Parkinson's disease(PD) has a complex and multifactorial pathophysiology. Various studies, conducted both in pre-clinical models and PD patients, have reported a link between the disruption of calcium(Ca^(2+)) hom...Parkinson's disease(PD) has a complex and multifactorial pathophysiology. Various studies, conducted both in pre-clinical models and PD patients, have reported a link between the disruption of calcium(Ca^(2+)) homeostasis and the subsequent development of PD. Ca^(2+) regulation is crucial for neuronal survival, differentiation,exocytosis at synapses,gene transcription,and proliferation.展开更多
Transplantation of olfactory ensheathing cells,the glia of the primary olfactory nervous system,has been trialed for spinal cord injury repair with promising but variable outcomes in animals and humans.Olfactory enshe...Transplantation of olfactory ensheathing cells,the glia of the primary olfactory nervous system,has been trialed for spinal cord injury repair with promising but variable outcomes in animals and humans.Olfactory ensheathing cells can be harvested either from the lamina propria beneath the neuroepithelium in the nasal cavity,or from the olfactory bulb in the brain.As these areas contain several other cell types,isolating and purifying olfactory ensheathing cells is a critical part of the process.It is largely unknown how contaminating cells such as fibroblasts,other glial cell types and supporting cells affect olfactory ensheathing cell function post-transplantation;these cells may also cause unwanted side-effects.It is also,however,possible that the presence of some of the contaminant cells can improve outcomes.Here,we reviewed the last decade of olfactory ensheathing cell transplantation studies in rodents,with a focus on olfactory ensheathing cell purity.We analyzed how purification methods and resultant cell purity differed between olfactory mucosa-and olfactory bulb-derived cell preparations.We analyzed how the studies reported on olfactory ensheathing cell purity and which criteria were used to define cells as olfactory ensheathing cells.Finally,we analyzed the correlation between cell purity and transplantation outcomes.We found that olfactory bulb-derived olfactory ensheathing cell preparations are typically purer than mucosa-derived preparations.We concluded that there is an association between high olfactory ensheathing cell purity and favourable outcomes,but the lack of olfactory ensheathing cell-specific markers severely hampers the field.展开更多
Oral cancer (OC) is the most common form of head and neck cancer. Despite the high incidence and unfavourable patient outcomes, currently, there are no biomarkers for the early detection of OC. This study aims to disc...Oral cancer (OC) is the most common form of head and neck cancer. Despite the high incidence and unfavourable patient outcomes, currently, there are no biomarkers for the early detection of OC. This study aims to discover, develop, and validate a novel saliva-based microRNA signature for early diagnosis and prediction of OC risk in oral potentially malignant disorders (OPMD).The Cancer Genome Atlas (TCGA) miRNA sequencing data and small RNA sequencing data of saliva samples were used to discover differentially expressed miRNAs. Identified miRNAs were validated in saliva samples of OC (n=50), OPMD (n=52), and controls(n=60) using quantitative real-time PCR. Eight differentially expressed miRNAs (miR-7-5p, miR-10b-5p, miR-182-5p, miR-215-5p,miR-431-5p, miR-486-3p, miR-3614-5p, and miR-4707-3p) were identified in the discovery phase and were validated. The efficiency of our eight-miRNA signature to discriminate OC and controls was:area under curve (AUC):0.954, sensitivity:86%, specificity:90%,positive predictive value (PPV):87.8%and negative predictive value (NPV):88.5%whereas between OC and OPMD was:AUC:0.911,sensitivity:90%, specificity:82.7%, PPV:74.2%and NPV:89.6%. We have developed a risk probability score to predict the presence or risk of OC in OPMD patients. We established a salivary miRNA signature that can aid in diagnosing and predicting OC,revolutionising the management of patients with OPMD. Together, our results shed new light on the management of OC by salivary miRNAs to the clinical utility of using miRNAs derived from saliva samples.展开更多
The olfactory system is one of a few areas in the nervous system which is capable of regeneration throughout the life.Olfactory sensory neurons reside in the nasal cavity are continuously replenished with new neurons ...The olfactory system is one of a few areas in the nervous system which is capable of regeneration throughout the life.Olfactory sensory neurons reside in the nasal cavity are continuously replenished with new neurons arising from stem cells.Some factors such as aging,neurodegenerative diseases,head trauma,brain tumor extraction and infection cause olfactory dysfunction which significantly influences physical wellbeing,quality of life,mental health,nutritional status,memory processes,identifying danger and is associated with increased mortality.Therefore,finding a treatment to improve olfactory dysfunction is needed.Recent research efforts in the field have shown some very promising new approaches to treat olfactory dysfunction.This review explores the current studies that have addressed therapeutic approaches to improve olfactory neuron regeneration based on cell transplantation therapy,modulation of physiological olfactory dysfunction and drug treatments.展开更多
Neurogenesis is a persistent and essential feature of the adult mammalian hippocampus.Granular neurons generated from resident pools of stem or progenitor cells provide a mechanism for the formation and consolidation ...Neurogenesis is a persistent and essential feature of the adult mammalian hippocampus.Granular neurons generated from resident pools of stem or progenitor cells provide a mechanism for the formation and consolidation of new memories.Regulation of hippocampal neurogenesis is complex and multifaceted,and numerous signaling pathways converge to modulate cell proliferation,apoptosis,and clearance of cellular debris,as well as synaptic integration of newborn immature neurons.The expression of functional P2X7 receptors in the central nervous system has attracted much interest and the regulatory role of this purinergic receptor during adult neurogenesis has only recently begun to be explored.P2X7 receptors are exceptionally versatile:in their canonical role they act as adenosine triphosphate-gated calcium channels and facilitate calcium-signaling cascades exerting control over the cell via calcium-encoded sensory proteins and transcription factor activation.P2X7 also mediates transmembrane pore formation to regulate cytokine release and facilitate extracellular communication,and when persistently stimulated by high extracellular adenosine triphosphate levels large P2X7 pores form,which induce apoptotic cell death through cytosolic ion dysregulation.Lastly,as a scavenger receptor P2X7 directly facilitates phagocytosis of the cellular debris that arises during neurogenesis,as well as during some disease states.Understanding how P2X7 receptors regulate the physiology of stem and progenitor cells in the adult hippocampus is an important step towards developing useful therapeutic models for regenerative medicine.This review considers the relevant aspects of adult hippocampal neurogenesis and explores how P2X7 receptor activity may influence the molecular physiology of the hippocampus,and neural stem and progenitor cells.展开更多
The olfactory receptor neurons lining the nasal cavity have a remarkable capacity to regenerate throughout life. They are replenished continuously and their axons make new connections within the olfactory bulb. Howeve...The olfactory receptor neurons lining the nasal cavity have a remarkable capacity to regenerate throughout life. They are replenished continuously and their axons make new connections within the olfactory bulb. However, some factors such as head trauma and skull base surgery damage the olfactory nerve which lead to olfactory dysfunction. Losing the sense of smell has considerable effects on quality of life and life-expectancy. Therefore, there is a clear need to find a treatment for olfactory dysfunction. One such potential treatment is growth factor therapy which showed promising results in the spinal cord and brain injuries. The aim of the present study was to investigate whether combined delivery of two growth factors, vascular endothelial growth factor and platelet-derived growth factor treatment can improve the olfactory neurons regeneration in mice. The degeneration of the olfactory neurons was induced by unilateral bulbectomy. The treatment group received 1.5 μg of the combined growth factors intranasally, while the control injured group received saline. Growth factor treatment significantly increased the number of immature neurons at 5 and 7 days post injury and also the number of mature olfactory neurons at 10 and 14 days post bulbectomy. Regenerating axons extended over a larger volume in the operated cavity in the treatment group compared to control group at 14 days post bulbectomy. The growth factor treatment also significantly reduced astrocytic glia scar in the operated cavity. The results indicate that the combined delivery of the growth factors has the potential to improve olfactory dysfunction.展开更多
Therapeutic manipulation of the immune system in cancer has been an extensive area of research in the field of oncoimmunology.Immunosuppression regulates antitumour immune responses.An immunosuppressive enzyme,indolea...Therapeutic manipulation of the immune system in cancer has been an extensive area of research in the field of oncoimmunology.Immunosuppression regulates antitumour immune responses.An immunosuppressive enzyme,indoleamine 2,3-dioxygenase(IDO)mediates tumour immune escape in various malignancies including breast cancer.IDO upregulation in breast cancer cells may lead to the recruitment of regulatory T(T-regs)cells into the tumour microenvironment,thus inhibiting local immune responses and promoting metastasis.Immunosuppression induced by myeloid derived suppressor cells activated in an IDOdependent manner may enhance the possibility of immune evasion in breast cancer.IDO overexpression has independent prognostic significance in a subtype of breast cancer of emerging interest,basal-like breast carcinoma.IDO inhibitors as adjuvant therapeutic agents may have clinical implications in breast cancer.This review proposes future prospects of IDO not only as a therapeutic target but also as a valuable prognostic marker for breast cancer.展开更多
The nerves of the peripheral nervous system are not able to effectively regenerate in cases of severe neural injury.This can result in debilitating consequences,including morbidity and lifelong impairments affecting t...The nerves of the peripheral nervous system are not able to effectively regenerate in cases of severe neural injury.This can result in debilitating consequences,including morbidity and lifelong impairments affecting the quality of the patient’s life.Recent findings in neural tissue engineering have opened promising avenues to apply fibrous tissue-engineered scaffolds to promote tissue regeneration and functional recovery.These scaffolds,known as neural scaffolds,are able to improve neural regeneration by playing two major roles,namely,by being a carrier for transplanted peripheral nervous system cells or biological cues and by providing structural support to direct growing nerve fibers towards the target area.However,successful implementation of scaffold-based therapeutic approaches calls for an appropriate design of the neural scaffold structure that is capable of up-and down-regulation of neuron-scaffold interactions in the extracellular matrix environment.This review discusses the main challenges that need to be addressed to develop and apply fibrous tissue-engineered scaffolds in clinical practice.It describes some promising solutions that,so far,have shown to promote neural cell adhesion and growth and a potential to repair peripheral nervous system injuries.展开更多
Olfactory ensheathing cells(OECs)are crucial players in the continuous regeneration of the olfactory nervous system that occurs through out life and are thought to have unique growth-promoting properties.For this reas...Olfactory ensheathing cells(OECs)are crucial players in the continuous regeneration of the olfactory nervous system that occurs through out life and are thought to have unique growth-promoting properties.For this reason,OEC transplantation has been thoroughly explored for the potential to promote neural repair after both central and peripheral nervous system injuries.Numerous studies have shown that OEC transplantation is safe and can promote recovery after spinal cord injury(SCI),both in animal models and in human clinical trials.To date,a variety of injury types and time-points after injury,as well as different delivery methods,have been tested.Outcomes have been encouraging(in rodent models including,for example,restoration of locomotion,breathing and climbing ability along with induction of axonal sprouting and some axonal regeneration)but highly variable(Barnett and Riddell,2007;Gomez et al.,2018).展开更多
One of the key challenges in neuroscience is that the central nervous system(CNS;the brain and spinal cord), is largely unable to regene rate after injury. One factor contributing to this lack of repair is the accumul...One of the key challenges in neuroscience is that the central nervous system(CNS;the brain and spinal cord), is largely unable to regene rate after injury. One factor contributing to this lack of repair is the accumulation of cellular and myelin debris at the site of injury. The debris is not efficiently phagocytosed and can persist for years after the initial injury, resulting in an inflammatory environment which inhibits axonal regrowth(Lutz and Barres, 2014).展开更多
Intrinsic or acquired resistance to chemotherapy is a major hurdle in the treatment of cancer.One of the key mechanisms of resistance is the overexpression of the drug efflux transporter P-glycoprotein(Pgp).Pgp overex...Intrinsic or acquired resistance to chemotherapy is a major hurdle in the treatment of cancer.One of the key mechanisms of resistance is the overexpression of the drug efflux transporter P-glycoprotein(Pgp).Pgp overexpression renders a large number of mechanistically unrelated chemotherapies ineffective.Targeting Pgp inhibition directly to overcome drug resistance,although conceptually and mechanistically attractive,has not translated to the clinic,in part because Pgp also has a critical protective function in many healthy tissues.It was recently discovered that carbonic anhydrase XII(CA XII),an enzyme associated with pH regulation in cancer,is co-expressed and co-located with Pgp in drug resistant cancer cells.CA XII is also upregulated by hypoxia,which is another microenvironmental factor that contributes to drug resistance.Here,we review findings that demonstrate modulation of CA XII may offer a promising new approach towards overcoming the longstanding hurdle of drug resistance and therapy failure against solid cancers.This review covers the use of CA XII inhibitors,both small molecule and antibody,in combination with chemotherapeutics that are substrates for Pgp.This combination therapy approach restores the efficacy of chemotherapy in resistant cells and offers a potential new therapeutic window to re-examine the targeting of Pgp as a safe,effective,and novel anticancer strategy.展开更多
The toxicity of nanoparticles in a biological system is an integration of effects arising from surface functionali~ particle size, ionic dissolution, etc. This complexity suggests that generalization of a material＇s ...The toxicity of nanoparticles in a biological system is an integration of effects arising from surface functionali~ particle size, ionic dissolution, etc. This complexity suggests that generalization of a material＇s toxicity may be inappropriate. Moreover, from a medicinal point of view, toxicity can be used for treatment of malignant cells, such as cancer. In this stud~ highly biocompatible carbon nanodots （gCDs） were synthesized by reacting citric acid and urea in glycerol, which resulted in abundant hydroxyl functional groups on the particle surface. gCDs show excitation-dependent photoluminescence but with bright green to yellow emission. Importantly, a series of toxicity assessments showed that as-synthesized gCDs possessed exceptional biocompatibilities to various biological entities including 18 bacteria species, Petunia axillaris seedlings, and Artemia franciscana nauplii. Furthermore, the particles were shown to have low to no toxic effects on human embryonic kidney （HEK-293）, breast （MCF-7）, and oral squamous （CAL-27） carcinoma cell lines. Of particular interest, the gCDs displayed antiproliferative activities against ovarian choriocarcinoma cells （JAr/Jeg-3 cell lines）, which may be further explored for cancer drug discovery.展开更多
The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease,including the devastating COVID-19.Novel effective antivirals with broad-spectrum coverage are urgently needed....The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease,including the devastating COVID-19.Novel effective antivirals with broad-spectrum coverage are urgently needed.Herein,we reported a novel broad-spectrum antiviral compound PAC5.Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection.Strikingly,oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron(BA.1)infection significantly decreases viral loads and attenuates lung inflammation.Mechanistically,PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1.PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway,leading to the production of type I IFNs with antiviral activity.Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1,which may have a role in dealing with emerging infectious diseases now and in the future.展开更多
The growing number of sequenced microbial genomes has revealed a remarkably large number of secondary metabolite biosynthetic clusters for which the compounds are still unknown.The aim of the present work was to apply...The growing number of sequenced microbial genomes has revealed a remarkably large number of secondary metabolite biosynthetic clusters for which the compounds are still unknown.The aim of the present work was to apply a strategy to detect newly induced natural products by cultivating microorganisms in different fermentation conditions.The metabolomic analysis of 4160 fractions generated from 13 actinomycetes under 32 different culture conditions was carried out by 1H NMR spectroscopy and multivariate analysis.The principal component analysis(PCA)of the 1H NMR spectra showed a clear discrimination between those samples within PC1 and PC2.The fractions with induced metabolites that are only produced under specific growth conditions was identified by PCA analysis.This method allows an efficient differentiation within a large dataset with only one fractionation step.This work demonstrates the potential of NMR spectroscopy in combination with metabolomic data analysis for the screening of large sets of fractions.展开更多
Designer biosurfactants can be used to stabilise and functionalise interfaces.One particularly promising use is the stabilisation of oil-in-water emulsions,enabling fine tuning physical,chemical and biological surface...Designer biosurfactants can be used to stabilise and functionalise interfaces.One particularly promising use is the stabilisation of oil-in-water emulsions,enabling fine tuning physical,chemical and biological surface properties.The ability of emulsion systems to carry high payloads makes them attractive for applications in medicine,food and fragrances,and cosmetics.However,they have limited long-term stability.Here we sought to use the metal ion-chelating ability of the biosurfactant peptide,AM1,to precipitate the formation of a gold metal shell on AM1-stabilised emulsions by electroless plating.We found that replacing the commonly used zinc(Ⅱ)with palladium(Ⅱ)for coordination by histidine residues of adjacent AM1 peptides produced interfacial films that maintained elasticity at acidic pH.Proton NMR suggested a coordination mechanism independent of the imidazole ring of the histidines.Nevertheless.stabilisation of emulsions at low pH enabled the deposition of a gold shell,albeit by an unexpected mechanism.We propose that gold nanoparticles forming in bulk are adsorbed onto the peptide-stabilised interface,accumulating into a particulate coating.The resulting one-step method for nanoparticle precipitation and shell formation will be useful for the creation of biocompatible core-shell particles for applications where large payloads of hydrophobic active compounds require stability over long time periods.展开更多
In this mini-review,we summarize recent findings relating to the prion-like propagation ofα-synuclein(α-syn)and the development of novel therapeutic strategies to target synucleinopathy in Parkinson’s disease(PD).W...In this mini-review,we summarize recent findings relating to the prion-like propagation ofα-synuclein(α-syn)and the development of novel therapeutic strategies to target synucleinopathy in Parkinson’s disease(PD).We link the Braak’s staging hypothesis of PD with the recent evidence from in-vivo and in-vitro studies for the prion-like cell-to-cell propagation ofα-syn(via exocytosis and endocytosis).The classical accumulation of aggregatedα-syn in PD may result from an increased production or a failure in the mechanisms of clearance ofα-syn.We discuss novel agents,currently in clinical trial for PD including the ones that impact the aggregation ofα-syn and others that interfere withα-syn endocytosis as a means to target the progression of the disease.展开更多
文摘Parkinson's disease(PD) has a complex and multifactorial pathophysiology. Various studies, conducted both in pre-clinical models and PD patients, have reported a link between the disruption of calcium(Ca^(2+)) homeostasis and the subsequent development of PD. Ca^(2+) regulation is crucial for neuronal survival, differentiation,exocytosis at synapses,gene transcription,and proliferation.
文摘Transplantation of olfactory ensheathing cells,the glia of the primary olfactory nervous system,has been trialed for spinal cord injury repair with promising but variable outcomes in animals and humans.Olfactory ensheathing cells can be harvested either from the lamina propria beneath the neuroepithelium in the nasal cavity,or from the olfactory bulb in the brain.As these areas contain several other cell types,isolating and purifying olfactory ensheathing cells is a critical part of the process.It is largely unknown how contaminating cells such as fibroblasts,other glial cell types and supporting cells affect olfactory ensheathing cell function post-transplantation;these cells may also cause unwanted side-effects.It is also,however,possible that the presence of some of the contaminant cells can improve outcomes.Here,we reviewed the last decade of olfactory ensheathing cell transplantation studies in rodents,with a focus on olfactory ensheathing cell purity.We analyzed how purification methods and resultant cell purity differed between olfactory mucosa-and olfactory bulb-derived cell preparations.We analyzed how the studies reported on olfactory ensheathing cell purity and which criteria were used to define cells as olfactory ensheathing cells.Finally,we analyzed the correlation between cell purity and transplantation outcomes.We found that olfactory bulb-derived olfactory ensheathing cell preparations are typically purer than mucosa-derived preparations.We concluded that there is an association between high olfactory ensheathing cell purity and favourable outcomes,but the lack of olfactory ensheathing cell-specific markers severely hampers the field.
基金supported by a joint GUIPRS/AHEAD Scholarship and GU Postgraduate Research Scholarshipcurrently receiving funds from Cancer Australia (APP1145657)+2 种基金the National Health and Medical Research Council (APP 2002576 and APP 2012560)the Garnett Passe and Rodney Williams FoundationNIH R21 and the RBWH Foundation。
文摘Oral cancer (OC) is the most common form of head and neck cancer. Despite the high incidence and unfavourable patient outcomes, currently, there are no biomarkers for the early detection of OC. This study aims to discover, develop, and validate a novel saliva-based microRNA signature for early diagnosis and prediction of OC risk in oral potentially malignant disorders (OPMD).The Cancer Genome Atlas (TCGA) miRNA sequencing data and small RNA sequencing data of saliva samples were used to discover differentially expressed miRNAs. Identified miRNAs were validated in saliva samples of OC (n=50), OPMD (n=52), and controls(n=60) using quantitative real-time PCR. Eight differentially expressed miRNAs (miR-7-5p, miR-10b-5p, miR-182-5p, miR-215-5p,miR-431-5p, miR-486-3p, miR-3614-5p, and miR-4707-3p) were identified in the discovery phase and were validated. The efficiency of our eight-miRNA signature to discriminate OC and controls was:area under curve (AUC):0.954, sensitivity:86%, specificity:90%,positive predictive value (PPV):87.8%and negative predictive value (NPV):88.5%whereas between OC and OPMD was:AUC:0.911,sensitivity:90%, specificity:82.7%, PPV:74.2%and NPV:89.6%. We have developed a risk probability score to predict the presence or risk of OC in OPMD patients. We established a salivary miRNA signature that can aid in diagnosing and predicting OC,revolutionising the management of patients with OPMD. Together, our results shed new light on the management of OC by salivary miRNAs to the clinical utility of using miRNAs derived from saliva samples.
基金supported by a grant from the Perry Cross Spinal Research Foundation to FC,JASTby Queensland University of Technology to FC
文摘The olfactory system is one of a few areas in the nervous system which is capable of regeneration throughout the life.Olfactory sensory neurons reside in the nasal cavity are continuously replenished with new neurons arising from stem cells.Some factors such as aging,neurodegenerative diseases,head trauma,brain tumor extraction and infection cause olfactory dysfunction which significantly influences physical wellbeing,quality of life,mental health,nutritional status,memory processes,identifying danger and is associated with increased mortality.Therefore,finding a treatment to improve olfactory dysfunction is needed.Recent research efforts in the field have shown some very promising new approaches to treat olfactory dysfunction.This review explores the current studies that have addressed therapeutic approaches to improve olfactory neuron regeneration based on cell transplantation therapy,modulation of physiological olfactory dysfunction and drug treatments.
文摘Neurogenesis is a persistent and essential feature of the adult mammalian hippocampus.Granular neurons generated from resident pools of stem or progenitor cells provide a mechanism for the formation and consolidation of new memories.Regulation of hippocampal neurogenesis is complex and multifaceted,and numerous signaling pathways converge to modulate cell proliferation,apoptosis,and clearance of cellular debris,as well as synaptic integration of newborn immature neurons.The expression of functional P2X7 receptors in the central nervous system has attracted much interest and the regulatory role of this purinergic receptor during adult neurogenesis has only recently begun to be explored.P2X7 receptors are exceptionally versatile:in their canonical role they act as adenosine triphosphate-gated calcium channels and facilitate calcium-signaling cascades exerting control over the cell via calcium-encoded sensory proteins and transcription factor activation.P2X7 also mediates transmembrane pore formation to regulate cytokine release and facilitate extracellular communication,and when persistently stimulated by high extracellular adenosine triphosphate levels large P2X7 pores form,which induce apoptotic cell death through cytosolic ion dysregulation.Lastly,as a scavenger receptor P2X7 directly facilitates phagocytosis of the cellular debris that arises during neurogenesis,as well as during some disease states.Understanding how P2X7 receptors regulate the physiology of stem and progenitor cells in the adult hippocampus is an important step towards developing useful therapeutic models for regenerative medicine.This review considers the relevant aspects of adult hippocampal neurogenesis and explores how P2X7 receptor activity may influence the molecular physiology of the hippocampus,and neural stem and progenitor cells.
基金supported by Queensland University of Technology Start Up Grant(to FC)a grant from the Clem Jones Foundation(to JASJ)
文摘The olfactory receptor neurons lining the nasal cavity have a remarkable capacity to regenerate throughout life. They are replenished continuously and their axons make new connections within the olfactory bulb. However, some factors such as head trauma and skull base surgery damage the olfactory nerve which lead to olfactory dysfunction. Losing the sense of smell has considerable effects on quality of life and life-expectancy. Therefore, there is a clear need to find a treatment for olfactory dysfunction. One such potential treatment is growth factor therapy which showed promising results in the spinal cord and brain injuries. The aim of the present study was to investigate whether combined delivery of two growth factors, vascular endothelial growth factor and platelet-derived growth factor treatment can improve the olfactory neurons regeneration in mice. The degeneration of the olfactory neurons was induced by unilateral bulbectomy. The treatment group received 1.5 μg of the combined growth factors intranasally, while the control injured group received saline. Growth factor treatment significantly increased the number of immature neurons at 5 and 7 days post injury and also the number of mature olfactory neurons at 10 and 14 days post bulbectomy. Regenerating axons extended over a larger volume in the operated cavity in the treatment group compared to control group at 14 days post bulbectomy. The growth factor treatment also significantly reduced astrocytic glia scar in the operated cavity. The results indicate that the combined delivery of the growth factors has the potential to improve olfactory dysfunction.
文摘Therapeutic manipulation of the immune system in cancer has been an extensive area of research in the field of oncoimmunology.Immunosuppression regulates antitumour immune responses.An immunosuppressive enzyme,indoleamine 2,3-dioxygenase(IDO)mediates tumour immune escape in various malignancies including breast cancer.IDO upregulation in breast cancer cells may lead to the recruitment of regulatory T(T-regs)cells into the tumour microenvironment,thus inhibiting local immune responses and promoting metastasis.Immunosuppression induced by myeloid derived suppressor cells activated in an IDOdependent manner may enhance the possibility of immune evasion in breast cancer.IDO overexpression has independent prognostic significance in a subtype of breast cancer of emerging interest,basal-like breast carcinoma.IDO inhibitors as adjuvant therapeutic agents may have clinical implications in breast cancer.This review proposes future prospects of IDO not only as a therapeutic target but also as a valuable prognostic marker for breast cancer.
基金supported by a Garnett-Passe and Rodney Williams Memorial Foundation grant(to JE)a National Health and Medical Research Council grant,No.APP1183799(to JASJ and JAKE).
文摘The nerves of the peripheral nervous system are not able to effectively regenerate in cases of severe neural injury.This can result in debilitating consequences,including morbidity and lifelong impairments affecting the quality of the patient’s life.Recent findings in neural tissue engineering have opened promising avenues to apply fibrous tissue-engineered scaffolds to promote tissue regeneration and functional recovery.These scaffolds,known as neural scaffolds,are able to improve neural regeneration by playing two major roles,namely,by being a carrier for transplanted peripheral nervous system cells or biological cues and by providing structural support to direct growing nerve fibers towards the target area.However,successful implementation of scaffold-based therapeutic approaches calls for an appropriate design of the neural scaffold structure that is capable of up-and down-regulation of neuron-scaffold interactions in the extracellular matrix environment.This review discusses the main challenges that need to be addressed to develop and apply fibrous tissue-engineered scaffolds in clinical practice.It describes some promising solutions that,so far,have shown to promote neural cell adhesion and growth and a potential to repair peripheral nervous system injuries.
基金supported by a Clem Jones Foundation grant to JS and JEa Perry Cross Spinal Research Foundation grant to JE and JS+1 种基金a Motor Accident Insurance Commission grant to JS and JEa Griffith University International Postgraduate Research Scholarship to RR
文摘Olfactory ensheathing cells(OECs)are crucial players in the continuous regeneration of the olfactory nervous system that occurs through out life and are thought to have unique growth-promoting properties.For this reason,OEC transplantation has been thoroughly explored for the potential to promote neural repair after both central and peripheral nervous system injuries.Numerous studies have shown that OEC transplantation is safe and can promote recovery after spinal cord injury(SCI),both in animal models and in human clinical trials.To date,a variety of injury types and time-points after injury,as well as different delivery methods,have been tested.Outcomes have been encouraging(in rodent models including,for example,restoration of locomotion,breathing and climbing ability along with induction of axonal sprouting and some axonal regeneration)but highly variable(Barnett and Riddell,2007;Gomez et al.,2018).
基金supported by a Garnett-Passe and Rodney Williams Memorial Foundation Grant to JEa National Health and Medical Research Council Grant to JS and JE(grant No.APP1183799)+2 种基金a Motor Accident Insurance Commission Queensland Grant to JS and JEa Perry Cross Foundation Grant to JE and JSa Clem Jones Foundation grant to JS and JE。
文摘One of the key challenges in neuroscience is that the central nervous system(CNS;the brain and spinal cord), is largely unable to regene rate after injury. One factor contributing to this lack of repair is the accumulation of cellular and myelin debris at the site of injury. The debris is not efficiently phagocytosed and can persist for years after the initial injury, resulting in an inflammatory environment which inhibits axonal regrowth(Lutz and Barres, 2014).
文摘Intrinsic or acquired resistance to chemotherapy is a major hurdle in the treatment of cancer.One of the key mechanisms of resistance is the overexpression of the drug efflux transporter P-glycoprotein(Pgp).Pgp overexpression renders a large number of mechanistically unrelated chemotherapies ineffective.Targeting Pgp inhibition directly to overcome drug resistance,although conceptually and mechanistically attractive,has not translated to the clinic,in part because Pgp also has a critical protective function in many healthy tissues.It was recently discovered that carbonic anhydrase XII(CA XII),an enzyme associated with pH regulation in cancer,is co-expressed and co-located with Pgp in drug resistant cancer cells.CA XII is also upregulated by hypoxia,which is another microenvironmental factor that contributes to drug resistance.Here,we review findings that demonstrate modulation of CA XII may offer a promising new approach towards overcoming the longstanding hurdle of drug resistance and therapy failure against solid cancers.This review covers the use of CA XII inhibitors,both small molecule and antibody,in combination with chemotherapeutics that are substrates for Pgp.This combination therapy approach restores the efficacy of chemotherapy in resistant cells and offers a potential new therapeutic window to re-examine the targeting of Pgp as a safe,effective,and novel anticancer strategy.
文摘The toxicity of nanoparticles in a biological system is an integration of effects arising from surface functionali~ particle size, ionic dissolution, etc. This complexity suggests that generalization of a material＇s toxicity may be inappropriate. Moreover, from a medicinal point of view, toxicity can be used for treatment of malignant cells, such as cancer. In this stud~ highly biocompatible carbon nanodots （gCDs） were synthesized by reacting citric acid and urea in glycerol, which resulted in abundant hydroxyl functional groups on the particle surface. gCDs show excitation-dependent photoluminescence but with bright green to yellow emission. Importantly, a series of toxicity assessments showed that as-synthesized gCDs possessed exceptional biocompatibilities to various biological entities including 18 bacteria species, Petunia axillaris seedlings, and Artemia franciscana nauplii. Furthermore, the particles were shown to have low to no toxic effects on human embryonic kidney （HEK-293）, breast （MCF-7）, and oral squamous （CAL-27） carcinoma cell lines. Of particular interest, the gCDs displayed antiproliferative activities against ovarian choriocarcinoma cells （JAr/Jeg-3 cell lines）, which may be further explored for cancer drug discovery.
基金supported by the National Natural Science Foundation of China(Grant Nos.31960093,81973210,81873872,82071781,32160153)the Natural Science Foundation of Yunnan Province(Grant Nos.202001BC070001,202102AA100053,202105AD160008,202207AA110003)the Innovation Team of Chronic Kidney Disease with Integrated Traditional Chinese and Western Medicine(No.2019KCXTD014).
文摘The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease,including the devastating COVID-19.Novel effective antivirals with broad-spectrum coverage are urgently needed.Herein,we reported a novel broad-spectrum antiviral compound PAC5.Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection.Strikingly,oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron(BA.1)infection significantly decreases viral loads and attenuates lung inflammation.Mechanistically,PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1.PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway,leading to the production of type I IFNs with antiviral activity.Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1,which may have a role in dealing with emerging infectious diseases now and in the future.
基金This research was supported by an Australian Research Council(ARC)Linkage Project DP160101429,ARC project LP120100485the Bill&Melinda Gates Foundation Grand Challenges Explorations Grant Phase Ⅱ OPP1035218 GCE.M.Liu thanks Griffith University for the Publication Assistance Scholarship.
文摘The growing number of sequenced microbial genomes has revealed a remarkably large number of secondary metabolite biosynthetic clusters for which the compounds are still unknown.The aim of the present work was to apply a strategy to detect newly induced natural products by cultivating microorganisms in different fermentation conditions.The metabolomic analysis of 4160 fractions generated from 13 actinomycetes under 32 different culture conditions was carried out by 1H NMR spectroscopy and multivariate analysis.The principal component analysis(PCA)of the 1H NMR spectra showed a clear discrimination between those samples within PC1 and PC2.The fractions with induced metabolites that are only produced under specific growth conditions was identified by PCA analysis.This method allows an efficient differentiation within a large dataset with only one fractionation step.This work demonstrates the potential of NMR spectroscopy in combination with metabolomic data analysis for the screening of large sets of fractions.
基金the facilities,and the scientific and technical assistance,of the Microscopy Australia Facility at the Centre for Microscopy and Microanalysis(CMM),The University of Queenslandthe funding support from Australian Research Council projects(FT140100726,DPI 50100798)the funding support of the CSIRO Probing Biosystems Future Science Platform.
文摘Designer biosurfactants can be used to stabilise and functionalise interfaces.One particularly promising use is the stabilisation of oil-in-water emulsions,enabling fine tuning physical,chemical and biological surface properties.The ability of emulsion systems to carry high payloads makes them attractive for applications in medicine,food and fragrances,and cosmetics.However,they have limited long-term stability.Here we sought to use the metal ion-chelating ability of the biosurfactant peptide,AM1,to precipitate the formation of a gold metal shell on AM1-stabilised emulsions by electroless plating.We found that replacing the commonly used zinc(Ⅱ)with palladium(Ⅱ)for coordination by histidine residues of adjacent AM1 peptides produced interfacial films that maintained elasticity at acidic pH.Proton NMR suggested a coordination mechanism independent of the imidazole ring of the histidines.Nevertheless.stabilisation of emulsions at low pH enabled the deposition of a gold shell,albeit by an unexpected mechanism.We propose that gold nanoparticles forming in bulk are adsorbed onto the peptide-stabilised interface,accumulating into a particulate coating.The resulting one-step method for nanoparticle precipitation and shell formation will be useful for the creation of biocompatible core-shell particles for applications where large payloads of hydrophobic active compounds require stability over long time periods.
文摘In this mini-review,we summarize recent findings relating to the prion-like propagation ofα-synuclein(α-syn)and the development of novel therapeutic strategies to target synucleinopathy in Parkinson’s disease(PD).We link the Braak’s staging hypothesis of PD with the recent evidence from in-vivo and in-vitro studies for the prion-like cell-to-cell propagation ofα-syn(via exocytosis and endocytosis).The classical accumulation of aggregatedα-syn in PD may result from an increased production or a failure in the mechanisms of clearance ofα-syn.We discuss novel agents,currently in clinical trial for PD including the ones that impact the aggregation ofα-syn and others that interfere withα-syn endocytosis as a means to target the progression of the disease.
