietary state were tested:(1) the IRI group underwent 60 min partial hepatic ischemia and 4 h reperfusion;(2) the IPC group underwent IPC prior to same standard IRI; and(3) sham underwent t h e s a m e s u r g e r y w i t h o u t I R I o r I P C. H e p a t i c mitochondrial function was analyzed by oxygraphs. Mitochondrial Complex-Ⅰ, Complex-Ⅱ enzyme activity, serum alanine aminotransferase(ALT), and histological injury were measured.RESULTS: Steatotic-IRI livers had a greater increase in ALT(2476 ± 166 vs 1457 ± 103 IU/L, P < 0.01) and histological injury following IRI compared to the lean liver group. Steatotic-IRI demonstrated lower Complex-Ⅰ?activity at baseline [78.4 ± 2.5 vs 116.4 ± 6.0 nmol/(min.mg protein), P < 0.001] and following IRI [28.0 ± 6.2 vs 104.3 ± 12.6 nmol/(min.mg protein), P < 0.001]. Steatotic-IRI also demonstrated impaired Complex-Ⅰ?function post-IRI compared to the lean liver IRI group. Complex-Ⅱ activity was unaffected by hepatic steatosis or IRI. Lean liver mitochondrial function was unchanged following IRI. IPC normalized ALT and histological injury in steatotic livers but had no effect on overall steatotic liver mitochondrial function or individual mitochondrial complex enzyme activities. CONCLUSION: Warm IRI impairs steatotic liver Complex-Ⅰ?activity and function. The protective effects of IPC in steatotic livers may not be mediated through mitochondria.展开更多
BACKGROUND The development of new vasculatures(angiogenesis)is indispensable in supplying oxygen and nutrients to fuel tumor growth.Epigenetic dysregulation in the tumor vasculature is critical to colorectal cancer(CR...BACKGROUND The development of new vasculatures(angiogenesis)is indispensable in supplying oxygen and nutrients to fuel tumor growth.Epigenetic dysregulation in the tumor vasculature is critical to colorectal cancer(CRC)progression.Sirtuin(SIRT)enzymes are highly expressed in blood vessels.BZD9L1 benzimidazole analogue is a SIRT 1 and 2 inhibitor with reported anticancer activities in CRC.However,its role has yet to be explored in CRC tumor angiogenesis.AIM To investigate the anti-angiogenic potential of BZD9L1 on endothelial cells(EC)in vitro,ex vivo and in HCT116 CRC xenograft in vivo models.METHODS EA.hy926 EC were treated with half inhibitory concentration(IC50)(2.5μM),IC50(5.0μM),and double IC50(10.0μM)of BZD9L1 and assessed for cell proliferation,adhesion and SIRT 1 and 2 protein expression.Next,2.5μM and 5.0μM of BZD9L1 were employed in downstream in vitro assays,including cell cycle,cell death and sprouting in EC.The effect of BZD9L1 on cell adhesion molecules and SIRT 1 and 2 were assessed via real-time quantitative polymerase chain reaction(qPCR).The growth factors secreted by EC post-treatment were evaluated using the Quantibody Human Angiogenesis Array.Indirect co-culture with HCT116 CRC cells was performed to investigate the impact of growth factors modulated by BZD9L1-treated EC on CRC.The effect of BZD9L1 on sprouting impediment and vessel regression was determined using mouse choroids.HCT116 cells were also injected subcutaneously into nude mice and analyzed for the outcome of BZD9L1 on tumor necrosis,Ki67 protein expression indicative of proliferation,cluster of differentiation 31(CD31)and CD34 EC markers,and SIRT 1 and 2 genes via hematoxylin and eosin,immunohistochemistry and qPCR,respectively.RESULTS BZD9L1 impeded EC proliferation,adhesion,and spheroid sprouting through the downregulation of intercellular adhesion molecule 1,vascular endothelial cadherin,integrin-alpha V,SIRT1 and SIRT2 genes.The compound also arrested the cells at G1 phase and induced apoptosis in the EC.In mouse choroids,BZD9L1 inhibited sprouting and regressed sprouting vessels compared to the negative control.Compared to the negative control,the compound also reduced the protein levels of angiogenin,basic fibroblast growth factor,platelet-derived growth factor and placental growth factor,which then inhibited HCT116 CRC spheroid invasion in co-culture.In addition,a significant reduction in CRC tumor growth was noted alongside the downregulation of human SIRT1(hSIRT1),hSIRT2,CD31,and CD34 EC markers and murine SIRT2 gene,while the murine SIRT1 gene remained unaffected,compared to vehicle control.Histology analyses revealed that BZD9L1 at low(50 mg/kg)and high(250 mg/kg)doses reduced Ki-67 protein expression,while BZD9L1 at the high dose diminished tumor necrosis compared to vehicle control.CONCLUSION These results highlighted the anti-angiogenic potential of BZD9L1 to reduce CRC tumor progression.Furthermore,together with previous anticancer findings,this study provides valuable insights into the potential of BZD9L1 to co-target CRC tumor vasculatures and cancer cells via SIRT1 and/or SIRT2 down-regulation to improve the therapeutic outcome.展开更多
AIM: To explore the feasibility of using hypericin as an optical imaging probe with affinity for cholesterol for differential fluorescent detection of human gallstones.METHODS: Cholesterol, mixed and pigment stones fr...AIM: To explore the feasibility of using hypericin as an optical imaging probe with affinity for cholesterol for differential fluorescent detection of human gallstones.METHODS: Cholesterol, mixed and pigment stones from cholecystectomy patients were incubated with hypericin or solvent. After 72 h, the stones were analysed for fluorescence(365 nm) and treated with 2-propanol/dimethyl sulfoxide for high performance liquid chromatography(HPLC) analysis. Rats with virtual gallbladder containing human cholesterol, mixed or pigment gallstones(VGHG) received 5 mg/kg hypericin or solvent and VGHG rats with cholesterol stones were given different hypericin doses(5-15 mg/kg). Twelve hours later, the stones were analysed at 365 nm. Biliary excretion and metabolites of hypericin were assessed in common bile duct(CBD) cannulated rats for 9 h using fluorospectrometry, HPLC and matrixassisted laser desorption/ionization-time-of-flight mass spectrometry(MALDI-TOF MS).RESULTS: Homogeneous high fluorescence was seen on cholesterol stones either pre-incubated with hypericin or extracted from VGHG rats receiving hypericin. Mixed stones showed a dotted fluorescent pattern, whereas pigment and solvent-treated ones lacked fluorescence. HPLC showed 7.68, 6.65 and 0.08 × 10^(-3) M of cholesterol in extracts from cholesterol, mixed, and pigment gallstones, respectively. Hypericin accounted for 2.0, 0.5 and 0.2 × 10-6 M in that order. On cholesterol stones from VGHG rats receiving different hypericin doses, a positive correlation was observed between dose and fluorescence. In the bile from CBD-cannulated rats, fluorescence represented 20% of the injected dose with two peaks in 9 h. HPLC analysis revealed that hypericin conjugates reached 60% of the peak area. By MALDI-TOF MS, hypericinglucuronide was detected. CONCLUSION: This study proves the potential use of hypericin for differential fluorescent detection of human gallstones regarding their chemical composition.展开更多
This study investigates controlled micro/nano manipulation of polydimethylsiloxane (PDMS) using Atomic Force Microscopy (AFM). Lithographic results revealed stick-slip phenomena along the slow scan direction. Varying ...This study investigates controlled micro/nano manipulation of polydimethylsiloxane (PDMS) using Atomic Force Microscopy (AFM). Lithographic results revealed stick-slip phenomena along the slow scan direction. Varying the normal loading force, scan size, scan number and contact conditions allowed the control of certain lithographic outcomes e.g., channel spacing. The PDMS surface experienced significant in-plane deformation in response to the tip-induced lateral force. This displacement increased with increasing loading force, creating greater spacing between channels in the slow scan direction. Simultaneous generation of a lateral displacement in the fast scan direction caused a decrease in channel length with increasing loading force due to an increase in static friction with normal force, resulting in a greater surface relaxation, and shorter track length of dynamic friction. By controlling both the loading force and the number of scans over an area, frictional tiers were produced.展开更多
The antimalarial drug-resistance conundrum which threatens to reverse the great strides taken to curb the malaria scourge warrants an urgent need to find novel chemical scaffolds to serve as templates for the developm...The antimalarial drug-resistance conundrum which threatens to reverse the great strides taken to curb the malaria scourge warrants an urgent need to find novel chemical scaffolds to serve as templates for the development of new antimalarial drugs.Plants represent a viable alternative source for the discovery of unique potential antiplasmodial chemical scaffolds.To expedite the discovery of new antiplasmodial compounds from plants,the aim of this study was to use phylogenetic analysis to identify higher plant orders and families that can be rationally prioritised for antimalarial drug discovery.We queried the PubMed database for publications documenting antiplasmodial properties of natural compounds isolated from higher plants.Thereafter,we manually collated compounds reported along with plant species of origin and relevant pharmacological data.We systematically assigned antiplasmodial-associated plant species into recognised families and orders,and then computed the resistance index,selectivity index and physicochemical properties of the compounds from each taxonomic group.Correlating the generated phylogenetic trees and the biological data of each clade allowed for the identification of 3‘hot’plant orders and families.The top 3 ranked plant orders were the(i)Caryophyllales,(ii)Buxales,and(iii)Chloranthales.The top 3 ranked plant families were the(i)Ancistrocladaceae,(ii)Simaroubaceae,and(iii)Buxaceae.The highly active natural compounds(IC_(50)≤1μM)isolated from these plant orders and families are structurally unique to the‘legacy’antimalarial drugs.Our study was able to identify the most prolific taxa at order and family rank that we propose be prioritised in the search for potent,safe and drug-like antimalarial molecules.展开更多
The emergence and spread of drug-recalcitrant Plasmodium falciparum parasites threaten to reverse the gains made in the fight against malaria.Urgent measures need to be taken to curb this impending challenge.The highe...The emergence and spread of drug-recalcitrant Plasmodium falciparum parasites threaten to reverse the gains made in the fight against malaria.Urgent measures need to be taken to curb this impending challenge.The higher plant-derived sesquiterpene,quinoline alkaloids,and naphthoquinone natural product classes of compounds have previously served as phenomenal chemical scaffolds from which integral antimalarial drugs were developed.Historical successes serve as an inspiration for the continued investigation of plant-derived natural products compounds in search of novel molecular templates from which new antimalarial drugs could be developed.The aim of this study was to identify potential chemical scaffolds for malaria drug discovery following analysis of historical data on phytochemicals screened in vitro against P.falciparum.To identify these novel scaffolds,we queried an in-house manually curated database of plant-derived natural product compounds and their in vitro biological data.Natural products were assigned to different structural classes using NPClassifier.To identify the most promising chemical scaffolds,we then correlated natural compound class with bioactivity and other data,namely(i)potency,(ii)resistance index,(iii)selectivity index and(iv)physicochemical properties.We used an unbiased scoring system to rank the different natural product classes based on the assessment of their bioactivity data.From this analysis we identified the top-ranked natural product pathway as the alkaloids.The top three ranked super classes identified were(i)pseudoalkaloids,(ii)naphthalenes and(iii)tyrosine alkaloids and the top five ranked classes(i)quassinoids(of super class triterpenoids),(ii)steroidal alkaloids(of super class pseudoalkaloids)(iii)cycloeudesmane sesquiterpenoids(of super class triterpenoids)(iv)isoquinoline alkaloids(of super class tyrosine alkaloids)and(v)naphthoquinones(of super class naphthalenes).Launched chemical space of these identified classes of compounds was,by and large,distinct from that of‘legacy’antimalarial drugs.Our study was able to identify chemical scaffolds with acceptable biological properties that are structurally different from current and previously used antimalarial drugs.These molecules have the potential to be developed into new antimalarial drugs.展开更多
BACKGROUND Pancreatic cancer is the most aggressive cancer type.Gemcitabine is the first line chemo-drug used for pancreatic cancer but exerts a broad spectrum of organ toxicities and adverse effects in patients.AIM T...BACKGROUND Pancreatic cancer is the most aggressive cancer type.Gemcitabine is the first line chemo-drug used for pancreatic cancer but exerts a broad spectrum of organ toxicities and adverse effects in patients.AIM To evaluate the anti-tumour activity and toxicological effects of Orthosiphon stamineus extract formulation(ID:C5EOSEW5050ESA trademarked as Nuvastatic^(TM)),and gemcitabine combination on pancreatic xenograft model.METHODS Mice were randomly divided into six groups of 6 mice each(n=6)and given different treatments for 28 d.The study design consisted of a 2 x 3 factorial treatment structure,with gemcitabine(yes/no)by oral(at 1200 and 400 mg/kg per day).Human pancreatic cancer cells were injected subcutaneously into the flanks of athymic nude mice.C5EOSEW5050ESA(200 or 400 mg/kg per day)was administered orally,while gemcitabine(10 mg/kg per 3 d)was given intraperitoneally either alone or in combination treatment.Histopathological analyses of vital organs,tumour tissues,and incidence of lethality were analysed.Analyses of tumour necrosis and proliferation were determined by haematoxylin-eosin staining and immunohistochemistry for Ki-67,respectively.RESULTS No signs of toxicity or damage to vital organs were observed in all treatment groups compared to the untreated group.C5EOSEW5050ESA at 200 mg/kg and gemcitabine combination had no additive antitumor effects compared to a single treatment.Remarkably,a comparably greater response in a reduction in tumour growth,Ki-67 protein expression,and necrosis was demonstrated by 400 mg/kg of C5EOSEW5050ESA and gemcitabine combination than that of the individual agents.CONCLUSION These results highlighted the synergistic activity of C5EOSEW5050ESA with gemcitabine to reduce pancreatic tumour growth in mice compared to a single treatment.Thus,this study provides valuable insights into using C5EOSEW5050ESA as a complementary treatment with gemcitabine for pancreatic cancer.展开更多
Objective: To identify the differential gene expression profiles between the normal and aspermia human testes utilizing cDNA microarray. Methods: cDNA probes were prepared by labeling mRNA of aspermia testes tissues w...Objective: To identify the differential gene expression profiles between the normal and aspermia human testes utilizing cDNA microarray. Methods: cDNA probes were prepared by labeling mRNA of aspermia testes tissues with Cy5-dUTP and mRNA of normal testes tissues with Cy3-dUTP respectively through reverse transcription. The mixed cDNA probes were then hybridized with 4096 cDNA arrays (4096 unique human cDNA sequences), and the fluorescent signals were scanned by ScanArray 3000 scanner (General Scanning, Inc.). The values of Cy5-dUTP and Cy3-dUTP on each spot were analyzed and calculated by ImaGene 3.0 software (BioDiscovery, Inc.). Differentially expressed genes were screened according to the criterion that the absolute value of natural logarithm of the ratio of Cy5-dUTP to Cy3-dUTP was greater-than 2.0 or less-than 0.5. A randomly chosen gene RAP1A was studied by in situ hybridization to evaluate the accuracy of the results. Results: 623 differential expressed genes related to aspermia were found. There were 303 up-expressed genes and 320 down-expressed genes. A distinct up-expressed gene RAP1A was confirmed by in situ hybridization. Conclusions: Screening the differential gene expression profiles between the normal and aspermia human testis by cDNA microarray can be used in the study of aspermia-related genes and the further research due to its properties, RAP1A may play some roles in the development and progression of aspermia.展开更多
As we navigate the transition from the Fourth to the Fifth Industrial Revolution,the emerging fields of biomanufacturing and biofabrication are transforming life sciences and healthcare.These sectors are benefiting fr...As we navigate the transition from the Fourth to the Fifth Industrial Revolution,the emerging fields of biomanufacturing and biofabrication are transforming life sciences and healthcare.These sectors are benefiting from a synergy of synthetic and engineering biology,sustainable manufacturing,and integrated design principles.Advanced techniques such as 3D bioprinting,tissue engineering,directed assembly,and self-assembly are instrumental in creating biomimetic scaffolds,tissues,organoids,medical devices,and biohybrid systems.The field of biofabrication in the United Kingdom and Ireland is emerging as a pivotal force in bioscience and healthcare,propelled by cutting-edge research and development.Concentrating on the production of biologically functional products for use in drug delivery,in vitro models,and tissue engineering,research institutions across these regions are dedicated to innovating healthcare solutions that adhere to ethical standards while prioritising sustainability,affordability,and healthcare system benefits.展开更多
Mutations in the oncogene NRAS that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase(MAPK)and phosphoinos...Mutations in the oncogene NRAS that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase(MAPK)and phosphoinositide 3-kinase(PI3K)signalling pathways[1].These mutations occur in approximately 20%of melanomas and very rarely coexist with BRAF V600 mutations.NRASmutant melanoma is associated with poor survival[2]and represents an unmet clinical need,with no effective therapies available following immunotherapy failure.Identification of contextual essential genes that exert stronger fitness effects on NRAS-mutant melanoma cells presents an opportunity for the discovery of targeted therapies.In this study,we employed CRISPR-Cas9-mediated whole-genome dropout screens to identify genetic dependencies in NRAS-mutant melanoma.Typically,melanoma cell lines are cultured under ambient(∼20%)O_(2) conditions,despite O_(2 )concentrations of<8%at the epidermaldermal junction where melanocytes reside,resulting in adaptations in gene and protein expression[3].展开更多
The intestinal epithelium undergoes rapid renewal,with the entire epithelial layer replaced within five days.Intestinal stem cells(ISCs),located in the intestinal crypts,generate all differentiated cell types necessar...The intestinal epithelium undergoes rapid renewal,with the entire epithelial layer replaced within five days.Intestinal stem cells(ISCs),located in the intestinal crypts,generate all differentiated cell types necessary for intestinal function.Key signalling pathways involved in stem cell maintenance include Wnt,Notch,Hedgehog,and BMP.Wnt signalling,primarily driven by crypt cells,creates a signalling gradient to maintain homeostasis[1].However,nuclearβ-catenin,the key regulator of Wnt signalling,correlates positively with tumorigenesis.展开更多
Peptide-and protein-based therapeutics offer realized and potential benefits to health,due to their potent bioactivity,high specificity,and favorable safety characteristics.However,their widespread clinical applicatio...Peptide-and protein-based therapeutics offer realized and potential benefits to health,due to their potent bioactivity,high specificity,and favorable safety characteristics.However,their widespread clinical application is constrained by inherent limitations,including rapid enzymatic degradation,poor membrane permeability,and a reliance on parenteral administration,which reduces patient adherence.To overcome these challenges,extensive research has explored non-invasive delivery strategies,including topical,transdermal,and oral formulations.Despite promising advances in these delivery strategies,they are yet to overcome substantial biological and physicochemical barriers in peptide and protein therapeutics,such as enzymatic degradation in the gastrointestinal tract,limited epithelial transport,and inherently low systemic bioavailability.This review provides a comprehensive and up-to-date analysis of the structural and physiological barriers influencing peptide and protein bioavailability and therapeutic efficacy.It critically examines key challenges associated with various administration routes,including topical,transdermal,oral(including delivery targeting the brain),and others.Furthermore,it explores innovative strategies to enhance peptide and protein stability and bioavailability,including chemical modifications,enzyme inhibitors,penetration enhancers,physical delivery technologies,and advanced nanoparticulate formulations.Additionally,emerging trends in formulation optimization,regulatory considerations,and translational pathways for clinical implementation are discussed.By addressing these critical challenges and highlighting recent advances,this review serves as a roadmap for the development of next-generation peptide and protein therapeutics with improved stability and efficacy,and enhanced patient adherence,which is needed to fully realize the true potential of this class of therapeutics.展开更多
Proanthocyanidins(PAs)are natural flavan-3-ol polymers that contribute protection to plants under biotic and abiotic stress,benefits to human health,and bitterness and astringency to food products.They are also potent...Proanthocyanidins(PAs)are natural flavan-3-ol polymers that contribute protection to plants under biotic and abiotic stress,benefits to human health,and bitterness and astringency to food products.They are also potential targets for carbon sequestration for climate mitigation.In recent years,from model species to commercial crops,research has moved closer to elucidating the flux control and channeling,subunit biosynthesis and polymerization,transport mechanisms,and regulatory networks involved in plant PA metabolism.This review extends the conventional understanding with recent findings that provide new insights to address lingering questions and focus strategies for manipulating PA traits in plants.展开更多
Human growth hormone(GH)is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has pleiotropic effects across multiple physiological systems.GH is also expressed in extrapituitary...Human growth hormone(GH)is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has pleiotropic effects across multiple physiological systems.GH is also expressed in extrapituitary tissues and has localized autocrine/paracrine effects at these sites.In adults,hypersecretion of GH causes acromegaly,and strategies that block the release of GH or that inhibit GH receptor(GHR)activation are the primary forms of medical therapy for this disease.Overproduction of GH has also been linked to cancer and the microvascular complications that are associated with diabetes.However,studies to investigate the therapeutic potential of GHR antagonism in these diseases have been limited,most likely due to difficulty in accessing therapeutic tools to study the pharmacology of the receptor in vivo.This review will discuss current and emerging strategies for antagonizing GH function and the potential disease indications.展开更多
Cohesin is a multiprotein complex that not only is essential for cell division but also has key roles in genome organization that underpin its gene regulatory function.Recurrent mutations of genes encoding cohesin sub...Cohesin is a multiprotein complex that not only is essential for cell division but also has key roles in genome organization that underpin its gene regulatory function.Recurrent mutations of genes encoding cohesin subunits occur in myeloid malignancies at 10%–12%(Kon et al.,2013),and the frequency of cohesin mutation in Down syndrome-associated megakaryoblastic leukaemia is even higher(~50%)(Yoshida et al.,2013).Cohesin insufficiency reinforces stem cell programmes and impairs differentiation in haematopoietic stem cells(Mazumdar et al.,2015;Mullenders et al.,2015;Viny et al.,2015).The STAG2 subunit of cohesin is the most frequently mutated in myeloid malignancies(Kon et al.,2013).In contrast to other cohesin subunits,complete loss of STAG2 is tolerated due to partial compensation by STAG1.STAG2 and STAG1 have redundant roles in cell division(Benedetti et al.,2017;van der Lelij et al.,2017).However,cohesin-STAG1 and cohesin-STAG2 have non-redundant roles in facilitating 3D genome organization to delineate tissue-specific gene expression(Kojic et al.,2018).展开更多
The immune system protects organisms against endogenous and exogenous harm and plays a key role in tissue development,repair and regeneration.Traditional immunomodulatory biologics exhibit limitations including degrad...The immune system protects organisms against endogenous and exogenous harm and plays a key role in tissue development,repair and regeneration.Traditional immunomodulatory biologics exhibit limitations including degradation by enzymes,short half-life and lack of targeting ability.Encapsulating or binding these biologics within biomaterials is an effective way to address these problems.Hydrogels are promising immunomodulatory materials because of their prominent biocompatibility,tuneability and versatility.However,to take advantage of these opportunities and optimize material performance,it is important to more specifically elucidate,and leverage on,how hydrogels affect and control the immune response.Here,we summarize how key physical and chemical properties of hydrogels affect the immune response.We first provide an overview of underlying steps of the host immune response upon exposure to biomaterials.Then,we discuss recent advances in immunomodulatory strategies where hydrogels play a key role through(i)physical properties including dimensionality,stiffness,porosity and topography;(ii)chemical properties including wettability,electric property and molecular presentation;and(iii)the delivery of bioactive molecules via chemical or physical cues.Thus,this review aims to build a conceptual and practical toolkit for the design of immune-instructive hydrogels capable of modulating the host immune response.展开更多
基金state assignment 0671-2020-0058 of the Ministry of Education and Science of Russian FederationIIS and GAM were supported by the Russian Foundation for Basic Research grant 18-54-45023 Ind_aKazan Federal University Strategic Academic Leadership Program(to IIS).
文摘The intrinsic ability of peripheral nerves to regenerate after injury is extremely limited,especially in case of severe injury.This often leads to poor motor function and permanent disability.Existing approaches for the treatment of injured nerves do not provide appropriate conditions to support survival and growth of nerve cells.This drawback can be compensated by the use of gene therapy and cell therapy-based drugs that locally provide an increase in the key regulators of nerve growth,including neurotrophic factors and extracellular matrix proteins.Each growth factor plays its own specific angiotrophic or neurotrophic role.Currently,growth factors are widely studied as accelerators of nerve regeneration.Particularly noteworthy is synergy between various growth factors,that is essential for both angiogenesis and neurogenesis.Fibroblast growth factor 2 and vascular endothelial growth factor are widely known for their proangiogenic effects.At the same time,fibroblast growth factor 2 and vascular endothelial growth factor stimulate neural cell growth and play an important role in neurodegenerative diseases of the peripheral nervous system.Taken together,their neurotrophic and angiogenic properties have positive effect on the regeneration process.In this review we provide an in-depth overview of the role of fibroblast growth factor 2 and vascular endothelial growth factor in the regeneration of peripheral nerves,thus demonstrating their neurotherapeutic efficacy in improving neuron survival in the peripheral nervous system.
文摘Knee osteoarthritis is a chronic, indolent disease that will affect an ever increasing number of patients, especially the elderly and the obese. It is characterized by degeneration of the cartilage substance inside the knee which leads to pain, stiffness and tenderness. By some estimations in 2030, only in the United States, this medical condition will burden 67 million people. While conventional treatments like physiotherapy or drugs offer temporary relief of clinical symptoms, restoration of normal cartilage function has been difficult to achieve. Moreover, in severe cases of knee osteoarthritis total knee replacement may be required. Total knee replacements come together with high effort and costs and are not always successful. The aim of this review is to outline the latest advances in stem cell therapy for knee osteoarthritis as well as highlight some of the advantages of stem cell therapy over traditional approaches aimed at restoration of cartilage function in the knee. In addition to the latest advances in the field, challenges associated with stem cell therapy regarding knee cartilage regeneration and chondrogenesis in vitro and in vivo are also outlined and analyzed. Furthermore, based on their critical assessment of the present academic literature the authors of this review share their vision about the future of stem cell applications in the treatment of knee osteoarthritis.
基金supported by the Strategic Research Scholarship grant from Central Queensland University (CQU)in part supported by CQU Health CRNsupported by a Future Leader Fellowship (ID 100029) from the National Heart Foundation of Australia
文摘Background: Physical activity(PA) and diet are 2 lifestyle factors that affect cardiometabolic risk. However, data on how a high-fat highcarbohydrate(HFHC) diet influences the effect of different intensities of PA on cardiometabolic health and cardiovascular function in a controlled setting are yet to be fully established. This study investigated the effect of sedentary behavior, light-intensity training(LIT), and high-intensity interval training(HIIT) on cardiometabolic markers and vascular and cardiac function in HFHC-fed adult rats.Methods: Twelve-week-old Wistar rats were randomly allocated to 4 groups(12 rats/group): control(CTL), sedentary(SED), LIT, and HIIT.Biometric indices, glucose and lipid control, inflammatory and oxidative stress markers, vascular reactivity, and cardiac electrophysiology of the experimental groups were examined after 12 weeks of HFHC-diet feeding and PA interventions.Results: The SED group had slower cardiac conduction(p = 0.0426) and greater thoracic aortic contractile responses(p < 0.05) compared with the CTL group. The LIT group showed improved cardiac conduction compared with the SED group(p = 0.0003), and the HIIT group showed decreased mesenteric artery contractile responses compared with all other groups and improved endothelium-dependent mesenteric artery relaxation compared with the LIT group(both p < 0.05). The LIT and HIIT groups had lower visceral(p = 0.0057 for LIT, p = 0.0120 for HIIT)and epididymal fat(p < 0.0001 for LIT, p = 0.0002 for HIIT) compared with the CTL group.Conclusion: LIT induced positive adaptations on fat accumulation and cardiac conduction, and HIIT induced a positive effect on fat accumulation,mesenteric artery contraction, and endothelium-dependent relaxation. No other differences were observed between groups. These findings suggest that few positive health effects can be achieved through LIT and HIIT when consuming a chronic and sustained HFHC diet.
基金Supported by University of Auckland Faculty Research Development Fund
文摘AIM: To assess the effects of ischemic preconditioning(IPC, 10-min ischemia/10-min reperfusion) on steatotic liver mitochondrial function after normothermic ischemia-reperfusion injury(IRI).METHODS: Sixty male Sprague-Dawley rats were fed8-wk with either control chow or high-fat/high-sucrose diet inducing > 60% mixed steatosis. Three groups(n = 10/group) for each dietary state were tested:(1) the IRI group underwent 60 min partial hepatic ischemia and 4 h reperfusion;(2) the IPC group underwent IPC prior to same standard IRI; and(3) sham underwent t h e s a m e s u r g e r y w i t h o u t I R I o r I P C. H e p a t i c mitochondrial function was analyzed by oxygraphs. Mitochondrial Complex-Ⅰ, Complex-Ⅱ enzyme activity, serum alanine aminotransferase(ALT), and histological injury were measured.RESULTS: Steatotic-IRI livers had a greater increase in ALT(2476 ± 166 vs 1457 ± 103 IU/L, P < 0.01) and histological injury following IRI compared to the lean liver group. Steatotic-IRI demonstrated lower Complex-Ⅰ?activity at baseline [78.4 ± 2.5 vs 116.4 ± 6.0 nmol/(min.mg protein), P < 0.001] and following IRI [28.0 ± 6.2 vs 104.3 ± 12.6 nmol/(min.mg protein), P < 0.001]. Steatotic-IRI also demonstrated impaired Complex-Ⅰ?function post-IRI compared to the lean liver IRI group. Complex-Ⅱ activity was unaffected by hepatic steatosis or IRI. Lean liver mitochondrial function was unchanged following IRI. IPC normalized ALT and histological injury in steatotic livers but had no effect on overall steatotic liver mitochondrial function or individual mitochondrial complex enzyme activities. CONCLUSION: Warm IRI impairs steatotic liver Complex-Ⅰ?activity and function. The protective effects of IPC in steatotic livers may not be mediated through mitochondria.
基金Supported by the Ministry of Higher Education Malaysia for the Fundamental Research Grant Scheme,No. FRGS/1/2021/SKK06/USM/02/7
文摘BACKGROUND The development of new vasculatures(angiogenesis)is indispensable in supplying oxygen and nutrients to fuel tumor growth.Epigenetic dysregulation in the tumor vasculature is critical to colorectal cancer(CRC)progression.Sirtuin(SIRT)enzymes are highly expressed in blood vessels.BZD9L1 benzimidazole analogue is a SIRT 1 and 2 inhibitor with reported anticancer activities in CRC.However,its role has yet to be explored in CRC tumor angiogenesis.AIM To investigate the anti-angiogenic potential of BZD9L1 on endothelial cells(EC)in vitro,ex vivo and in HCT116 CRC xenograft in vivo models.METHODS EA.hy926 EC were treated with half inhibitory concentration(IC50)(2.5μM),IC50(5.0μM),and double IC50(10.0μM)of BZD9L1 and assessed for cell proliferation,adhesion and SIRT 1 and 2 protein expression.Next,2.5μM and 5.0μM of BZD9L1 were employed in downstream in vitro assays,including cell cycle,cell death and sprouting in EC.The effect of BZD9L1 on cell adhesion molecules and SIRT 1 and 2 were assessed via real-time quantitative polymerase chain reaction(qPCR).The growth factors secreted by EC post-treatment were evaluated using the Quantibody Human Angiogenesis Array.Indirect co-culture with HCT116 CRC cells was performed to investigate the impact of growth factors modulated by BZD9L1-treated EC on CRC.The effect of BZD9L1 on sprouting impediment and vessel regression was determined using mouse choroids.HCT116 cells were also injected subcutaneously into nude mice and analyzed for the outcome of BZD9L1 on tumor necrosis,Ki67 protein expression indicative of proliferation,cluster of differentiation 31(CD31)and CD34 EC markers,and SIRT 1 and 2 genes via hematoxylin and eosin,immunohistochemistry and qPCR,respectively.RESULTS BZD9L1 impeded EC proliferation,adhesion,and spheroid sprouting through the downregulation of intercellular adhesion molecule 1,vascular endothelial cadherin,integrin-alpha V,SIRT1 and SIRT2 genes.The compound also arrested the cells at G1 phase and induced apoptosis in the EC.In mouse choroids,BZD9L1 inhibited sprouting and regressed sprouting vessels compared to the negative control.Compared to the negative control,the compound also reduced the protein levels of angiogenin,basic fibroblast growth factor,platelet-derived growth factor and placental growth factor,which then inhibited HCT116 CRC spheroid invasion in co-culture.In addition,a significant reduction in CRC tumor growth was noted alongside the downregulation of human SIRT1(hSIRT1),hSIRT2,CD31,and CD34 EC markers and murine SIRT2 gene,while the murine SIRT1 gene remained unaffected,compared to vehicle control.Histology analyses revealed that BZD9L1 at low(50 mg/kg)and high(250 mg/kg)doses reduced Ki-67 protein expression,while BZD9L1 at the high dose diminished tumor necrosis compared to vehicle control.CONCLUSION These results highlighted the anti-angiogenic potential of BZD9L1 to reduce CRC tumor progression.Furthermore,together with previous anticancer findings,this study provides valuable insights into the potential of BZD9L1 to co-target CRC tumor vasculatures and cancer cells via SIRT1 and/or SIRT2 down-regulation to improve the therapeutic outcome.
基金Supported by Research Foundation-Flanders(FWO)the KU Leuven Molecular Small Animal Imaging Center Mo SAIC,No.KUL EF/05/08+4 种基金the center of excellence in vivo molecular imaging research(IMIR)KU Leuven projects,No.IOFHB/08/009 and No.IOF-HB/12/018the European Union,AsiaLink Cf P 2006-Europe Aid/123738/C/ACT/Multi-Proposal,No128-498/111National Natural Science Foundation of China,No.81071828Jiangsu Province Natural Science Foundation,No.BK2010594
文摘AIM: To explore the feasibility of using hypericin as an optical imaging probe with affinity for cholesterol for differential fluorescent detection of human gallstones.METHODS: Cholesterol, mixed and pigment stones from cholecystectomy patients were incubated with hypericin or solvent. After 72 h, the stones were analysed for fluorescence(365 nm) and treated with 2-propanol/dimethyl sulfoxide for high performance liquid chromatography(HPLC) analysis. Rats with virtual gallbladder containing human cholesterol, mixed or pigment gallstones(VGHG) received 5 mg/kg hypericin or solvent and VGHG rats with cholesterol stones were given different hypericin doses(5-15 mg/kg). Twelve hours later, the stones were analysed at 365 nm. Biliary excretion and metabolites of hypericin were assessed in common bile duct(CBD) cannulated rats for 9 h using fluorospectrometry, HPLC and matrixassisted laser desorption/ionization-time-of-flight mass spectrometry(MALDI-TOF MS).RESULTS: Homogeneous high fluorescence was seen on cholesterol stones either pre-incubated with hypericin or extracted from VGHG rats receiving hypericin. Mixed stones showed a dotted fluorescent pattern, whereas pigment and solvent-treated ones lacked fluorescence. HPLC showed 7.68, 6.65 and 0.08 × 10^(-3) M of cholesterol in extracts from cholesterol, mixed, and pigment gallstones, respectively. Hypericin accounted for 2.0, 0.5 and 0.2 × 10-6 M in that order. On cholesterol stones from VGHG rats receiving different hypericin doses, a positive correlation was observed between dose and fluorescence. In the bile from CBD-cannulated rats, fluorescence represented 20% of the injected dose with two peaks in 9 h. HPLC analysis revealed that hypericin conjugates reached 60% of the peak area. By MALDI-TOF MS, hypericinglucuronide was detected. CONCLUSION: This study proves the potential use of hypericin for differential fluorescent detection of human gallstones regarding their chemical composition.
文摘This study investigates controlled micro/nano manipulation of polydimethylsiloxane (PDMS) using Atomic Force Microscopy (AFM). Lithographic results revealed stick-slip phenomena along the slow scan direction. Varying the normal loading force, scan size, scan number and contact conditions allowed the control of certain lithographic outcomes e.g., channel spacing. The PDMS surface experienced significant in-plane deformation in response to the tip-induced lateral force. This displacement increased with increasing loading force, creating greater spacing between channels in the slow scan direction. Simultaneous generation of a lateral displacement in the fast scan direction caused a decrease in channel length with increasing loading force due to an increase in static friction with normal force, resulting in a greater surface relaxation, and shorter track length of dynamic friction. By controlling both the loading force and the number of scans over an area, frictional tiers were produced.
文摘The antimalarial drug-resistance conundrum which threatens to reverse the great strides taken to curb the malaria scourge warrants an urgent need to find novel chemical scaffolds to serve as templates for the development of new antimalarial drugs.Plants represent a viable alternative source for the discovery of unique potential antiplasmodial chemical scaffolds.To expedite the discovery of new antiplasmodial compounds from plants,the aim of this study was to use phylogenetic analysis to identify higher plant orders and families that can be rationally prioritised for antimalarial drug discovery.We queried the PubMed database for publications documenting antiplasmodial properties of natural compounds isolated from higher plants.Thereafter,we manually collated compounds reported along with plant species of origin and relevant pharmacological data.We systematically assigned antiplasmodial-associated plant species into recognised families and orders,and then computed the resistance index,selectivity index and physicochemical properties of the compounds from each taxonomic group.Correlating the generated phylogenetic trees and the biological data of each clade allowed for the identification of 3‘hot’plant orders and families.The top 3 ranked plant orders were the(i)Caryophyllales,(ii)Buxales,and(iii)Chloranthales.The top 3 ranked plant families were the(i)Ancistrocladaceae,(ii)Simaroubaceae,and(iii)Buxaceae.The highly active natural compounds(IC_(50)≤1μM)isolated from these plant orders and families are structurally unique to the‘legacy’antimalarial drugs.Our study was able to identify the most prolific taxa at order and family rank that we propose be prioritised in the search for potent,safe and drug-like antimalarial molecules.
文摘The emergence and spread of drug-recalcitrant Plasmodium falciparum parasites threaten to reverse the gains made in the fight against malaria.Urgent measures need to be taken to curb this impending challenge.The higher plant-derived sesquiterpene,quinoline alkaloids,and naphthoquinone natural product classes of compounds have previously served as phenomenal chemical scaffolds from which integral antimalarial drugs were developed.Historical successes serve as an inspiration for the continued investigation of plant-derived natural products compounds in search of novel molecular templates from which new antimalarial drugs could be developed.The aim of this study was to identify potential chemical scaffolds for malaria drug discovery following analysis of historical data on phytochemicals screened in vitro against P.falciparum.To identify these novel scaffolds,we queried an in-house manually curated database of plant-derived natural product compounds and their in vitro biological data.Natural products were assigned to different structural classes using NPClassifier.To identify the most promising chemical scaffolds,we then correlated natural compound class with bioactivity and other data,namely(i)potency,(ii)resistance index,(iii)selectivity index and(iv)physicochemical properties.We used an unbiased scoring system to rank the different natural product classes based on the assessment of their bioactivity data.From this analysis we identified the top-ranked natural product pathway as the alkaloids.The top three ranked super classes identified were(i)pseudoalkaloids,(ii)naphthalenes and(iii)tyrosine alkaloids and the top five ranked classes(i)quassinoids(of super class triterpenoids),(ii)steroidal alkaloids(of super class pseudoalkaloids)(iii)cycloeudesmane sesquiterpenoids(of super class triterpenoids)(iv)isoquinoline alkaloids(of super class tyrosine alkaloids)and(v)naphthoquinones(of super class naphthalenes).Launched chemical space of these identified classes of compounds was,by and large,distinct from that of‘legacy’antimalarial drugs.Our study was able to identify chemical scaffolds with acceptable biological properties that are structurally different from current and previously used antimalarial drugs.These molecules have the potential to be developed into new antimalarial drugs.
基金Supported by the NKEA Research Grant Scheme (NRGS) by the Ministry of Agriculture MalaysiaNo. 304/CIPPM/650736/k123
文摘BACKGROUND Pancreatic cancer is the most aggressive cancer type.Gemcitabine is the first line chemo-drug used for pancreatic cancer but exerts a broad spectrum of organ toxicities and adverse effects in patients.AIM To evaluate the anti-tumour activity and toxicological effects of Orthosiphon stamineus extract formulation(ID:C5EOSEW5050ESA trademarked as Nuvastatic^(TM)),and gemcitabine combination on pancreatic xenograft model.METHODS Mice were randomly divided into six groups of 6 mice each(n=6)and given different treatments for 28 d.The study design consisted of a 2 x 3 factorial treatment structure,with gemcitabine(yes/no)by oral(at 1200 and 400 mg/kg per day).Human pancreatic cancer cells were injected subcutaneously into the flanks of athymic nude mice.C5EOSEW5050ESA(200 or 400 mg/kg per day)was administered orally,while gemcitabine(10 mg/kg per 3 d)was given intraperitoneally either alone or in combination treatment.Histopathological analyses of vital organs,tumour tissues,and incidence of lethality were analysed.Analyses of tumour necrosis and proliferation were determined by haematoxylin-eosin staining and immunohistochemistry for Ki-67,respectively.RESULTS No signs of toxicity or damage to vital organs were observed in all treatment groups compared to the untreated group.C5EOSEW5050ESA at 200 mg/kg and gemcitabine combination had no additive antitumor effects compared to a single treatment.Remarkably,a comparably greater response in a reduction in tumour growth,Ki-67 protein expression,and necrosis was demonstrated by 400 mg/kg of C5EOSEW5050ESA and gemcitabine combination than that of the individual agents.CONCLUSION These results highlighted the synergistic activity of C5EOSEW5050ESA with gemcitabine to reduce pancreatic tumour growth in mice compared to a single treatment.Thus,this study provides valuable insights into using C5EOSEW5050ESA as a complementary treatment with gemcitabine for pancreatic cancer.
文摘Objective: To identify the differential gene expression profiles between the normal and aspermia human testes utilizing cDNA microarray. Methods: cDNA probes were prepared by labeling mRNA of aspermia testes tissues with Cy5-dUTP and mRNA of normal testes tissues with Cy3-dUTP respectively through reverse transcription. The mixed cDNA probes were then hybridized with 4096 cDNA arrays (4096 unique human cDNA sequences), and the fluorescent signals were scanned by ScanArray 3000 scanner (General Scanning, Inc.). The values of Cy5-dUTP and Cy3-dUTP on each spot were analyzed and calculated by ImaGene 3.0 software (BioDiscovery, Inc.). Differentially expressed genes were screened according to the criterion that the absolute value of natural logarithm of the ratio of Cy5-dUTP to Cy3-dUTP was greater-than 2.0 or less-than 0.5. A randomly chosen gene RAP1A was studied by in situ hybridization to evaluate the accuracy of the results. Results: 623 differential expressed genes related to aspermia were found. There were 303 up-expressed genes and 320 down-expressed genes. A distinct up-expressed gene RAP1A was confirmed by in situ hybridization. Conclusions: Screening the differential gene expression profiles between the normal and aspermia human testis by cDNA microarray can be used in the study of aspermia-related genes and the further research due to its properties, RAP1A may play some roles in the development and progression of aspermia.
基金supported by the W.D.Armstrong Trust.YYSH is funded by the European Research Council(ERC-St G,758865)the UK Research and Innovations(UKRI)Biotechnology and Biological Sciences Research Council(BB/W014564/1)+9 种基金funding from a UKRI Future Leaders Fellowship(MR/V024965/1)supported by the BBSRC London Interdisciplinary Doctoral(LIDo)Programmethe funding support of EPSRC(EP/W004860/1,EP/X033686/1)and MRC(MR/V029827/1,MR/W030381/1)the European Research Council(Pro Li Cell,772462)for supportthe NIHR Nottingham Biomedical Research Centre,University of Nottingham,Nottingham,UK and the AO Foundation,AO CMF(AOCMF-21-04S)funding support from grant MR/W01470X/1the EPSRC(EP/W018977/1)for financial supportfunding from the EPSRC(EP/T020792/1)funding from Biomat DB+(Horizon Europe 101058779)funding received from Science Foundation Ireland(SFI)—Grant No.13/RC/2073_P2。
文摘As we navigate the transition from the Fourth to the Fifth Industrial Revolution,the emerging fields of biomanufacturing and biofabrication are transforming life sciences and healthcare.These sectors are benefiting from a synergy of synthetic and engineering biology,sustainable manufacturing,and integrated design principles.Advanced techniques such as 3D bioprinting,tissue engineering,directed assembly,and self-assembly are instrumental in creating biomimetic scaffolds,tissues,organoids,medical devices,and biohybrid systems.The field of biofabrication in the United Kingdom and Ireland is emerging as a pivotal force in bioscience and healthcare,propelled by cutting-edge research and development.Concentrating on the production of biologically functional products for use in drug delivery,in vitro models,and tissue engineering,research institutions across these regions are dedicated to innovating healthcare solutions that adhere to ethical standards while prioritising sustainability,affordability,and healthcare system benefits.
基金funded by the Cancer Society of New Zealand(18.14)Cancer Research Trust New Zealand(2005-PGS)University of Auckland Genomics into Medicine Strategic Research Initiatives Fund and Maurice Wilkins Centre for Molecular Biodiscovery Flexible Research Programme.
文摘Mutations in the oncogene NRAS that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase(MAPK)and phosphoinositide 3-kinase(PI3K)signalling pathways[1].These mutations occur in approximately 20%of melanomas and very rarely coexist with BRAF V600 mutations.NRASmutant melanoma is associated with poor survival[2]and represents an unmet clinical need,with no effective therapies available following immunotherapy failure.Identification of contextual essential genes that exert stronger fitness effects on NRAS-mutant melanoma cells presents an opportunity for the discovery of targeted therapies.In this study,we employed CRISPR-Cas9-mediated whole-genome dropout screens to identify genetic dependencies in NRAS-mutant melanoma.Typically,melanoma cell lines are cultured under ambient(∼20%)O_(2) conditions,despite O_(2 )concentrations of<8%at the epidermaldermal junction where melanocytes reside,resulting in adaptations in gene and protein expression[3].
基金supported by the Medical Research Council(MRC)(grant number G0700763)by the University of Nottingham,Nottingham,UK.
文摘The intestinal epithelium undergoes rapid renewal,with the entire epithelial layer replaced within five days.Intestinal stem cells(ISCs),located in the intestinal crypts,generate all differentiated cell types necessary for intestinal function.Key signalling pathways involved in stem cell maintenance include Wnt,Notch,Hedgehog,and BMP.Wnt signalling,primarily driven by crypt cells,creates a signalling gradient to maintain homeostasis[1].However,nuclearβ-catenin,the key regulator of Wnt signalling,correlates positively with tumorigenesis.
文摘Peptide-and protein-based therapeutics offer realized and potential benefits to health,due to their potent bioactivity,high specificity,and favorable safety characteristics.However,their widespread clinical application is constrained by inherent limitations,including rapid enzymatic degradation,poor membrane permeability,and a reliance on parenteral administration,which reduces patient adherence.To overcome these challenges,extensive research has explored non-invasive delivery strategies,including topical,transdermal,and oral formulations.Despite promising advances in these delivery strategies,they are yet to overcome substantial biological and physicochemical barriers in peptide and protein therapeutics,such as enzymatic degradation in the gastrointestinal tract,limited epithelial transport,and inherently low systemic bioavailability.This review provides a comprehensive and up-to-date analysis of the structural and physiological barriers influencing peptide and protein bioavailability and therapeutic efficacy.It critically examines key challenges associated with various administration routes,including topical,transdermal,oral(including delivery targeting the brain),and others.Furthermore,it explores innovative strategies to enhance peptide and protein stability and bioavailability,including chemical modifications,enzyme inhibitors,penetration enhancers,physical delivery technologies,and advanced nanoparticulate formulations.Additionally,emerging trends in formulation optimization,regulatory considerations,and translational pathways for clinical implementation are discussed.By addressing these critical challenges and highlighting recent advances,this review serves as a roadmap for the development of next-generation peptide and protein therapeutics with improved stability and efficacy,and enhanced patient adherence,which is needed to fully realize the true potential of this class of therapeutics.
基金supported by the Program of Introducing Talents of Discipline to Universities(111 Project,B13007)the National Natural Science Foundation of China(32030010)the China Postdoctoral Science Foundation(2020M680404 to K.Y.).
文摘Proanthocyanidins(PAs)are natural flavan-3-ol polymers that contribute protection to plants under biotic and abiotic stress,benefits to human health,and bitterness and astringency to food products.They are also potential targets for carbon sequestration for climate mitigation.In recent years,from model species to commercial crops,research has moved closer to elucidating the flux control and channeling,subunit biosynthesis and polymerization,transport mechanisms,and regulatory networks involved in plant PA metabolism.This review extends the conventional understanding with recent findings that provide new insights to address lingering questions and focus strategies for manipulating PA traits in plants.
文摘Human growth hormone(GH)is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has pleiotropic effects across multiple physiological systems.GH is also expressed in extrapituitary tissues and has localized autocrine/paracrine effects at these sites.In adults,hypersecretion of GH causes acromegaly,and strategies that block the release of GH or that inhibit GH receptor(GHR)activation are the primary forms of medical therapy for this disease.Overproduction of GH has also been linked to cancer and the microvascular complications that are associated with diabetes.However,studies to investigate the therapeutic potential of GHR antagonism in these diseases have been limited,most likely due to difficulty in accessing therapeutic tools to study the pharmacology of the receptor in vivo.This review will discuss current and emerging strategies for antagonizing GH function and the potential disease indications.
文摘Cohesin is a multiprotein complex that not only is essential for cell division but also has key roles in genome organization that underpin its gene regulatory function.Recurrent mutations of genes encoding cohesin subunits occur in myeloid malignancies at 10%–12%(Kon et al.,2013),and the frequency of cohesin mutation in Down syndrome-associated megakaryoblastic leukaemia is even higher(~50%)(Yoshida et al.,2013).Cohesin insufficiency reinforces stem cell programmes and impairs differentiation in haematopoietic stem cells(Mazumdar et al.,2015;Mullenders et al.,2015;Viny et al.,2015).The STAG2 subunit of cohesin is the most frequently mutated in myeloid malignancies(Kon et al.,2013).In contrast to other cohesin subunits,complete loss of STAG2 is tolerated due to partial compensation by STAG1.STAG2 and STAG1 have redundant roles in cell division(Benedetti et al.,2017;van der Lelij et al.,2017).However,cohesin-STAG1 and cohesin-STAG2 have non-redundant roles in facilitating 3D genome organization to delineate tissue-specific gene expression(Kojic et al.,2018).
基金supported by the ERC Proof-of-Concept Grant(MINGRAFT),the AO Foundation Grant(AOCMF-17-19M)the Medical Research Council(UK Regenerative Medicine Platform Acellular/Smart Materials-3D Architecture,MR/R015651/1)+2 种基金the National Natural Science Foundation of China(81870741,82001023),China Postdoctoral Science Foundation(2019M661177)Natural Science Foundation of Liaoning Province(2020-MS-154)China Scholarship Council([2020]50).
文摘The immune system protects organisms against endogenous and exogenous harm and plays a key role in tissue development,repair and regeneration.Traditional immunomodulatory biologics exhibit limitations including degradation by enzymes,short half-life and lack of targeting ability.Encapsulating or binding these biologics within biomaterials is an effective way to address these problems.Hydrogels are promising immunomodulatory materials because of their prominent biocompatibility,tuneability and versatility.However,to take advantage of these opportunities and optimize material performance,it is important to more specifically elucidate,and leverage on,how hydrogels affect and control the immune response.Here,we summarize how key physical and chemical properties of hydrogels affect the immune response.We first provide an overview of underlying steps of the host immune response upon exposure to biomaterials.Then,we discuss recent advances in immunomodulatory strategies where hydrogels play a key role through(i)physical properties including dimensionality,stiffness,porosity and topography;(ii)chemical properties including wettability,electric property and molecular presentation;and(iii)the delivery of bioactive molecules via chemical or physical cues.Thus,this review aims to build a conceptual and practical toolkit for the design of immune-instructive hydrogels capable of modulating the host immune response.
