Secretome of Hypoxia-Preconditioned Mesenchymal Stem Cells Ameliorates Hyperglycemia in Type 2 Diabetes Mellitus Rats Widyaningsih, Wita Widyaningsih In: 2024. @article{noKey,
title = {Secretome of Hypoxia-Preconditioned Mesenchymal Stem Cells Ameliorates Hyperglycemia in Type 2 Diabetes Mellitus Rats},
author = {Widyaningsih, Wita Widyaningsih},
url = {https://tis.wu.ac.th/index.php/tis/article/view/7278},
doi = {https://doi.org/10.48048/tis.2024.7278},
year = {2024},
date = {2024-03-01},
abstract = {Introduction: Type 2 diabetes mellitus (T2DM) is a prevalent form of diabetes that affects 90 - 95 % of all diabetic patients. Insulin sensitizers and insulin exogenous supply could temporarily ameliorate hyperglycaemia; however, they are accompanied by side effects. As a result, new approaches are required to address insulin resistance and regenerate beta cells simultaneously. The secretome of hypoxic mesenchymal stem cells (SH-MSCs) contains various growth factors and anti-inflammatory cytokines that could potentially enhance insulin resistance and improve pancreatic function. Objectives: In this study, we performed SH-MSCs infusion to ameliorate HFD-induced hyperglycaemia in T2DM rats. Methods: We created a T2DM rat model using a combination of a high-fat diet (HFD) and streptozotocin (STZ) administration. Then, we administered SH-MSCs injection at doses of 250 and 500 µL and assessed the therapeutic effects of SH-MSCs. We also investigated the potential underlying mechanisms involved. Results: The administration of SH-MSCs improved hyperglycemia in rats with T2DM. Infusion of SH-MSCs at 500 µL dose decreased homeostatic model assessment for insulin resistance (HOMA-IR). Histological analysis revealed that injection of SH-MSCs alleviated morphological damage of pancreas. SH-MSCs administration also inhibit the level of IL-6 and promote the expression of CD163 type 2 macrophage. Conclusion: The results of our study indicate that SH-MSCs have the potential to improve hyperglycemia and exert a protective effect on T2DM rats.},
keywords = {µPULSE},
pubstate = {published},
tppubtype = {article}
}
Introduction: Type 2 diabetes mellitus (T2DM) is a prevalent form of diabetes that affects 90 - 95 % of all diabetic patients. Insulin sensitizers and insulin exogenous supply could temporarily ameliorate hyperglycaemia; however, they are accompanied by side effects. As a result, new approaches are required to address insulin resistance and regenerate beta cells simultaneously. The secretome of hypoxic mesenchymal stem cells (SH-MSCs) contains various growth factors and anti-inflammatory cytokines that could potentially enhance insulin resistance and improve pancreatic function. Objectives: In this study, we performed SH-MSCs infusion to ameliorate HFD-induced hyperglycaemia in T2DM rats. Methods: We created a T2DM rat model using a combination of a high-fat diet (HFD) and streptozotocin (STZ) administration. Then, we administered SH-MSCs injection at doses of 250 and 500 µL and assessed the therapeutic effects of SH-MSCs. We also investigated the potential underlying mechanisms involved. Results: The administration of SH-MSCs improved hyperglycemia in rats with T2DM. Infusion of SH-MSCs at 500 µL dose decreased homeostatic model assessment for insulin resistance (HOMA-IR). Histological analysis revealed that injection of SH-MSCs alleviated morphological damage of pancreas. SH-MSCs administration also inhibit the level of IL-6 and promote the expression of CD163 type 2 macrophage. Conclusion: The results of our study indicate that SH-MSCs have the potential to improve hyperglycemia and exert a protective effect on T2DM rats. |
Combination Effect of Rotator Cuff Repair with Secretome-hypoxia MSCs Ameliorates TNMD, RUNX2, and Healing Histology Score in Rotator Cuff Tear Rats Fredianto et al., Meiky In: 2023. @article{noKey,
title = {Combination Effect of Rotator Cuff Repair with Secretome-hypoxia MSCs Ameliorates TNMD, RUNX2, and Healing Histology Score in Rotator Cuff Tear Rats},
author = {Fredianto et al., Meiky},
url = {https://abjs.mums.ac.ir/article_22788_fc78bb4038b5420a87712ecd4c664e9e.pdf},
doi = {10.22038/ABJS.2023.67933.3218},
year = {2023},
date = {2023-10-10},
abstract = {Objectives: In order to treat a rat model of rotator cuff rupture, this work concentrated on the expression
of TNMD and RUNX2, followed by rotator cuff repair and secretome-hMSCs.
Methods: A total of thirty 10-weeks-old male Sprague–Dawley rats were separated into five groups randomly, RC
on week 0, lesion treated with a rotator cuff repair and saline (RC + NaCl group, n = 6) for 2 and 8 weeks, and lesion
treated with a rotator cuff repair and secretome-hMSCs (RC + secretome-hMSC group, n = 6) for 2 and 8 weeks.
The supraspinatus and infraspinatus muscle–tendon units were obtained for histological and biomechanical
investigation at 0, 2 and 8 weeks following injury.
Results: The findings showed that, in comparison with the RC + NaCl group, secretome-hMSCs significantly
improved tendon repair by upregulating TNMD and RUNX2 expression and histology score.
Conclusion: Combining Secretome-hypoxia MSCs with RC healing may help rats with rotator cuff tears.
Level of evidence: IV},
keywords = {µPULSE},
pubstate = {published},
tppubtype = {article}
}
Objectives: In order to treat a rat model of rotator cuff rupture, this work concentrated on the expression
of TNMD and RUNX2, followed by rotator cuff repair and secretome-hMSCs.
Methods: A total of thirty 10-weeks-old male Sprague–Dawley rats were separated into five groups randomly, RC
on week 0, lesion treated with a rotator cuff repair and saline (RC + NaCl group, n = 6) for 2 and 8 weeks, and lesion
treated with a rotator cuff repair and secretome-hMSCs (RC + secretome-hMSC group, n = 6) for 2 and 8 weeks.
The supraspinatus and infraspinatus muscle–tendon units were obtained for histological and biomechanical
investigation at 0, 2 and 8 weeks following injury.
Results: The findings showed that, in comparison with the RC + NaCl group, secretome-hMSCs significantly
improved tendon repair by upregulating TNMD and RUNX2 expression and histology score.
Conclusion: Combining Secretome-hypoxia MSCs with RC healing may help rats with rotator cuff tears.
Level of evidence: IV |
The Effect of Secreted IL-10 from Mesenchymal Stem Cell on Immune Checkpoint Molecules Sari et al, Mutiara Indah Sari In: 2023. @article{noKey,
title = {The Effect of Secreted IL-10 from Mesenchymal Stem Cell on Immune Checkpoint Molecules},
author = {Sari et al, Mutiara Indah Sari},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10540748/},
doi = {https://doi.org/10.5455/aim.2023.31.172-175},
year = {2023},
date = {2023-08-25},
abstract = {Background: Immunosuppression in sepsis is hypothesized to result from the increased
expression of the immune checkpoint molecules programmed death-1 (PD-1) and pro
grammed death ligand-1 (PD-L1). PD-1 and PD-L1 blockade therapies have been reported
to increase survival in septic animals. Currently, the interleukin (IL)-10 within mesenchymal
stem cell (MSC) secretome is known for its immunomodulatory capacity. Objective: To
study the effect of IL-10 within MSC secretome on the expression of immune check
points in the rat model of sepsis. Methods: We used 48 male Rattus norvegicus rats
in this research and divided them into four groups: sham (rats without sepsis induction
and treatment), control (sepsis-induced rats without treatment), T1 (sepsis-induced rats
treated with 150 µL of secreted IL-10 from MSC), and T2 (sepsis-induced rats treated
with 300 µL of secreted IL-10 from MSC). Forty-eight hours after sepsis induction, we
terminated the rats and collected the blood to examine the PD-1 and PD-L1 expression
levels. Results: We found a decrease in the relative expression of PD-1 in the septic rat
group given 150 µL and 300 µL of secreted IL-10 from MSC compared to the control
group, but the decrease was not significant. We also found a decrease in the relative
expression of PD-L1 mRNA in the septic rat group given 150 µL and 300 µL of secreted
IL-10 from MSC compared to the control group. Conclusion: Administering secreted IL-10
from MSC reduces the expression of PD-1 and PD-L1 in sepsis. These findings suggest
that MSC secretome can improve the immunosuppression in sepsis.},
keywords = {µPULSE},
pubstate = {published},
tppubtype = {article}
}
Background: Immunosuppression in sepsis is hypothesized to result from the increased
expression of the immune checkpoint molecules programmed death-1 (PD-1) and pro
grammed death ligand-1 (PD-L1). PD-1 and PD-L1 blockade therapies have been reported
to increase survival in septic animals. Currently, the interleukin (IL)-10 within mesenchymal
stem cell (MSC) secretome is known for its immunomodulatory capacity. Objective: To
study the effect of IL-10 within MSC secretome on the expression of immune check
points in the rat model of sepsis. Methods: We used 48 male Rattus norvegicus rats
in this research and divided them into four groups: sham (rats without sepsis induction
and treatment), control (sepsis-induced rats without treatment), T1 (sepsis-induced rats
treated with 150 µL of secreted IL-10 from MSC), and T2 (sepsis-induced rats treated
with 300 µL of secreted IL-10 from MSC). Forty-eight hours after sepsis induction, we
terminated the rats and collected the blood to examine the PD-1 and PD-L1 expression
levels. Results: We found a decrease in the relative expression of PD-1 in the septic rat
group given 150 µL and 300 µL of secreted IL-10 from MSC compared to the control
group, but the decrease was not significant. We also found a decrease in the relative
expression of PD-L1 mRNA in the septic rat group given 150 µL and 300 µL of secreted
IL-10 from MSC compared to the control group. Conclusion: Administering secreted IL-10
from MSC reduces the expression of PD-1 and PD-L1 in sepsis. These findings suggest
that MSC secretome can improve the immunosuppression in sepsis. |
The Role of Mesenchymal Stem Cell Secretome in the Inflammatory Mediators and the Survival Rate of Rat Model of Sepsis Sari et al, Mutiara Indah Sari In: 2023. @article{noKey,
title = {The Role of Mesenchymal Stem Cell Secretome in the Inflammatory Mediators and the Survival Rate of Rat Model of Sepsis},
author = {Sari et al, Mutiara Indah Sari},
url = {https://www.mdpi.com/2227-9059/11/8/2325},
doi = {https://doi.org/10.3390/biomedicines11082325},
year = {2023},
date = {2023-08-21},
abstract = {In sepsis, simultaneously elevated levels of pro-inflammatory cytokines and interleukin (IL)-10 indicate immune response dysregulation, increasing the mortality of the host. As mesenchymal stem cell (MSC) secretome is known to have immunomodulatory effects, we aim to assess the role of MSC secretome in the inflammatory mediators (NF-κB p65 and p50, TNF-α, IL-10) and the survival rate of a rat model of sepsis. In this study, forty-eight male Rattus norvegicus rats were divided into one sham group and three groups with sepsis induction: the control group and the sepsis-induced rat groups treated with 150 μL (T1) and 300 μL (T2) of secretome. The survival rate was observed per 6 h for 48 h and plotted using the Kaplan–Meier method. Compared to the control group, T2 showed a significant decrease in the relative expression of NF-κB and the serum TNF-α level, and a significant increase in the serum IL-10 level. Meanwhile, T1 showed a significant decrease in the serum TNF-α level compared to the control group. The Kaplan–Meier Log Rank test did not show significance in the distribution of survival between T1, T2, and the control group. However, from the 18th to the 36th hour, the survival rate of T2 was lower than the survival rate of the control group and T1, with a noticeable difference between T2 and the control group, as well as T1 at the 36th hour. At the 42nd hour, the survival rate of T2 was the same as the control group and remained lower than T1. In conclusion, MSC secretome regulated the inflammatory mediators in rat model of sepsis, with a dose of 150 μL being more effective.},
keywords = {µPULSE},
pubstate = {published},
tppubtype = {article}
}
In sepsis, simultaneously elevated levels of pro-inflammatory cytokines and interleukin (IL)-10 indicate immune response dysregulation, increasing the mortality of the host. As mesenchymal stem cell (MSC) secretome is known to have immunomodulatory effects, we aim to assess the role of MSC secretome in the inflammatory mediators (NF-κB p65 and p50, TNF-α, IL-10) and the survival rate of a rat model of sepsis. In this study, forty-eight male Rattus norvegicus rats were divided into one sham group and three groups with sepsis induction: the control group and the sepsis-induced rat groups treated with 150 μL (T1) and 300 μL (T2) of secretome. The survival rate was observed per 6 h for 48 h and plotted using the Kaplan–Meier method. Compared to the control group, T2 showed a significant decrease in the relative expression of NF-κB and the serum TNF-α level, and a significant increase in the serum IL-10 level. Meanwhile, T1 showed a significant decrease in the serum TNF-α level compared to the control group. The Kaplan–Meier Log Rank test did not show significance in the distribution of survival between T1, T2, and the control group. However, from the 18th to the 36th hour, the survival rate of T2 was lower than the survival rate of the control group and T1, with a noticeable difference between T2 and the control group, as well as T1 at the 36th hour. At the 42nd hour, the survival rate of T2 was the same as the control group and remained lower than T1. In conclusion, MSC secretome regulated the inflammatory mediators in rat model of sepsis, with a dose of 150 μL being more effective. |
The ice age – A review on formulation of Adeno-associated virus therapeutics Grossen, Philip In: 2023. @article{noKey,
title = {The ice age – A review on formulation of Adeno-associated virus therapeutics},
author = {Grossen, Philip},
url = {https://www.sciencedirect.com/science/article/pii/S0939641123001741},
doi = {https://doi.org/10.1016/j.ejpb.2023.07.002},
year = {2023},
date = {2023-07-07},
abstract = {Gene therapies offer promising therapeutic alternatives for many disorders that currently lack efficient treatment options. Due to their chemical nature and physico-chemical properties, delivery of polynucleic acids into target cells and subcellular compartments remains a significant challenge. Adeno associated viruses (AAV) have gained a lot of interest for the efficient delivery of therapeutic single-stranded DNA (ssDNA) genomes over the past decades. More than a hundred products have been tested in clinical settings and three products have received
market authorization by the US FDA in recent years. A lot of effort is being made to generate potent recombinant AAV (rAAV) vectors that show favorable safety and immunogenicity profiles for either local or systemic administration. Manufacturing processes are gradually being optimized to deliver a consistently high product quality and to serve potential market needs beyond rare indications. In contrast to protein therapeutics, most rAAV products are still supplied as frozen liquids within rather simple formulation buffers to enable sufficient product shelf life, significantly hampering global distribution and access. In this review, we aim to outline the hurdles of rAAV drug product development and discuss critical formulation and composition aspects of rAAV
products under clinical evaluation. Further, we highlight recent development efforts in order to achieve stable liquid or lyophilized products. This review therefore provides a comprehensive overview on current state-of-the- art rAAV formulations and can further serve as a map for rational formulation development activities in the
future.},
keywords = {µPULSE},
pubstate = {published},
tppubtype = {article}
}
Gene therapies offer promising therapeutic alternatives for many disorders that currently lack efficient treatment options. Due to their chemical nature and physico-chemical properties, delivery of polynucleic acids into target cells and subcellular compartments remains a significant challenge. Adeno associated viruses (AAV) have gained a lot of interest for the efficient delivery of therapeutic single-stranded DNA (ssDNA) genomes over the past decades. More than a hundred products have been tested in clinical settings and three products have received
market authorization by the US FDA in recent years. A lot of effort is being made to generate potent recombinant AAV (rAAV) vectors that show favorable safety and immunogenicity profiles for either local or systemic administration. Manufacturing processes are gradually being optimized to deliver a consistently high product quality and to serve potential market needs beyond rare indications. In contrast to protein therapeutics, most rAAV products are still supplied as frozen liquids within rather simple formulation buffers to enable sufficient product shelf life, significantly hampering global distribution and access. In this review, we aim to outline the hurdles of rAAV drug product development and discuss critical formulation and composition aspects of rAAV
products under clinical evaluation. Further, we highlight recent development efforts in order to achieve stable liquid or lyophilized products. This review therefore provides a comprehensive overview on current state-of-the- art rAAV formulations and can further serve as a map for rational formulation development activities in the
future. |
Structural and functional analyses of Pcal_0917, an α-glucosidase from hyperthermophilic archaeon Pyrobaculum calidifontis Muhammad et al., Majida Atta In: 2023. @article{noKey,
title = {Structural and functional analyses of Pcal_0917, an α-glucosidase from hyperthermophilic archaeon Pyrobaculum calidifontis},
author = {Muhammad et al., Majida Atta},
url = {https://doi.org/10.1016/j.ijbiomac.2023.125446},
doi = {https://doi.org/10.1016/j.ijbiomac.2023.125446},
year = {2023},
date = {2023-06-19},
abstract = {Genome analysis of Pyrobaculum calidifontis revealed the presence of α-glucosidase (Pcal_0917) gene. Structural analysis affirmed the presence of signature sequences of Type II α-glucosidases in Pcal_0917. We have heterologously expressed the gene and produced recombinant Pcal_0917 in Escherichia coli. Biochemical characteristics of the recombinant enzyme resembled to that of Type I α-glucosidases, instead of Type II. Recombinant Pcal_0917 existed in a tetrameric form in solution and displayed highest activity at 95 °C and pH 6.0, independent of any metal ions. A short heat-treatment at 90 °C resulted in a 35 % increase in enzyme activity. A slight structural shift was observed by CD spectrometry at this temperature. Half-life of the enzyme was >7 h at 90 °C. Pcal_0917 exhibited apparent Vmax values of 1190 ± 5 and 3.9 ± 0.1 U/mg against p-nitrophenyl α-D-glucopyranoside and maltose, respectively. To the best of our knowledge, Pcal_0917 displayed the highest ever reported p-nitrophenyl α-D-glucopyranosidase activity among the characterized counterparts. Moreover, Pcal_0917 displayed transglycosylation activity in addition to α-glucosidase activity. Furthermore, in combination with α-amylase, Pcal_0917 was capable of producing glucose syrup from starch with >40 % glucose content. These properties make Pcal_0917 a potential candidate for starch hydrolyzing industry.},
keywords = {µPULSE},
pubstate = {published},
tppubtype = {article}
}
Genome analysis of Pyrobaculum calidifontis revealed the presence of α-glucosidase (Pcal_0917) gene. Structural analysis affirmed the presence of signature sequences of Type II α-glucosidases in Pcal_0917. We have heterologously expressed the gene and produced recombinant Pcal_0917 in Escherichia coli. Biochemical characteristics of the recombinant enzyme resembled to that of Type I α-glucosidases, instead of Type II. Recombinant Pcal_0917 existed in a tetrameric form in solution and displayed highest activity at 95 °C and pH 6.0, independent of any metal ions. A short heat-treatment at 90 °C resulted in a 35 % increase in enzyme activity. A slight structural shift was observed by CD spectrometry at this temperature. Half-life of the enzyme was >7 h at 90 °C. Pcal_0917 exhibited apparent Vmax values of 1190 ± 5 and 3.9 ± 0.1 U/mg against p-nitrophenyl α-D-glucopyranoside and maltose, respectively. To the best of our knowledge, Pcal_0917 displayed the highest ever reported p-nitrophenyl α-D-glucopyranosidase activity among the characterized counterparts. Moreover, Pcal_0917 displayed transglycosylation activity in addition to α-glucosidase activity. Furthermore, in combination with α-amylase, Pcal_0917 was capable of producing glucose syrup from starch with >40 % glucose content. These properties make Pcal_0917 a potential candidate for starch hydrolyzing industry. |
Secretome of Hypoxia-Preconditioned Mesenchymal Stem Cells Enhance Angiogenesis in Diabetic Rats with Peripheral Artery Disease Sazli, Brama Ihsan, Lindarto, Dharma, et al. In: 2023. @article{noKey,
title = {Secretome of Hypoxia-Preconditioned Mesenchymal Stem Cells Enhance Angiogenesis in Diabetic Rats with Peripheral Artery Disease},
author = {Sazli, Brama Ihsan, Lindarto, Dharma, et al.},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10227841/},
doi = {https://doi.org/10.5455/medarh.2023.77.90-96},
year = {2023},
date = {2023-04-01},
abstract = {Background:
Lower limb peripheral artery disease (PAD) is the main risk of diabetes mellitus which result to high mortality rate. Approximately, 50% of patients who receive several treatments have passed away or lost limbs at a year’s follow-up. Secretome of hypoxia mesenchymal stem cells (S-MSCs) contains several active soluble molecules from hypoxia MSCs (H-MSCs) that capable inducing anti-inflammatory and vascular regeneration in PAD.
Objective:
In this study, we investigated the therapeutic potential of S-MSCs in improving dynamic function and angiogenesis of PAD diabetic rats.
Methods:
The PAD was established by the incision from the groin to the inner thigh and distal ligation of femoral arteries in rats with diabetes. Rats were administered with 200 µL and 400 µL S-MSCs that successfully filtrated using tangential flow filtration (TFF) system based on various molecular weight cut-off categories intravenously. ELISA assay was used to analyze the cytokines and growth factors contained in S-MSCs. Tarlov score were examined at day 1, 3, 5, 7, 10 and 14. The rats were sacrificed at day 14 and muscle tissues were collected for immunohistochemistry (IHC) and gene expression analysis.
Results:
ELISA assay showed that S-MSCs provides abundant level of VEGF, PDGF, bFGF, IL-10 and TGFβ. In vivo administration of S-MSCs remarkably enhanced the Tarlov score. S-MSCs improved angiogenesis through enhancing VEGF gene expression and significantly increasing CD31 positive area in muscle tissue of PAD diabetic rats.
Conclusion:
Our findings suggest that S-MSCs could improves dynamic function and angiogenesis in PAD diabetic rats.},
keywords = {µPULSE},
pubstate = {published},
tppubtype = {article}
}
Background:
Lower limb peripheral artery disease (PAD) is the main risk of diabetes mellitus which result to high mortality rate. Approximately, 50% of patients who receive several treatments have passed away or lost limbs at a year’s follow-up. Secretome of hypoxia mesenchymal stem cells (S-MSCs) contains several active soluble molecules from hypoxia MSCs (H-MSCs) that capable inducing anti-inflammatory and vascular regeneration in PAD.
Objective:
In this study, we investigated the therapeutic potential of S-MSCs in improving dynamic function and angiogenesis of PAD diabetic rats.
Methods:
The PAD was established by the incision from the groin to the inner thigh and distal ligation of femoral arteries in rats with diabetes. Rats were administered with 200 µL and 400 µL S-MSCs that successfully filtrated using tangential flow filtration (TFF) system based on various molecular weight cut-off categories intravenously. ELISA assay was used to analyze the cytokines and growth factors contained in S-MSCs. Tarlov score were examined at day 1, 3, 5, 7, 10 and 14. The rats were sacrificed at day 14 and muscle tissues were collected for immunohistochemistry (IHC) and gene expression analysis.
Results:
ELISA assay showed that S-MSCs provides abundant level of VEGF, PDGF, bFGF, IL-10 and TGFβ. In vivo administration of S-MSCs remarkably enhanced the Tarlov score. S-MSCs improved angiogenesis through enhancing VEGF gene expression and significantly increasing CD31 positive area in muscle tissue of PAD diabetic rats.
Conclusion:
Our findings suggest that S-MSCs could improves dynamic function and angiogenesis in PAD diabetic rats. |
