Cardamonin is a natural chalcone that has been extensively investigated for its anticancer activity.However,its clinical relevance is still not explicit,limiting its progression into clinical trials and highlighting a...Cardamonin is a natural chalcone that has been extensively investigated for its anticancer activity.However,its clinical relevance is still not explicit,limiting its progression into clinical trials and highlighting a persistent gap between preclinical evidence and practical application.This review aims to assess the readiness of cardamonin to progress from laboratory research to clinical application as an anticancer agent by examining both scientific evidence and translational challenges.Preclinical pharmacokinetic and pharmacodynamic data suggest that cardamonin’s therapeutic potential as an anticancer agent is hindered by its poor oral bioavailability.Although its molecular targets remain undefined,evidence indicates that cardamonin can inhibit various signaling pathways,including nuclear factor kappa-light-chain-enhancer of activated B cells,mammalian target of rapamycin,signal transducer and activator of transcription 3,and Wnt/β-catenin.The lack of in vivo toxicity studies creates uncertainty regarding the balance between its therapeutic benefits and potential adverse effects when moving from laboratory research to human trials.Despite these limitations,cardamonin has,however,demonstrated antiproliferative,anti-metastatic,and chemosensitizing effects,mainly against breast,colorectal,and ovarian cancers.Nevertheless,exploring its combination with standard chemotherapeutic agents may offer a promising foundation for advancing cardamonin into clinical trials.展开更多
Any new report on the anticancer properties of natural products always awakens new satisfaction and hope about the role of the international scientific community in its continuous contributions to human health,particu...Any new report on the anticancer properties of natural products always awakens new satisfaction and hope about the role of the international scientific community in its continuous contributions to human health,particularly when those reports contribute to both the understanding and therapeutics of cancer.For many de-cades,natural products have been pivotal in drug discovery programs because they offer a diverse array of anticancer therapeutic possibilities.Recently,two manuscripts published in the World Journal of Gastrointestinal Oncology added new data to the already extensive body of anticancer preclinical evidence for resvera-trol and senegenin,two compounds widely present in herbal preparations used in traditional Chinese medicine.The first one,with comprehensive and recognized anticancer properties,and the second one,shows a compelling body of evidence supporting its neuroprotective effects,but with emerging anticancer activities.Natural products have become key elements in the expanding and dynamic field of anticancer drug discovery.However,urgent and collective efforts are still needed to bridge the gap between preclinical and clinical research and thus bring new anticancer therapeutic breakthroughs.展开更多
Background This preclinical study in sheep sought to demonstrate the initial safety and feasibility of a novel transcatheter mitral valve system(Mi-thos valve)composed of a self-expanding frame and a bovine pericardia...Background This preclinical study in sheep sought to demonstrate the initial safety and feasibility of a novel transcatheter mitral valve system(Mi-thos valve)composed of a self-expanding frame and a bovine pericardial tissue bioprosthesis.Methods The valve was implanted in 26 sheep using a transapical approach for short-and long-term evaluation.The technical feasibility,safety,durability,and valve function were evaluated during and 6 months after the procedure using intracardiac and transthoracic echocardiography,multisliced computed tomography,histological analysis,and electron microscopy.Results The success rate of valve implantation was 100%,and the immediate survival rate after surgery was 84%.Five animals died within 90 min after the development of the prosthetic valve due to an acute left ventricular outflow tract obstruction(n=2)and sudden intraoperative ventricular fibrillation(n=3).Twelve animals died within 1 month due to acute left heart dysfunction.Mild(n=5)and moderate(n=2)paravalvular leakage occurred in seven animals,and two moderate PVL animals died of chronic heart failure within three months.Multimodality imaging studies of the remaining seven animals showed excellent function and alignment of the valves,with no coronary artery obstruction,no left ventricular outflow tract obstruction,no severe transvalvular gradients and no paravalvular leakage.Macroscopic evaluation demonstrated stable,secure positioning of the valve,with full endothelialization of the valve leaflets without injury to the ventricular or atrial walls.Histological and electron microscopic examinations at six months showed no obvious macro-or microcalcification in the leaflets.Conclusions Preclinical studies indicate that transcatheter implantation of the Mi-thos valve is technically safe and feasible.The durability,functionality,and lack of leaflet calcification were all verified in animal experiments.The information from these preclinical studies will be applied to patient selection criteria and the first-in-human studies.展开更多
We recently reported several driver genes of biliary tract carcinoma(BTC) that are known to play important roles in oncogenesis and disease progression. Although the need for developing novel therapeutic strategies is...We recently reported several driver genes of biliary tract carcinoma(BTC) that are known to play important roles in oncogenesis and disease progression. Although the need for developing novel therapeutic strategies is increasing, there are very few BTC cell lines and xenograft models currently available for conducting preclinical studies. Using a total of 88 surgical BTC specimens and 536 immunodeficient mice, 28 xenograft models and 13 new BTC cell lines, including subtypes, were established. Some of our cell lines were found to be resistant to gemcitabine, which is currently the first choice of treatment, thereby allowing highly practical preclinical studies to be conducted. Using the aforementioned cell lines and xenograft models and a clinical pathological database of patients undergoing BTC resection, we can establish a preclinical study system and appropriate parameters for drug efficacy studies to explore new biomarkers for practical applications in the future studies.展开更多
The Rasayana plant Withania somnifera(W.somnifera)Dunal,also known as“Ashwagandha”,has been mentioned in various classical Ayurvedic texts,such as Charaka Samhita,Sushruta Samhita,and Nighantus.This Ayurvedic drug h...The Rasayana plant Withania somnifera(W.somnifera)Dunal,also known as“Ashwagandha”,has been mentioned in various classical Ayurvedic texts,such as Charaka Samhita,Sushruta Samhita,and Nighantus.This Ayurvedic drug has been referred to as a tonic that renews the body,provides physical and mental vigor in weakened states,and promotes endurance and longevity.W.somnifera possesses notable biological activity in many ailments,such as diabetes,conjunctivitis,insomnia,senile dementia,Parkinson’s disease,nervous system disorders,rheumatism,and arthritis.These pharmacological activities are due to the presence of diverse active components and their derivatives.Some lead compounds are found to be effective against anxiety and other central nervous system disorders.W.somnifera has been proven to be effective and safe for a wide range of ailments from ancient to modern times.Its reported properties represent the traditional use of W.somnifera as indicated in the literature;furthermore,W.somnifera is one of the most important prescribed drugs in Ayurveda for its multimodal effects.This current review highlights the bioactive present and provides an overview of the toxicological and pharmacological studies on W.somnifera,including preclinical and clinical studies.From its earliest utilization to its current application,W.somnifera has been recognized to be effective at clinical levels for human health and welfare.Greater attention to the safety and efficacy of W.somnifera would provide more scientific evidence,promoting global acceptance of the Ayurvedic plant.展开更多
Introduction: Diabetes is a serious public health problem requiring complex treatment. Numerous ethnopharmacological studies have reported the traditional use of Sclerocarya birrea in managing diabetic patients. This ...Introduction: Diabetes is a serious public health problem requiring complex treatment. Numerous ethnopharmacological studies have reported the traditional use of Sclerocarya birrea in managing diabetic patients. This study aims to demonstrate, preclinically, the antidiabetic effects of the aqueous decoction of S. birrea trunk bark. Methods: Phytochemical analysis was performed by HPLC-MS. The effects of the extracts (Sb5 and Sb25) and 0.9% NaCl on the normal blood glucose levels of the animals were determined. Diabetes induction was performed intraperitoneally by administering a single dose of alloxan (150 mg/kg) in normoglycemic rats. The antidiabetic effects of the extracts (Allox + Sb5, Allox + Sb25) and glibenclamide (Allox + Glib5) were determined in Alloxan-induced diabetic animals for four weeks. Results: Interpretation of mass spectra obtained by HPLC-MS allowed the tentative identification of vanillic acid-4-sulfate and rhamnetin in Sb extract. Investigated doses of Sb extract showed an antidiabetic impact similar to the reference, glibenclamide, with a return to normal blood glucose in all treated rats only after 4 days of treatment. Furthermore, Sb extract treatments reduced weight loss in diabetic rats. Sb had no negative impact on the balance of total cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL). Conclusion: The present study demonstrated the antidiabetic efficacy and, to some extent, the beneficial effects of Sb extract on Alloxan-induced diabetic rats’ health. Detection of antidiabetic phytochemicals such as vanillic acid-4-sulfate and rhamnetin would justify this pharmacological property of the aqueous decoction of S. birrea trunk bark.展开更多
Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced ...Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.展开更多
Microglial cells（or microglia）are the mononuclear phagocytes residing in the central nervous system（CNS）.In homeostasis,they showed ramified morphology with relative small cell bodies and long processes（Figure 1A...Microglial cells（or microglia）are the mononuclear phagocytes residing in the central nervous system（CNS）.In homeostasis,they showed ramified morphology with relative small cell bodies and long processes（Figure 1A）.They detect injury signals in the CNS and get activated.展开更多
The U.S.Food and Drug Administration(FDA)'s program documents regarding the animal-free approach for the efficacy,pharmacokinetics,and safety evaluation of new drug preclinical studies have been rolled out gradual...The U.S.Food and Drug Administration(FDA)'s program documents regarding the animal-free approach for the efficacy,pharmacokinetics,and safety evaluation of new drug preclinical studies have been rolled out gradually.This process has taken the FDA seven years.Starting from the reduction of funding for animal of data from organ-on-a-chip solely for pharmacodynamic studies[[1],[2],[3]],to the explicit proposal of the animal-free approach for pharmacodynamic studies in the FDA Modernization Act in Reference[4],and to the indication in 2025 that safety studies should also prioritize safety research data from in vitro microphysiological systems[5],this demonstrates the FDAs determination to gradually achieve the animal-free approach and also signals a profound paradigm shift in the field of drug research and development.This policy direction not only addresses the requirements of ethics and technological advancement but may also reshape the entire new drug development industrial chain.展开更多
The article by Granjeiro et al provided a thorough review of the role of stem cell models in the development of advanced therapy medicinal products.It emphasized the potential of stem cell models to refine preclinical...The article by Granjeiro et al provided a thorough review of the role of stem cell models in the development of advanced therapy medicinal products.It emphasized the potential of stem cell models to refine preclinical studies and align with regulatory requirements for clinical applications.This article introduced a new perspective on enhancing the transition of stem cell research into clinical practice,focusing on the importance of international regulatory harmonization and the need for standardization in stem cell-based therapies.展开更多
Multiple sclerosis is a chronic autoimmune disease of the central nervous system and is generally considered to be a non-traumatic,physically debilitating neurological disorder.In addition to experiencing motor disabi...Multiple sclerosis is a chronic autoimmune disease of the central nervous system and is generally considered to be a non-traumatic,physically debilitating neurological disorder.In addition to experiencing motor disability,patients with multiple sclerosis also experience a variety of nonmotor symptoms,including cognitive deficits,anxiety,depression,sensory impairments,and pain.However,the pathogenesis and treatment of such non-motor symptoms in multiple scle rosis are still under research.Preclinical studies for multiple sclerosis benefit from the use of disease-appropriate animal models,including experimental autoimmune encephalomyelitis.Prior to understanding the pathophysiology and developing treatments for non-motor symptoms,it is critical to chara cterize the animal model in terms of its ability to replicate certain non-motor features of multiple sclerosis.As such,no single animal model can mimic the entire spectrum of symptoms.This review focuses on the non-motor symptoms that have been investigated in animal models of multiple sclerosis as well as possible underlying mechanisms.Further,we highlighted gaps in the literature to explain the nonmotor aspects of multiple sclerosis in expe rimental animal models,which will serve as the basis for future studies.展开更多
The patient-derived xenografts (PDX) model is an animal model established by transplanting primary tumors or fresh tumor tissues of patient origin directly into immunodeficient mice, which preserves the heterogeneity ...The patient-derived xenografts (PDX) model is an animal model established by transplanting primary tumors or fresh tumor tissues of patient origin directly into immunodeficient mice, which preserves the heterogeneity and survival microenvironment of the primary tumor and is widely used in preclinical and precision medicine research of tumors. This article reviews the construction of the PDX model of human bladder cancer and the progress of the application of the PDX model in bladder cancer.展开更多
Traumatic brain injury remains a global health crisis that spans all demographics,yet there exist limited treatment options that may effectively curtail its lingering symptoms.Traumatic brain injury pathology entails ...Traumatic brain injury remains a global health crisis that spans all demographics,yet there exist limited treatment options that may effectively curtail its lingering symptoms.Traumatic brain injury pathology entails a progression from primary injury to inflammation-mediated secondary cell death.Sequestering this inflammation as a means of ameliorating the greater symptomology of traumatic brain injury has emerged as an attractive treatment prospect.In this review,we recapitulate and evaluate the important developments relating to regulating traumatic brain injury-induced neuroinflammation,edema,and blood-brain barrier disintegration through pharmacotherapy and stem cell transplants.Although these studies of stand-alone treatments have yielded some positive results,more therapeutic outcomes have been documented from the promising area of combined drug and stem cell therapy.Harnessing the facilitatory properties of certain pharmaceuticals with the anti-inflammatory and regenerative effects of stem cell transplants creates a synergistic effect greater than the sum of its parts.The burgeoning evidence in favor of combined drug and stem cell therapies warrants more elaborate preclinical studies on this topic in order to pave the way for later clinical trials.展开更多
Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the und...Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.展开更多
Paclitaxel is a promising antineoplastic agent against a variety of human solid tumors, such as ovary, breast, lung, head and neck tumors, and melanoma. Owing to its poor solubility, the fast available formulation ofp...Paclitaxel is a promising antineoplastic agent against a variety of human solid tumors, such as ovary, breast, lung, head and neck tumors, and melanoma. Owing to its poor solubility, the fast available formulation ofpaclitaxel （Taxol） exists as a non-aqueous concentrate composed of Cremophor EL （polyethoxylated castor oil） and ethanol. It must be diluted to a suitable aqueous solution prior to long time intravenous infusion. Based on the components and usage, Taxol has serious adverse effects and is inconvenient for clinical use. To address these problems, the development of a less-toxic, better-tolerated, Cremophor EL-free formulation of paclitaxel has been attempted. In recent years, new drug delivery systems （DDS） including albumin-based nanoparticles, micelles, liposomes, etc. have been investigated. In this review, we present the formulations and delivery technologies of paclitaxel for injection and focus on some of preclinical and clinical experience on the formulations which are already on the market or under clinical stages. Finally, possible nanotechnology advantages, existing challenges and future perspectives of paclitaxel delivery are highlighted.展开更多
Genetic neurodevelopmental disorders are characterized by abnormal neurophysiological and behavioral phenotypes,affecting individuals worldwide.While the subject has been heavily researched,current treatment options r...Genetic neurodevelopmental disorders are characterized by abnormal neurophysiological and behavioral phenotypes,affecting individuals worldwide.While the subject has been heavily researched,current treatment options relate mostly to alleviating symptoms,rather than targeting the altered genome itself.In this review,we address the neurogenetic basis of neurodevelopmental disorders,genetic tools that are enabling precision research of these disorders in animal models,and postnatal gene-therapy approaches for neurodevelopmental disorders derived from preclinical studies in the laboratory.展开更多
Preclinical studies have indicated that the combination of mTORC1/2 inhibitors with PD-1 antibodies exhibits synergistic effects on solid tumors.However,no clinical data supporting this combination have been reported....Preclinical studies have indicated that the combination of mTORC1/2 inhibitors with PD-1 antibodies exhibits synergistic effects on solid tumors.However,no clinical data supporting this combination have been reported.Therefore,we conducted a clinical trial(NCT 04337463)to investigate the efficacy and safety of combining onatasertib,an mTORC1/2 inhibitor,with toripalimab,a PD-1 antibody in patients with advanced solid tumors.This open-label,phase 1/2 clinical trial included dose escalation and dose expansion cohorts to evaluate safety,tolerability,objective response rate(ORR),disease control rate(DCR)and progression-free survival(PFS).A total of 46 patients were enrolled and received onatasertib at doses of 15 mg,20 mg,or 30 mg once daily(QD),combined with toripalimab 240 mg every 3 weeks(Q3W).No dose-limiting toxicities were observed,and the most common grade 3 or 4 treatment emergent adverse events were lymphopenia(23.9%)and rash(19.6%).The overall ORR was 26.1%,with a DCR of 73.9%,and a median PFS of 4.3 months.In cervical cancer patients,regardless of PD-L1 expression,the ORR was 52.4%,DCR was 90.5%and median PFS was 5.8 months.Notably,the 15 mg combination dose demonstrated a median PFS of 7.8 months.In conclusion,the safety profile of onatasertib in combination with toripalimab was manageable and showed encouraging clinical activity in advanced solid tumors,particularly among cervical cancer patients,irrespective of PD-L1 expression.The recommended phase 2 dose for the combination was determined to be onatasertib 15 mg QD and toripalimab 240 mg Q3W.展开更多
Central poststroke pain(CPSP)is a medical complication that arises poststroke and significantly impacts the quality of life and social functioning of affected individuals.Despite ongoing research,the exact pathomechan...Central poststroke pain(CPSP)is a medical complication that arises poststroke and significantly impacts the quality of life and social functioning of affected individuals.Despite ongoing research,the exact pathomechanisms of CPSP remain unclear,and practical treatments are still unavailable.Our review aims to systematically analyse current clinical and preclinical studies on CPSP,which is critical for identifying gaps in knowledge and guiding the development of effective therapies.The review will clarify the clinical characteristics,evaluation scales and contemporary therapeutic approaches for CPSP based on clinical investigations.It will particularly emphasise the CPSP model initiated by stroke,shedding light on its underlying mechanisms and evaluating treatments validated in preclinical studies.Furthermore,the review will not only highlight methodological limitations in animal trials but also offer specific recommendations to researchers to improve the quality of future investigations and guide the development of effective therapies.This review is expected to provide valuable insights into the current knowledge regarding CPSP and can serve as a guide for future research and clinical practice.The review will contribute to the scientific understanding of CPSP and help develop effective clinical interventions.展开更多
While the expression of programmed death ligand-1(PD-L1)is associated with response to immune therapy,PD-L1-negative patients may still benefit from immune treatment.Programmed death ligand-2(PD-L2),another crucial im...While the expression of programmed death ligand-1(PD-L1)is associated with response to immune therapy,PD-L1-negative patients may still benefit from immune treatment.Programmed death ligand-2(PD-L2),another crucial immune checkpoint molecule interacting with PD-1,correlates with the efficacy of various tumor immune therapies.This study investigates the expression of PD-L2 in non-small cell lung cancer(NSCLC)patients following anti-PD-1 therapy and its predictive value for clinical survival outcomes.Additionally,we explore the noninvasive,real-time,and dynamic quantitative analysis potential of PD-L2 positron emission tomography(PET)imaging in transplanted tumors.We utilized[^(68)Ga]Ga-labeled peptide HN11-1 for PD-L2 PET imaging.The results indicate a higher response rate to anti-PD-1 therapy in patients positive for both PD-L1 and PD-L2,with PD-L2 status independently predicting progression-free survival(PFS)with pembrolizumab treatment.Furthermore,[^(68)Ga]Ga-HN11-1 PET imaging demonstrates specificity in assessing PD-L2 status.Overall,we confirm the correlation between high PD-L2 expression and favorable PFS in NSCLC patients post anti-PD-1 therapy and highlight the promising potential of[^(68)Ga]Ga-HN11-1 as a specific tracer for PD-L2 in preclinical and initial human trials.展开更多
Background:Wound healing has always been a serious issue for doctors and primary health care systems.In addition,adipose stem cell-derived exosomes have been proven to play a positive and effective role in tissue repa...Background:Wound healing has always been a serious issue for doctors and primary health care systems.In addition,adipose stem cell-derived exosomes have been proven to play a positive and effective role in tissue repair and regeneration.A systematic review of these preclinical studies was performed to assess the efficacy of adipose stem cell-derived exosomes(ADSC-Exos)in treating wounds.This article aimed to study the effectiveness of ADSC-Exos for the treatment of animal skin wounds and includes a meta-analysis of exosomes from general wounds and diabetic ulcer wounds in in vitro models of animals to provide a theoretical basis for clinical translation.Methods:A total of 19 studies with 356 animals were identified by searching the PubMed,Cochrane,MEDLINE Complete,Web of Science,CNKI and Wanfang databases from inception to 15 November 2022.No language or time restrictions were applied.Stata17 was used for all the data analyses.Results:The meta-analysis showed that ADSC-Exo therapy significantly improved the wound healing rate in the control group,except in the diabetes group on day 7.Day 7 of general wounds[standard mean difference(SMD)2.87,95%confidence interval(CI 1.91-3.83)]and day 14(SMD 2.89,95%CI 1.47-4.30).Day 14(SMD 3.43,95%CI 1.28-5.58)of diabetic wounds.Other outcomes,such as blood vessel density,collagen deposition and wound re-epithelization,improved with the administration of ADSC-Exos.Conclusions:A meta-analysis showed that ADSC-Exo therapy applied to general and diabetic wounds can promote neovascularization,improve epithelization and collagen fiber deposition,promote healing,and reduce scar formation.ADSC-Exos have broad potential in preclinical research and clinical fields.展开更多
基金Supported by Malaysian Ministry of Higher Education through the Fundamental Research Grant Scheme,No.FP103-2019.
文摘Cardamonin is a natural chalcone that has been extensively investigated for its anticancer activity.However,its clinical relevance is still not explicit,limiting its progression into clinical trials and highlighting a persistent gap between preclinical evidence and practical application.This review aims to assess the readiness of cardamonin to progress from laboratory research to clinical application as an anticancer agent by examining both scientific evidence and translational challenges.Preclinical pharmacokinetic and pharmacodynamic data suggest that cardamonin’s therapeutic potential as an anticancer agent is hindered by its poor oral bioavailability.Although its molecular targets remain undefined,evidence indicates that cardamonin can inhibit various signaling pathways,including nuclear factor kappa-light-chain-enhancer of activated B cells,mammalian target of rapamycin,signal transducer and activator of transcription 3,and Wnt/β-catenin.The lack of in vivo toxicity studies creates uncertainty regarding the balance between its therapeutic benefits and potential adverse effects when moving from laboratory research to human trials.Despite these limitations,cardamonin has,however,demonstrated antiproliferative,anti-metastatic,and chemosensitizing effects,mainly against breast,colorectal,and ovarian cancers.Nevertheless,exploring its combination with standard chemotherapeutic agents may offer a promising foundation for advancing cardamonin into clinical trials.
文摘Any new report on the anticancer properties of natural products always awakens new satisfaction and hope about the role of the international scientific community in its continuous contributions to human health,particularly when those reports contribute to both the understanding and therapeutics of cancer.For many de-cades,natural products have been pivotal in drug discovery programs because they offer a diverse array of anticancer therapeutic possibilities.Recently,two manuscripts published in the World Journal of Gastrointestinal Oncology added new data to the already extensive body of anticancer preclinical evidence for resvera-trol and senegenin,two compounds widely present in herbal preparations used in traditional Chinese medicine.The first one,with comprehensive and recognized anticancer properties,and the second one,shows a compelling body of evidence supporting its neuroprotective effects,but with emerging anticancer activities.Natural products have become key elements in the expanding and dynamic field of anticancer drug discovery.However,urgent and collective efforts are still needed to bridge the gap between preclinical and clinical research and thus bring new anticancer therapeutic breakthroughs.
基金This paper was supported by the National Key Research and Development Plan(2016YFC1101000)National Natural Science Foundation of China(81600240 and 81470500)The Distinguished Young Scholar Cultivation Project of Xijing Hospital(XJZT14J03,XJZT15ZL01,and 13QNP129)。
文摘Background This preclinical study in sheep sought to demonstrate the initial safety and feasibility of a novel transcatheter mitral valve system(Mi-thos valve)composed of a self-expanding frame and a bovine pericardial tissue bioprosthesis.Methods The valve was implanted in 26 sheep using a transapical approach for short-and long-term evaluation.The technical feasibility,safety,durability,and valve function were evaluated during and 6 months after the procedure using intracardiac and transthoracic echocardiography,multisliced computed tomography,histological analysis,and electron microscopy.Results The success rate of valve implantation was 100%,and the immediate survival rate after surgery was 84%.Five animals died within 90 min after the development of the prosthetic valve due to an acute left ventricular outflow tract obstruction(n=2)and sudden intraoperative ventricular fibrillation(n=3).Twelve animals died within 1 month due to acute left heart dysfunction.Mild(n=5)and moderate(n=2)paravalvular leakage occurred in seven animals,and two moderate PVL animals died of chronic heart failure within three months.Multimodality imaging studies of the remaining seven animals showed excellent function and alignment of the valves,with no coronary artery obstruction,no left ventricular outflow tract obstruction,no severe transvalvular gradients and no paravalvular leakage.Macroscopic evaluation demonstrated stable,secure positioning of the valve,with full endothelialization of the valve leaflets without injury to the ventricular or atrial walls.Histological and electron microscopic examinations at six months showed no obvious macro-or microcalcification in the leaflets.Conclusions Preclinical studies indicate that transcatheter implantation of the Mi-thos valve is technically safe and feasible.The durability,functionality,and lack of leaflet calcification were all verified in animal experiments.The information from these preclinical studies will be applied to patient selection criteria and the first-in-human studies.
文摘We recently reported several driver genes of biliary tract carcinoma(BTC) that are known to play important roles in oncogenesis and disease progression. Although the need for developing novel therapeutic strategies is increasing, there are very few BTC cell lines and xenograft models currently available for conducting preclinical studies. Using a total of 88 surgical BTC specimens and 536 immunodeficient mice, 28 xenograft models and 13 new BTC cell lines, including subtypes, were established. Some of our cell lines were found to be resistant to gemcitabine, which is currently the first choice of treatment, thereby allowing highly practical preclinical studies to be conducted. Using the aforementioned cell lines and xenograft models and a clinical pathological database of patients undergoing BTC resection, we can establish a preclinical study system and appropriate parameters for drug efficacy studies to explore new biomarkers for practical applications in the future studies.
文摘The Rasayana plant Withania somnifera(W.somnifera)Dunal,also known as“Ashwagandha”,has been mentioned in various classical Ayurvedic texts,such as Charaka Samhita,Sushruta Samhita,and Nighantus.This Ayurvedic drug has been referred to as a tonic that renews the body,provides physical and mental vigor in weakened states,and promotes endurance and longevity.W.somnifera possesses notable biological activity in many ailments,such as diabetes,conjunctivitis,insomnia,senile dementia,Parkinson’s disease,nervous system disorders,rheumatism,and arthritis.These pharmacological activities are due to the presence of diverse active components and their derivatives.Some lead compounds are found to be effective against anxiety and other central nervous system disorders.W.somnifera has been proven to be effective and safe for a wide range of ailments from ancient to modern times.Its reported properties represent the traditional use of W.somnifera as indicated in the literature;furthermore,W.somnifera is one of the most important prescribed drugs in Ayurveda for its multimodal effects.This current review highlights the bioactive present and provides an overview of the toxicological and pharmacological studies on W.somnifera,including preclinical and clinical studies.From its earliest utilization to its current application,W.somnifera has been recognized to be effective at clinical levels for human health and welfare.Greater attention to the safety and efficacy of W.somnifera would provide more scientific evidence,promoting global acceptance of the Ayurvedic plant.
文摘Introduction: Diabetes is a serious public health problem requiring complex treatment. Numerous ethnopharmacological studies have reported the traditional use of Sclerocarya birrea in managing diabetic patients. This study aims to demonstrate, preclinically, the antidiabetic effects of the aqueous decoction of S. birrea trunk bark. Methods: Phytochemical analysis was performed by HPLC-MS. The effects of the extracts (Sb5 and Sb25) and 0.9% NaCl on the normal blood glucose levels of the animals were determined. Diabetes induction was performed intraperitoneally by administering a single dose of alloxan (150 mg/kg) in normoglycemic rats. The antidiabetic effects of the extracts (Allox + Sb5, Allox + Sb25) and glibenclamide (Allox + Glib5) were determined in Alloxan-induced diabetic animals for four weeks. Results: Interpretation of mass spectra obtained by HPLC-MS allowed the tentative identification of vanillic acid-4-sulfate and rhamnetin in Sb extract. Investigated doses of Sb extract showed an antidiabetic impact similar to the reference, glibenclamide, with a return to normal blood glucose in all treated rats only after 4 days of treatment. Furthermore, Sb extract treatments reduced weight loss in diabetic rats. Sb had no negative impact on the balance of total cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL). Conclusion: The present study demonstrated the antidiabetic efficacy and, to some extent, the beneficial effects of Sb extract on Alloxan-induced diabetic rats’ health. Detection of antidiabetic phytochemicals such as vanillic acid-4-sulfate and rhamnetin would justify this pharmacological property of the aqueous decoction of S. birrea trunk bark.
文摘Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.
基金supported by National Natural Science Foundation of China(31600839 to BP)Guangdong Innovative and Entrepreneurial Research Team Program(2013S046 to BP)Shenzhen Peacock Plan(to BP)
文摘Microglial cells（or microglia）are the mononuclear phagocytes residing in the central nervous system（CNS）.In homeostasis,they showed ramified morphology with relative small cell bodies and long processes（Figure 1A）.They detect injury signals in the CNS and get activated.
文摘The U.S.Food and Drug Administration(FDA)'s program documents regarding the animal-free approach for the efficacy,pharmacokinetics,and safety evaluation of new drug preclinical studies have been rolled out gradually.This process has taken the FDA seven years.Starting from the reduction of funding for animal of data from organ-on-a-chip solely for pharmacodynamic studies[[1],[2],[3]],to the explicit proposal of the animal-free approach for pharmacodynamic studies in the FDA Modernization Act in Reference[4],and to the indication in 2025 that safety studies should also prioritize safety research data from in vitro microphysiological systems[5],this demonstrates the FDAs determination to gradually achieve the animal-free approach and also signals a profound paradigm shift in the field of drug research and development.This policy direction not only addresses the requirements of ethics and technological advancement but may also reshape the entire new drug development industrial chain.
文摘The article by Granjeiro et al provided a thorough review of the role of stem cell models in the development of advanced therapy medicinal products.It emphasized the potential of stem cell models to refine preclinical studies and align with regulatory requirements for clinical applications.This article introduced a new perspective on enhancing the transition of stem cell research into clinical practice,focusing on the importance of international regulatory harmonization and the need for standardization in stem cell-based therapies.
基金supported by a grant from the National Research Foundation(NRF)of Korea funded by the Korean Government,No.NRF-2022R1A2C1004022(to CM)。
文摘Multiple sclerosis is a chronic autoimmune disease of the central nervous system and is generally considered to be a non-traumatic,physically debilitating neurological disorder.In addition to experiencing motor disability,patients with multiple sclerosis also experience a variety of nonmotor symptoms,including cognitive deficits,anxiety,depression,sensory impairments,and pain.However,the pathogenesis and treatment of such non-motor symptoms in multiple scle rosis are still under research.Preclinical studies for multiple sclerosis benefit from the use of disease-appropriate animal models,including experimental autoimmune encephalomyelitis.Prior to understanding the pathophysiology and developing treatments for non-motor symptoms,it is critical to chara cterize the animal model in terms of its ability to replicate certain non-motor features of multiple sclerosis.As such,no single animal model can mimic the entire spectrum of symptoms.This review focuses on the non-motor symptoms that have been investigated in animal models of multiple sclerosis as well as possible underlying mechanisms.Further,we highlighted gaps in the literature to explain the nonmotor aspects of multiple sclerosis in expe rimental animal models,which will serve as the basis for future studies.
文摘The patient-derived xenografts (PDX) model is an animal model established by transplanting primary tumors or fresh tumor tissues of patient origin directly into immunodeficient mice, which preserves the heterogeneity and survival microenvironment of the primary tumor and is widely used in preclinical and precision medicine research of tumors. This article reviews the construction of the PDX model of human bladder cancer and the progress of the application of the PDX model in bladder cancer.
基金CVB was funded by National Institutes of Health(NIH)R01NS071956,NIH R01NS090962,NIH R21NS089851,NIH R21NS094087Veterans Affairs Merit Review I01 BX001407
文摘Traumatic brain injury remains a global health crisis that spans all demographics,yet there exist limited treatment options that may effectively curtail its lingering symptoms.Traumatic brain injury pathology entails a progression from primary injury to inflammation-mediated secondary cell death.Sequestering this inflammation as a means of ameliorating the greater symptomology of traumatic brain injury has emerged as an attractive treatment prospect.In this review,we recapitulate and evaluate the important developments relating to regulating traumatic brain injury-induced neuroinflammation,edema,and blood-brain barrier disintegration through pharmacotherapy and stem cell transplants.Although these studies of stand-alone treatments have yielded some positive results,more therapeutic outcomes have been documented from the promising area of combined drug and stem cell therapy.Harnessing the facilitatory properties of certain pharmaceuticals with the anti-inflammatory and regenerative effects of stem cell transplants creates a synergistic effect greater than the sum of its parts.The burgeoning evidence in favor of combined drug and stem cell therapies warrants more elaborate preclinical studies on this topic in order to pave the way for later clinical trials.
基金funded by the Spanish Ministry of Economy and Competitiveness,No.PID(2019)-106498GB-100 (to MVS)by the Instituto de Salud CarlosⅢ,Fondo Europeo de Desarrollo Regional"Una manera de hacer Europa",No.PI19/00071 (to MAB)+2 种基金the RETICS subprograms of Spanish Networks OftoRed,Nos.RD16/0008/0026 (to DGB) and RD16/0008/0016 (to DGB)RICORS Terav,No.RD16/0011/0001 (to DGB)from Instituto de Salud CarlosⅢby the Fundacion Seneca,Agencia de Cienciay Tecnologia Región de Murcia,No.19881/GERM/15 (all to MVS)
文摘Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.
基金Key Project from the Ministry of Science and Technology(Grant No.2014ZX09507001-010)Innovation Team of Ministry of Education(Grant No.BMU20110263)
文摘Paclitaxel is a promising antineoplastic agent against a variety of human solid tumors, such as ovary, breast, lung, head and neck tumors, and melanoma. Owing to its poor solubility, the fast available formulation ofpaclitaxel （Taxol） exists as a non-aqueous concentrate composed of Cremophor EL （polyethoxylated castor oil） and ethanol. It must be diluted to a suitable aqueous solution prior to long time intravenous infusion. Based on the components and usage, Taxol has serious adverse effects and is inconvenient for clinical use. To address these problems, the development of a less-toxic, better-tolerated, Cremophor EL-free formulation of paclitaxel has been attempted. In recent years, new drug delivery systems （DDS） including albumin-based nanoparticles, micelles, liposomes, etc. have been investigated. In this review, we present the formulations and delivery technologies of paclitaxel for injection and focus on some of preclinical and clinical experience on the formulations which are already on the market or under clinical stages. Finally, possible nanotechnology advantages, existing challenges and future perspectives of paclitaxel delivery are highlighted.
基金supported by grants from Fritz Thyssen Stiftung,Brain Boost Innovation Center by Sagol School of Neuroscience at TAU,and SPARK Tel Avivsupported by the Eshkol Fellowship from The Ministry of Science and Technologythe recipient of The Alon Fellowship for outstanding young researchers awarded by the Israeli Council for Higher Education。
文摘Genetic neurodevelopmental disorders are characterized by abnormal neurophysiological and behavioral phenotypes,affecting individuals worldwide.While the subject has been heavily researched,current treatment options relate mostly to alleviating symptoms,rather than targeting the altered genome itself.In this review,we address the neurogenetic basis of neurodevelopmental disorders,genetic tools that are enabling precision research of these disorders in animal models,and postnatal gene-therapy approaches for neurodevelopmental disorders derived from preclinical studies in the laboratory.
文摘Preclinical studies have indicated that the combination of mTORC1/2 inhibitors with PD-1 antibodies exhibits synergistic effects on solid tumors.However,no clinical data supporting this combination have been reported.Therefore,we conducted a clinical trial(NCT 04337463)to investigate the efficacy and safety of combining onatasertib,an mTORC1/2 inhibitor,with toripalimab,a PD-1 antibody in patients with advanced solid tumors.This open-label,phase 1/2 clinical trial included dose escalation and dose expansion cohorts to evaluate safety,tolerability,objective response rate(ORR),disease control rate(DCR)and progression-free survival(PFS).A total of 46 patients were enrolled and received onatasertib at doses of 15 mg,20 mg,or 30 mg once daily(QD),combined with toripalimab 240 mg every 3 weeks(Q3W).No dose-limiting toxicities were observed,and the most common grade 3 or 4 treatment emergent adverse events were lymphopenia(23.9%)and rash(19.6%).The overall ORR was 26.1%,with a DCR of 73.9%,and a median PFS of 4.3 months.In cervical cancer patients,regardless of PD-L1 expression,the ORR was 52.4%,DCR was 90.5%and median PFS was 5.8 months.Notably,the 15 mg combination dose demonstrated a median PFS of 7.8 months.In conclusion,the safety profile of onatasertib in combination with toripalimab was manageable and showed encouraging clinical activity in advanced solid tumors,particularly among cervical cancer patients,irrespective of PD-L1 expression.The recommended phase 2 dose for the combination was determined to be onatasertib 15 mg QD and toripalimab 240 mg Q3W.
基金supported by the National Natural Science Foundation of China(82371339 and U1704166)the Key Scientific Research Projects of Higher Education Institutions in Henan Province(24A320029).
文摘Central poststroke pain(CPSP)is a medical complication that arises poststroke and significantly impacts the quality of life and social functioning of affected individuals.Despite ongoing research,the exact pathomechanisms of CPSP remain unclear,and practical treatments are still unavailable.Our review aims to systematically analyse current clinical and preclinical studies on CPSP,which is critical for identifying gaps in knowledge and guiding the development of effective therapies.The review will clarify the clinical characteristics,evaluation scales and contemporary therapeutic approaches for CPSP based on clinical investigations.It will particularly emphasise the CPSP model initiated by stroke,shedding light on its underlying mechanisms and evaluating treatments validated in preclinical studies.Furthermore,the review will not only highlight methodological limitations in animal trials but also offer specific recommendations to researchers to improve the quality of future investigations and guide the development of effective therapies.This review is expected to provide valuable insights into the current knowledge regarding CPSP and can serve as a guide for future research and clinical practice.The review will contribute to the scientific understanding of CPSP and help develop effective clinical interventions.
基金the National Natural Science Foundation of China(Grant numbers 91859207 and 81771873)the Science and Technology Innovation Team Talent Project of Hunan Province(Grant number 2021RC4056)+2 种基金the Natural Science Foundation of Hunan Province(Grant number 2023JJ30976)the National Natural Science Foundation of China(Grant number 82372003)the Postdoctoral Fellowship Program of CPSF(Grant number GZC20233586).
文摘While the expression of programmed death ligand-1(PD-L1)is associated with response to immune therapy,PD-L1-negative patients may still benefit from immune treatment.Programmed death ligand-2(PD-L2),another crucial immune checkpoint molecule interacting with PD-1,correlates with the efficacy of various tumor immune therapies.This study investigates the expression of PD-L2 in non-small cell lung cancer(NSCLC)patients following anti-PD-1 therapy and its predictive value for clinical survival outcomes.Additionally,we explore the noninvasive,real-time,and dynamic quantitative analysis potential of PD-L2 positron emission tomography(PET)imaging in transplanted tumors.We utilized[^(68)Ga]Ga-labeled peptide HN11-1 for PD-L2 PET imaging.The results indicate a higher response rate to anti-PD-1 therapy in patients positive for both PD-L1 and PD-L2,with PD-L2 status independently predicting progression-free survival(PFS)with pembrolizumab treatment.Furthermore,[^(68)Ga]Ga-HN11-1 PET imaging demonstrates specificity in assessing PD-L2 status.Overall,we confirm the correlation between high PD-L2 expression and favorable PFS in NSCLC patients post anti-PD-1 therapy and highlight the promising potential of[^(68)Ga]Ga-HN11-1 as a specific tracer for PD-L2 in preclinical and initial human trials.
基金supported by grants from the National Natural Science Foundation of China(No.82272261)Shanxi Province Foundation of China(No.2022JC-58,No.2021SF-341).
文摘Background:Wound healing has always been a serious issue for doctors and primary health care systems.In addition,adipose stem cell-derived exosomes have been proven to play a positive and effective role in tissue repair and regeneration.A systematic review of these preclinical studies was performed to assess the efficacy of adipose stem cell-derived exosomes(ADSC-Exos)in treating wounds.This article aimed to study the effectiveness of ADSC-Exos for the treatment of animal skin wounds and includes a meta-analysis of exosomes from general wounds and diabetic ulcer wounds in in vitro models of animals to provide a theoretical basis for clinical translation.Methods:A total of 19 studies with 356 animals were identified by searching the PubMed,Cochrane,MEDLINE Complete,Web of Science,CNKI and Wanfang databases from inception to 15 November 2022.No language or time restrictions were applied.Stata17 was used for all the data analyses.Results:The meta-analysis showed that ADSC-Exo therapy significantly improved the wound healing rate in the control group,except in the diabetes group on day 7.Day 7 of general wounds[standard mean difference(SMD)2.87,95%confidence interval(CI 1.91-3.83)]and day 14(SMD 2.89,95%CI 1.47-4.30).Day 14(SMD 3.43,95%CI 1.28-5.58)of diabetic wounds.Other outcomes,such as blood vessel density,collagen deposition and wound re-epithelization,improved with the administration of ADSC-Exos.Conclusions:A meta-analysis showed that ADSC-Exo therapy applied to general and diabetic wounds can promote neovascularization,improve epithelization and collagen fiber deposition,promote healing,and reduce scar formation.ADSC-Exos have broad potential in preclinical research and clinical fields.
