The pandemic SARS-CoV-2 has become an undying virus to spread a sustainable disease named COVID-19 for upcoming few years.Mortality rates are rising rapidly as approved drugs are not yet available.Isolation from the i...The pandemic SARS-CoV-2 has become an undying virus to spread a sustainable disease named COVID-19 for upcoming few years.Mortality rates are rising rapidly as approved drugs are not yet available.Isolation from the infected person or community is the preferred choice to protect our health.Since humans are the only carriers,it might be possible to control the positive rate if the infected population or host carriers are isolated from each other.Isolation alone may not be a proper solution.These are the resolutions of previous research work carried out on COVID-19 throughout the world.The present scenario of the world and public health is knocking hard with a big question of critical uncertainty of COVID-19 because of its imprecise database as per daily positive cases recorded all over the world and in India as well.In this research work,we have pre-sented an optimal control model for COVID-19 using granular differentiability based on fuzzy dynamical systems.In the first step,we created a fuzzy Susceptible-Exposed-Infected-Asymptomatic-Hospitalized-Recovered-Death(SEIAHRD)model for COVID-19,analyzed it using granular differentiability,and reported disease dynamics for time-independent disease control parameters.In the second step,we upgraded the fuzzy dynamical system and granular differentiability model related to time-dependent disease control parameters as an optimal control problem invader.Theoretical studies have been validated with some practical data from the epidemic COVID-19 related to the Indian perspective during first wave and early second wave.展开更多
Let X be a real uniformly convex and uniformly smooth Banach space and C a nonempty closed and convex subset of X.Let Π_(C):X→C denote the generalized metric projection operator introduced by Alber in[1].In this pap...Let X be a real uniformly convex and uniformly smooth Banach space and C a nonempty closed and convex subset of X.Let Π_(C):X→C denote the generalized metric projection operator introduced by Alber in[1].In this paper,we define the Gâteaux directional differentiability of Π_(C).We investigate some properties of the Gâteaux directional differentiability of Π_(C).In particular,if C is a closed ball,or a closed and convex cone(including proper closed subspaces),or a closed and convex cylinder,then,we give the exact representations of the directional derivatives of Π_(C).By comparing the results in[12]and this paper,we see the significant difference between the directional derivatives of the generalized metric projection operator Π_(C) and the Gâteaux directional derivatives of the standard metric projection operator PC.展开更多
This paper considers the differentiability of C 0 semigroups with respect to (w.r.t.) parameters contained in their infinitesimal generators.It is proved that the generalized continuity and strong differentiability ...This paper considers the differentiability of C 0 semigroups with respect to (w.r.t.) parameters contained in their infinitesimal generators.It is proved that the generalized continuity and strong differentiability of their infinitesimal generators w.r.t.parameters imply the differentiability of the C 0 semigroups.The results are applied to the differentiability of the solution of a linear delay differential equation w.r.t.its delays.展开更多
This paper deals with Mckean-Vlasov backward stochastic differential equations with weak monotonicity coefficients.We first establish the existence and uniqueness of solutions to Mckean-Vlasov backward stochastic diff...This paper deals with Mckean-Vlasov backward stochastic differential equations with weak monotonicity coefficients.We first establish the existence and uniqueness of solutions to Mckean-Vlasov backward stochastic differential equations.Then we obtain a comparison theorem in one-dimensional situation.展开更多
背景:非创伤性股骨头坏死的发病机制尚不明确,其中血脂代谢紊乱是引起非创伤性股骨头坏死的重要假说,通过调节血脂代谢来抑制股骨头坏死的进展,已成为当前治疗非创伤性股骨头坏死的重要方法。目的:综述非创伤性股骨头坏死与脂质代谢紊...背景:非创伤性股骨头坏死的发病机制尚不明确,其中血脂代谢紊乱是引起非创伤性股骨头坏死的重要假说,通过调节血脂代谢来抑制股骨头坏死的进展,已成为当前治疗非创伤性股骨头坏死的重要方法。目的:综述非创伤性股骨头坏死与脂质代谢紊乱的关系及治疗研究进展。方法:以“股骨头坏死,非创伤性股骨头坏死,骨坏死,骨与脂质代谢,股骨头坏死与脂质,股骨头坏死机制,股骨头坏死通路,股骨头坏死治疗”为中文检索词,以“osteonecrosis of femoral head,Nontraumatic osteonecrosis of femoral head,femoral head necrosis,osteonecrosis and lipid,lipid metabolism osteonecrosis,polymorphisms osteonecrosis of femoral head,pathway osteonecrosis of femoral head,steroid-induced osteonecrosis of the femoral head,alcohol-induced osteonecrosis of femoral head”为英文检索词,检索中国知网、万方医学网、中华医学期刊数据库、PubMed数据库,最终纳入104篇文献进行归纳总结。结果与结论:①股骨头坏死患者常伴随血脂异常,研究发现总胆固醇、三酰甘油、低密度脂蛋白胆固醇、载脂蛋白B水平升高与载脂蛋白A1水平降低是引起股骨头坏死的危险因素,并且不同诱因的股骨头坏死患者血脂水平存在差异;②激素和酒精作为非创伤性股骨头坏死的两大诱因,可以诱导骨髓间充质干细胞的成脂分化,使骨髓腔内脂肪细胞增多、脂滴聚集,最终导致股骨头坏死;③许多与脂质代谢相关的分子和脂肪因子,如脂联素、瘦素、脂质运载蛋白2等都被证实与股骨头坏死有关;④过氧化物酶体增殖物激活受体γ、Wnt/β-catenin、腺苷酸环化蛋白激酶等信号通路可以改变骨髓间充质干细胞的成骨-成脂分化潜能,从而参与股骨头坏死的发生发展;磷脂酰肌醇3激酶/蛋白激酶B、骨形态发生蛋白2等脂代谢信号通路也与股骨头坏死有关,可能通过调节脂质代谢影响股骨头坏死的进展;⑤研究发现,虫草素、三七总皂苷、骨蚀灵胶囊等中药和他汀类药物可以通过改善脂质代谢紊乱达到治疗非创伤性股骨头坏死的效果。展开更多
Stem cell proliferation is tightly regulated in developing and adult tissues through the coordinated action of cell-intrinsic and extracellular signals.Although many extracellular cues were identified,the cell-intrins...Stem cell proliferation is tightly regulated in developing and adult tissues through the coordinated action of cell-intrinsic and extracellular signals.Although many extracellular cues were identified,the cell-intrinsic mechanisms underlying the decision of a stem cell to proliferate,enter a dormant quiescent state or differentiate into a specific cell type remains incompletely understood.展开更多
BACKGROUND The treatment technology of liver cancer is progressing.In addition to traditional surgical resection,combined therapies of immunotherapy based on immune checkpoint inhibitors,chemotherapy,and transcatheter...BACKGROUND The treatment technology of liver cancer is progressing.In addition to traditional surgical resection,combined therapies of immunotherapy based on immune checkpoint inhibitors,chemotherapy,and transcatheter arterial chemoembolization for hepatocellular carcinoma are more and more widely used.Accurate preoperative diagnosis of liver cancer will provide important information for comprehensive treatment and prognosis evaluation of liver cancer.Sonazoidcontrast-enhanced ultrasound is not only helpful for the qualitative diagnosis of liver lesions,but also has great potential in the diagnosis of histological differentiation of liver cancer.AIM To assess the differentiation of hepatocellular carcinoma(HCC)by utilizing the parameters and imaging features of Sonazoid-contrast-enhanced ultrasound(CEUS).METHODS A retrospective analysis was conducted on the CEUS data of 239 lesions through case-control study.These patients received Sonazoid-CEUS within one week before surgery and were confirmed as HCC by postoperative pathology.Within the cases,patients were further categorized into well-differentiated and poorlydifferentiated group.Time-intensity curves of the region of interest in both arterial and Kupffer phases were generated,allowing for the acquisition of quantitative parameters to assess the diagnostic efficacy in distinguishing lesions between these two groups and determining an appropriate cut-off value.RESULTS Univariate analysis showed that the absolute value of enhancement intensity(EIAV),intensity ratio(IR)and intensity difference(ID)in Kupffer phase were statistically different between the groups with different degree(P=0.015,P=0.000,P=0.000).The sensitivity and specificity were 40.2%,82.4%,80.4% and 78.1%,86.9% and 74.5%,respectively,for differentiating HCC lesions with EIAV≥56.384 dB,IR≥1.215 and ID≥9.184 dB.The area under the receiver operating characteristic curve were 0.590,0.877,0.815.There was no significant difference in the parameters of arterial phase,including peak time,initial growth time,rise time and the absolute value of peak intensity of lesions between the two groups(P>0.05).Multivariate analysis showed that the level of alphafetoprotein(AFP)and IR were risk factors for poor differentiation(P=0.001).CONCLUSION Among the parameters of Sonazoid-CEUS,IR in Kupffer phase exhibits superior diagnostic efficacy with high sensitivity and specificity in the diagnose of pathological differentiation of HCC.Combined with preoperative AFP level,a more accurate diagnosis will be obtained.Compared with portal vein phase,Kupffer phase showed the ability to identify HCC lesions more sensitive.These findings hold significant guiding implications and reference value for clinical practice.展开更多
BACKGROUND Mesenchymal stem cells(MSCs)are considered a promising therapy for various diseases due to their strong potential in regenerative medicine and immunomodulation.The tissue source of MSCs has gained attention...BACKGROUND Mesenchymal stem cells(MSCs)are considered a promising therapy for various diseases due to their strong potential in regenerative medicine and immunomodulation.The tissue source of MSCs has gained attention for its role in influencing their function,accessibility,and readiness for clinical use.AIM To identify the most suitable adipose source for MSC isolation and expansion for further applications.METHODS We isolated MSCs from solid adipose tissue and liposuction aspirates using the enzyme method.The MSCs were examined for their expansion using population doubling time,differentiation capacity using multilineage differentiation induction,surface markers using flow cytometry,and stability of chromosomes using the karyotyping method.Growth factors and cytokines in MSC-conditioned media were analyzed using the Luminex assay.RESULTS MSCs were isolated from solid adipose tissue and lipoaspirates and expanded from passage 0 to passage 2.All adipose-derived MSCs(AD-MSCs)exhibited the typical elongated,spindle-shaped morphology and comparable proliferation rate.They expressed positive surface markers(cluster of differentiation 73[CD73]:>97%,CD90:>98%,and CD105:>95%),and negative markers(<1%).All MSCs expressed similar levels of stemness genes(octamer-binding transcription factor 4,SRY-box 2,Krüppel-like factor,and MYC),colonyforming,and trilineage differentiation potential.Karyotyping analysis revealed normal chromosomal patterns in all samples,except one sample exhibiting a polymorphism(1qh+).Furthermore,the growth factors and cytokines of hepatocyte growth factor,vascular endothelial growth factor A,interleukin 6(IL-6),and IL-8 were detected in all AD-MSC conditioned media;but fibroblast growth factor-2 and keratinocyte growth factor were selectively expressed in conditioned media from solid or lipoaspirate AD-MSCs,respectively.CONCLUSION These findings indicate that AD-MSCs from both adipose sources possess all of the characteristic features of MSCs with source-specific secretome differences,which are suitable for further expansion and various clinical applications.展开更多
BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese med...BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.展开更多
Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplanta...Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplantation of retinal progenitor cells alone.Bone marrow mesenchymal stem cells regulate and interact with various cells in the retinal microenvironment by secreting neurotrophic factors and extracellular vesicles.Small extracellular vesicles derived from bone marrow mesenchymal stem cells,which offer low immunogenicity,minimal tumorigenic risk,and ease of transportation,have been utilized in the treatment of various neurological diseases.These vesicles exhibit various activities,including anti-inflammatory actions,promotion of tissue repair,and immune regulation.Therefore,novel strategies using human retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles may represent an innovation in stem cell therapy for retinal degeneration.In this study,we developed such an approach utilizing retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles to treat retinal degeneration in Royal College of Surgeons rats,a genetic model of retinal degeneration.Our findings revealed that the combination of bone marrow mesenchymal stem cell-derived small extracellular vesicles and retinal progenitor cells significantly improved visual function in these rats.The addition of bone marrow mesenchymal stem cell-derived small extracellular vesicles as adjuvants to stem cell transplantation with retinal progenitor cells enhanced the survival,migration,and differentiation of the exogenous retinal progenitor cells.Concurrently,these small extracellular vesicles inhibited the activation of regional microglia,promoted the migration of transplanted retinal progenitor cells to the inner nuclear layer of the retina,and facilitated their differentiation into photoreceptors and bipolar cells.These findings suggest that bone marrow mesenchymal stem cell-derived small extracellular vesicles potentiate the therapeutic efficacy of retinal progenitor cells in retinal degeneration by promoting their survival and differentiation.展开更多
The NSC-34 cell line is a widely recognized motor neuron model and various neuronal differentiation protocols have been exploited. Under previously reported experimental conditions, only part of the cells resemble dif...The NSC-34 cell line is a widely recognized motor neuron model and various neuronal differentiation protocols have been exploited. Under previously reported experimental conditions, only part of the cells resemble differentiated neurons;however, they do not exhibit extensive and time-prolonged neuritogenesis, and maintain their duplication capacity in culture. The aim of the present work was to facilitate long-term and more homogeneous neuronal differentiation in motor neuron–like NSC-34 cells. We found that the antimitotic drug cytosine arabinoside promoted robust and persistent neuronal differentiation in the entire cell population. Long and interconnecting neuronal processes with abundant growth cones were homogeneously induced and were durable for up to at least 6 weeks in culture. Moreover, cytosine arabinoside was permissive, dispensable, and mostly irreversible in priming NSC-34 cells for neurite initiation and regeneration after mechanical dislodgement. Finally, the expression of the cell proliferation antigen Ki67 was inhibited by cytosine arabinoside, whereas the expression levels of neuronal growth associated protein 43, vimentin, and motor neuron–specific p75, Islet2, homeobox 9 markers were upregulated, as confirmed by western blot and/or confocal immunofluorescence analysis. Overall, these findings support the use of NSC-34 cells as a motor neuron model for properly investigating neurodegenerative mechanisms and prospectively identifying neuroprotective strategies.展开更多
文摘The pandemic SARS-CoV-2 has become an undying virus to spread a sustainable disease named COVID-19 for upcoming few years.Mortality rates are rising rapidly as approved drugs are not yet available.Isolation from the infected person or community is the preferred choice to protect our health.Since humans are the only carriers,it might be possible to control the positive rate if the infected population or host carriers are isolated from each other.Isolation alone may not be a proper solution.These are the resolutions of previous research work carried out on COVID-19 throughout the world.The present scenario of the world and public health is knocking hard with a big question of critical uncertainty of COVID-19 because of its imprecise database as per daily positive cases recorded all over the world and in India as well.In this research work,we have pre-sented an optimal control model for COVID-19 using granular differentiability based on fuzzy dynamical systems.In the first step,we created a fuzzy Susceptible-Exposed-Infected-Asymptomatic-Hospitalized-Recovered-Death(SEIAHRD)model for COVID-19,analyzed it using granular differentiability,and reported disease dynamics for time-independent disease control parameters.In the second step,we upgraded the fuzzy dynamical system and granular differentiability model related to time-dependent disease control parameters as an optimal control problem invader.Theoretical studies have been validated with some practical data from the epidemic COVID-19 related to the Indian perspective during first wave and early second wave.
文摘Let X be a real uniformly convex and uniformly smooth Banach space and C a nonempty closed and convex subset of X.Let Π_(C):X→C denote the generalized metric projection operator introduced by Alber in[1].In this paper,we define the Gâteaux directional differentiability of Π_(C).We investigate some properties of the Gâteaux directional differentiability of Π_(C).In particular,if C is a closed ball,or a closed and convex cone(including proper closed subspaces),or a closed and convex cylinder,then,we give the exact representations of the directional derivatives of Π_(C).By comparing the results in[12]and this paper,we see the significant difference between the directional derivatives of the generalized metric projection operator Π_(C) and the Gâteaux directional derivatives of the standard metric projection operator PC.
文摘This paper considers the differentiability of C 0 semigroups with respect to (w.r.t.) parameters contained in their infinitesimal generators.It is proved that the generalized continuity and strong differentiability of their infinitesimal generators w.r.t.parameters imply the differentiability of the C 0 semigroups.The results are applied to the differentiability of the solution of a linear delay differential equation w.r.t.its delays.
基金Supported by the National Natural Science Foundation of China(12001074)the Research Innovation Program of Graduate Students in Hunan Province(CX20220258)+1 种基金the Research Innovation Program of Graduate Students of Central South University(1053320214147)the Key Scientific Research Project of Higher Education Institutions in Henan Province(25B110025)。
文摘This paper deals with Mckean-Vlasov backward stochastic differential equations with weak monotonicity coefficients.We first establish the existence and uniqueness of solutions to Mckean-Vlasov backward stochastic differential equations.Then we obtain a comparison theorem in one-dimensional situation.
文摘背景:非创伤性股骨头坏死的发病机制尚不明确,其中血脂代谢紊乱是引起非创伤性股骨头坏死的重要假说,通过调节血脂代谢来抑制股骨头坏死的进展,已成为当前治疗非创伤性股骨头坏死的重要方法。目的:综述非创伤性股骨头坏死与脂质代谢紊乱的关系及治疗研究进展。方法:以“股骨头坏死,非创伤性股骨头坏死,骨坏死,骨与脂质代谢,股骨头坏死与脂质,股骨头坏死机制,股骨头坏死通路,股骨头坏死治疗”为中文检索词,以“osteonecrosis of femoral head,Nontraumatic osteonecrosis of femoral head,femoral head necrosis,osteonecrosis and lipid,lipid metabolism osteonecrosis,polymorphisms osteonecrosis of femoral head,pathway osteonecrosis of femoral head,steroid-induced osteonecrosis of the femoral head,alcohol-induced osteonecrosis of femoral head”为英文检索词,检索中国知网、万方医学网、中华医学期刊数据库、PubMed数据库,最终纳入104篇文献进行归纳总结。结果与结论:①股骨头坏死患者常伴随血脂异常,研究发现总胆固醇、三酰甘油、低密度脂蛋白胆固醇、载脂蛋白B水平升高与载脂蛋白A1水平降低是引起股骨头坏死的危险因素,并且不同诱因的股骨头坏死患者血脂水平存在差异;②激素和酒精作为非创伤性股骨头坏死的两大诱因,可以诱导骨髓间充质干细胞的成脂分化,使骨髓腔内脂肪细胞增多、脂滴聚集,最终导致股骨头坏死;③许多与脂质代谢相关的分子和脂肪因子,如脂联素、瘦素、脂质运载蛋白2等都被证实与股骨头坏死有关;④过氧化物酶体增殖物激活受体γ、Wnt/β-catenin、腺苷酸环化蛋白激酶等信号通路可以改变骨髓间充质干细胞的成骨-成脂分化潜能,从而参与股骨头坏死的发生发展;磷脂酰肌醇3激酶/蛋白激酶B、骨形态发生蛋白2等脂代谢信号通路也与股骨头坏死有关,可能通过调节脂质代谢影响股骨头坏死的进展;⑤研究发现,虫草素、三七总皂苷、骨蚀灵胶囊等中药和他汀类药物可以通过改善脂质代谢紊乱达到治疗非创伤性股骨头坏死的效果。
基金supported by the Argentine Agency for the Promotion of Science and Technology ANPCyT(PICT2019-1472 to GP,PICT2019-4597 to FL,PICT2020-1524 to GP,and PICT2021-00627 to FL)supported by an Independent Career Position from CONICETsupported by a postdoctoral fellowship from ANPCyT。
文摘Stem cell proliferation is tightly regulated in developing and adult tissues through the coordinated action of cell-intrinsic and extracellular signals.Although many extracellular cues were identified,the cell-intrinsic mechanisms underlying the decision of a stem cell to proliferate,enter a dormant quiescent state or differentiate into a specific cell type remains incompletely understood.
文摘BACKGROUND The treatment technology of liver cancer is progressing.In addition to traditional surgical resection,combined therapies of immunotherapy based on immune checkpoint inhibitors,chemotherapy,and transcatheter arterial chemoembolization for hepatocellular carcinoma are more and more widely used.Accurate preoperative diagnosis of liver cancer will provide important information for comprehensive treatment and prognosis evaluation of liver cancer.Sonazoidcontrast-enhanced ultrasound is not only helpful for the qualitative diagnosis of liver lesions,but also has great potential in the diagnosis of histological differentiation of liver cancer.AIM To assess the differentiation of hepatocellular carcinoma(HCC)by utilizing the parameters and imaging features of Sonazoid-contrast-enhanced ultrasound(CEUS).METHODS A retrospective analysis was conducted on the CEUS data of 239 lesions through case-control study.These patients received Sonazoid-CEUS within one week before surgery and were confirmed as HCC by postoperative pathology.Within the cases,patients were further categorized into well-differentiated and poorlydifferentiated group.Time-intensity curves of the region of interest in both arterial and Kupffer phases were generated,allowing for the acquisition of quantitative parameters to assess the diagnostic efficacy in distinguishing lesions between these two groups and determining an appropriate cut-off value.RESULTS Univariate analysis showed that the absolute value of enhancement intensity(EIAV),intensity ratio(IR)and intensity difference(ID)in Kupffer phase were statistically different between the groups with different degree(P=0.015,P=0.000,P=0.000).The sensitivity and specificity were 40.2%,82.4%,80.4% and 78.1%,86.9% and 74.5%,respectively,for differentiating HCC lesions with EIAV≥56.384 dB,IR≥1.215 and ID≥9.184 dB.The area under the receiver operating characteristic curve were 0.590,0.877,0.815.There was no significant difference in the parameters of arterial phase,including peak time,initial growth time,rise time and the absolute value of peak intensity of lesions between the two groups(P>0.05).Multivariate analysis showed that the level of alphafetoprotein(AFP)and IR were risk factors for poor differentiation(P=0.001).CONCLUSION Among the parameters of Sonazoid-CEUS,IR in Kupffer phase exhibits superior diagnostic efficacy with high sensitivity and specificity in the diagnose of pathological differentiation of HCC.Combined with preoperative AFP level,a more accurate diagnosis will be obtained.Compared with portal vein phase,Kupffer phase showed the ability to identify HCC lesions more sensitive.These findings hold significant guiding implications and reference value for clinical practice.
文摘BACKGROUND Mesenchymal stem cells(MSCs)are considered a promising therapy for various diseases due to their strong potential in regenerative medicine and immunomodulation.The tissue source of MSCs has gained attention for its role in influencing their function,accessibility,and readiness for clinical use.AIM To identify the most suitable adipose source for MSC isolation and expansion for further applications.METHODS We isolated MSCs from solid adipose tissue and liposuction aspirates using the enzyme method.The MSCs were examined for their expansion using population doubling time,differentiation capacity using multilineage differentiation induction,surface markers using flow cytometry,and stability of chromosomes using the karyotyping method.Growth factors and cytokines in MSC-conditioned media were analyzed using the Luminex assay.RESULTS MSCs were isolated from solid adipose tissue and lipoaspirates and expanded from passage 0 to passage 2.All adipose-derived MSCs(AD-MSCs)exhibited the typical elongated,spindle-shaped morphology and comparable proliferation rate.They expressed positive surface markers(cluster of differentiation 73[CD73]:>97%,CD90:>98%,and CD105:>95%),and negative markers(<1%).All MSCs expressed similar levels of stemness genes(octamer-binding transcription factor 4,SRY-box 2,Krüppel-like factor,and MYC),colonyforming,and trilineage differentiation potential.Karyotyping analysis revealed normal chromosomal patterns in all samples,except one sample exhibiting a polymorphism(1qh+).Furthermore,the growth factors and cytokines of hepatocyte growth factor,vascular endothelial growth factor A,interleukin 6(IL-6),and IL-8 were detected in all AD-MSC conditioned media;but fibroblast growth factor-2 and keratinocyte growth factor were selectively expressed in conditioned media from solid or lipoaspirate AD-MSCs,respectively.CONCLUSION These findings indicate that AD-MSCs from both adipose sources possess all of the characteristic features of MSCs with source-specific secretome differences,which are suitable for further expansion and various clinical applications.
基金Supported by the Provincial Key Cultivation Laboratory for Digestive Disease Research,No.2021SYS13Shanxi Province’s“Si Ge Yi Pi”Science and Technology Driven Medical Innovation Project,No.2021MX03Shanxi Provincial Basic Research Program,No.202403021222423.
文摘BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.
基金supported by the National Natural Science Foundation of China,Nos.82271132(to YL),82101167(to BB)the Natural Science Foundation of Chongqing,Nos.CSTB2022NSCQ-MSX0020(to BB),cstc2019jcyj-msxmX0473(to FC).
文摘Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplantation of retinal progenitor cells alone.Bone marrow mesenchymal stem cells regulate and interact with various cells in the retinal microenvironment by secreting neurotrophic factors and extracellular vesicles.Small extracellular vesicles derived from bone marrow mesenchymal stem cells,which offer low immunogenicity,minimal tumorigenic risk,and ease of transportation,have been utilized in the treatment of various neurological diseases.These vesicles exhibit various activities,including anti-inflammatory actions,promotion of tissue repair,and immune regulation.Therefore,novel strategies using human retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles may represent an innovation in stem cell therapy for retinal degeneration.In this study,we developed such an approach utilizing retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles to treat retinal degeneration in Royal College of Surgeons rats,a genetic model of retinal degeneration.Our findings revealed that the combination of bone marrow mesenchymal stem cell-derived small extracellular vesicles and retinal progenitor cells significantly improved visual function in these rats.The addition of bone marrow mesenchymal stem cell-derived small extracellular vesicles as adjuvants to stem cell transplantation with retinal progenitor cells enhanced the survival,migration,and differentiation of the exogenous retinal progenitor cells.Concurrently,these small extracellular vesicles inhibited the activation of regional microglia,promoted the migration of transplanted retinal progenitor cells to the inner nuclear layer of the retina,and facilitated their differentiation into photoreceptors and bipolar cells.These findings suggest that bone marrow mesenchymal stem cell-derived small extracellular vesicles potentiate the therapeutic efficacy of retinal progenitor cells in retinal degeneration by promoting their survival and differentiation.
基金supported by FATALSDrug Project [Progetti di Ricerca@CNR SAC.AD002.173.058] from National Research Council,Italy (to CV)。
文摘The NSC-34 cell line is a widely recognized motor neuron model and various neuronal differentiation protocols have been exploited. Under previously reported experimental conditions, only part of the cells resemble differentiated neurons;however, they do not exhibit extensive and time-prolonged neuritogenesis, and maintain their duplication capacity in culture. The aim of the present work was to facilitate long-term and more homogeneous neuronal differentiation in motor neuron–like NSC-34 cells. We found that the antimitotic drug cytosine arabinoside promoted robust and persistent neuronal differentiation in the entire cell population. Long and interconnecting neuronal processes with abundant growth cones were homogeneously induced and were durable for up to at least 6 weeks in culture. Moreover, cytosine arabinoside was permissive, dispensable, and mostly irreversible in priming NSC-34 cells for neurite initiation and regeneration after mechanical dislodgement. Finally, the expression of the cell proliferation antigen Ki67 was inhibited by cytosine arabinoside, whereas the expression levels of neuronal growth associated protein 43, vimentin, and motor neuron–specific p75, Islet2, homeobox 9 markers were upregulated, as confirmed by western blot and/or confocal immunofluorescence analysis. Overall, these findings support the use of NSC-34 cells as a motor neuron model for properly investigating neurodegenerative mechanisms and prospectively identifying neuroprotective strategies.
