Effect of human umbilical cord blood-mesenchymal stem cells on cisplatin-induced nephrotoxicity in rats.

BACKGROUND: Cisplatin-containing regimen is an effective treatment for several malignancies. However, cisplatin is an important cause of nephrotoxicity. So, many trials were performed to transplant stem cells systemically or locally to control cisplatin-induced nephrotoxicity. Stem cell therapeutic effect may be dependent on the regulation of inflammation and oxidant stress. AIM: To investigate the effect of human umbilical cord blood-mesenchymal stem cells (hUCB-MSCs) on the histological structure, the oxidant stress, and the inflammatory gene expression in an experimental model of cisplatin-induced nephrotoxicity in rats. METHOD: The rats were divided into 6 equal groups (each of 10 rats): Group I included normal rats that received no treatment. Group II included healthy rats that received IV hUCB-MSCs. Group III included untreated cisplatin-induced nephrotoxic rats. Group IV included cisplatin-induced nephrotoxic rats that received magnesium (Mg) injections after injury. Group V was injected with hUCB-MSCs after injury. Group VI received both Mg and hUCB-MSCs after injury. In tissue homogenates, reduced glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) activities were measured. Quantitative real-time-polymerase chain reaction (qRT-PCR) was performed to assess iNOS, TLR4, and NF-kB gene expression. Hematoxylin and eosin (H&E) staining was performed to study the histological structure of the kidney. Immunohistochemical staining of iNOS and NF-κB was performed, as well. RESULTS: Disturbed kidney functions, oxidative status, and histological structure were seen in the rats that received cisplatin. Treated groups showed improvements in kidney functions, oxidative status, and histological structure, particularly in the combined treatment group. CONCLUSION: In the cisplatin-induced nephrotoxicity model, hUCB-MSCs could improve the functional and morphological kidney structure by modulation of oxidative and inflammatory status.

Ameliorative Potential of Bone Marrow-Derived Mesenchymal Stem Cells Versus Prednisolone in a Rat Model of Lung Fibrosis: A Histological, Immunohistochemical, and Biochemical Study.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown origin with limited treatment options and poor prognosis. The encouraging findings from preclinical investigations utilizing mesenchymal stem cells (MSCs) indicated that they could serve as a promising therapeutic alternative for managing chronic lung conditions, such as IPF. The objective of this study was to compare the efficiency of bone marrow-derived MSCs (BM-MSCs) versus prednisolone, the standard anti-inflammatory medication, in rats with bleomycin (BLM)-induced lung fibrosis. Four groups were created: a control group, a BLM group, a prednisolone-treated group, and a BM-MSCs-treated group. To induce lung fibrosis, 5 mg/kg of BLM was administered intratracheally. BLM significantly increased serum levels of pro-inflammatory cytokines and oxidative stress markers. The disturbed lung structure was also revealed by light and transmission electron microscopic studies. Upregulation in the immune expression of alpha-smooth muscle actin, transforming growth factor beta-1, and Bax was demonstrated. Interestingly, all findings significantly regressed on treatment with prednisolone and BM-MSCs. However, treatment with BM-MSCs showed better results than with prednisolone. In conclusion, BM-MSCs could be a promising approach for managing lung fibrosis.

Effect of Liraglutide on Osteoporosis in a Rat Model of Type 2 Diabetes Mellitus: A Histological, Immunohistochemical, and Biochemical Study.

Diabetic osteoporosis (DOP) is a diabetic complication associated with a significant disability rate. Liraglutide, a glucagon-like peptide-1 receptor agonist, is a promising and innovative drug for type 2 diabetes mellitus (T2DM), with potential therapeutic implications for bone disorders. This investigation examined the impact of liraglutide on osteoporosis in rats with T2DM and studied the influence of vitamin D receptor Bsm1 polymorphism on liraglutide-induced outcomes. Thirty rats were divided into control, T2DM induced by a combination of a high-fat diet and 25 mg/kg streptozotocin, and T2DM-liraglutide (T2DM treated with 0.4 mg/kg/day liraglutide) groups. After 8 weeks of liraglutide treatment, femurs and blood samples were obtained from all rats for subsequent investigations. Diabetes induced a remarkable rise in the serum levels of receptor activator of nuclear factor kappa B ligand (RANKL) and C-telopeptide of type I collagen (CTX-1) associated with a remarkable decline in osteocalcin and osteoprotegerin (OPG). Impaired bone architecture was also demonstrated by light and scanning electron microscopic study. The immune expression of OPG was down-regulated, while RANKL was up-regulated. Interestingly, the administration of liraglutide ameliorated the previous changes induced by diabetes mellitus. In conclusion, liraglutide can prevent DOP, mostly due to liraglutide's ability to increase bone growth, while inhibiting bone resorption.

Beneficial effects of metformin on muscle atrophy induced by obesity in rats.

AIM: A growing interest to understand the signaling pathways mediating obesity-induced muscle atrophy is given. Metformin (Met) was reported to possess positive effects on preventing muscle damage and promoting muscle mass maintenance. The aim of the present study to investigate pathways involved in Met effect on obesity induced muscle atrophy. METHODS: Thirty adult male albino rats were assigned into two groups: normal chew diet fed group as control group (C; n = 10) and high-fat-diet (HFD) fed group ( n = 20). After 16 weeks, the HFD-fed animals were subdivided into two groups; HFD group ( n = 10) and HFD fed treated with oral Met (320 mg/day) treatment (Met, n = 10) for 4 weeks. At the end of the experiment; final body weight, visceral fat weight, fasting blood glucose, insulin, lactate, total cholesterol, triglycerides were measured and calculated homeostatic model assessment insulin resistant (HOMA-IR) for all groups. Soleus muscle weight, histopathlogical examination and expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), forkhead box O3 (FoxO3), atrogin-1/MAFbx, and muscle RING finger 1 (MuRF-1) were performed. RESULTS: HFD-fed animals showed significant increase in final body weight, visceral fat mass, fasting blood glucose, insulin, calculated HOMA-IR, lactate, total cholesterol and triglycerides with significant decrease in soleus muscle weight, PGC-1α and significant increase in FoxO3, atrogin-1/MAFbx, and MuRF-1 expression. Also, there was significant decrease in fiber diameter, myosin heavy chain (MHC) I content while collagen content and myosin heavy chain IIa were increased compared with control group. Met-treated group showed a significant decrease in the measured parameters compared with the HFD group. It also restored the gene expression, morphometric measures and MHC composition toward normal. CONCLUSION: The current study is the first to provide evidence that Met could ameliorate muscle atrophy in high-fat diet induced obesity and this effect may be in part due to regulation of PGC-1α-FoxO3 pathway.

Mechanistic aspects of ameliorative effects of Eicosapentanoic acid ethyl ester on methotrexate-evoked testiculopathy in rats.

Disrupted spermatogenesis and testicular injury are among the devastating outcomes of methotrexate. A major contributor to methotrexate-induced testiculopathy is oxidative damage which triggers apoptosis and altered autophagy responses. Eicosapentaenoic acid ethyl ester (EPA-E) is an antihyperlipidemic derivative of omega-3 fatty acids that exhibited affinity to peroxisome proliferator-activated receptor-γ (PPAR-γ) that possesses both antioxidant and autophagy modulating properties. This is an exploratory study aiming at assessing the effectiveness of EPA-E to alleviate testicular damage induced by methotrexate. The specific exploratory hypothesis of this experiment is: EPA-E administration for 1 week to methotrexate-treated rats reduces testicular damage compared to control rats. As a secondary outcome, we were interested in identifying the implicated mechanism that mediates the action of EPA-E. In adult male Wistar rats, testiculopathy was achieved by a single methotrexate injection (20 mg/kg, ip). Rats received vehicle, EPA-E (0.3 g/kg/day, po) alone or with selective PPAR-γ antagonist (bisphenol A diglycidyl ether, BADGE) at 30 mg/kg/day, ip for 1 week. EPA-E recuperated methotrexate-attenuated serum total testosterone while reduced testicular inflammation and oxidative stress, restoring superoxide dismutase (SOD) while reducing malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Methotrexate-induced testicular apoptosis (caspase-3 and p53) was suppressed upon EPA-E treatment. Besides, EPA-E curbed methotrexate-induced abnormal autophagy by downregulating LC3A/B and beclin-1. Interestingly, BADGE-coadministration reversed EPA-E beneficial actions. Collectively, our findings suggest PPAR-γ role in EPA-E-mediated mitigation of methotrexate-evoked testiculopathy via suppression of oxidative stress, apoptosis, as well as abnormal autophagy. Furthermore, EPA-E could be used as a preventive therapy for some testiculopathies mediated by oxidative stress.

Bone marrow mesenchymal stem cells expressing Neat-1, Hotair-1, miR-21, miR-644, and miR-144 subsided cyclophosphamide-induced ovarian insufficiency by remodeling the IGF-1-kisspeptin system, ovarian apoptosis, and angiogenesis.

Ovarian insufficiency is one of the common reproductive disorders affecting women with limited therapeutic aids. Mesenchymal stem cells have been investigated in such disorders before yet, the exact mechanism of MSCs in ovarian regeneration regarding their epigenetic regulation remains elusive. The current study is to investigate the role of the bone marrow-derived mesenchymal stem cells (BM-MSCs) lncRNA (Neat-1 and Hotair1) and miRNA (mir-21-5p, mir-144-5p, and mir-664-5p) in mitigating ovarian granulosa cell apoptosis as well as searching BM-MSCs in altering the expression of ovarian and hypothalamic IGF-1 - kisspeptin system in connection to HPG axis in a cyclophosphamide-induced ovarian failure rat model. Sixty mature female Sprague Dawley rats were divided into 3 equal groups; control group, premature ovarian insufficiency (POI) group, and POI + BM-MSCs. POI female rat model was established with cyclophosphamide. The result revealed that BM-MSCs and their conditioned media displayed a significant expression level of Neat-1, Hotair-1, mir-21-5p, mir-144-5p, and mir-664-5p. Moreover, BM-MSCs transplantation in POI rats improves; the ovarian and hypothalamic IGF-1 - kisspeptin, HPG axis, ovarian granulosa cell apoptosis, steroidogenesis, angiogenesis, energy balance, and oxidative stress. BM-MSCs expressed higher levels of antiapoptotic lncRNAs and microRNAs that mitigate ovarian insufficiency.

Anticancer Effects of Tacrolimus on Induced Hepatocellular Carcinoma in Mice.

BACKGROUND: Tacrolimus is a calcineurin inhibitor widely used for immunological disorders. However, there is significant controversy regarding its effect on the liver. The present study was conducted to evaluate the anticancer effects of tacrolimus on an induced murine hepatocellular carcinoma (HCC) model and its possible hepatotoxicity at standard therapeutic doses. METHODS: Fifty-four male mice were divided into five groups: a control healthy group, control HCC group, tacrolimus-treated group, doxorubicin (DOXO)-treated group, and combined tacrolimus- and DOXO-treated group. The activity of liver enzymes, including alkaline phosphatase, gamma- glutamyl transferase, lactate dehydrogenase, alanine transaminase, and aspartate transaminase, was determined. Serum vascular endothelial growth factor (VEGF) was measured using an enzyme- linked immunosorbent assay. A quantitative real time- polymerase chain reaction (qRTPCR) was conducted to measure the expression of proliferating cell nuclear antigen (PCNA), Bax, and p53 mRNA. Immunohistochemical staining for cyclin D1 and VEGF was performed. RESULTS: Mice that received combined treatment with tacrolimus and DOXO exhibited the best improvement in all parameters when compared with the groups that received DOXO or tacrolimus alone (p < 0.001). CONCLUSION: The combination of DOXO and tacrolimus was more effective in the management of HCC compared with either agent alone. This improvement was detected by the reduction of liver enzymes and the improvement of the histopathological profile. The involved mechanisms included significant apoptosis induction demonstrated by upregulation of bax along with a reduction in angiogenesis demonstrated by downregulation of VEGF. This was accompanied by inhibition of cell cycle progression mediated by upregulated p53 and downregulated PCNA and cyclin D1.

Effect of Bone-Marrow-Derived Mesenchymal Stem Cells on the Healing of Bone Fractures.

This study was performed to evaluate the effectiveness of mesenchymal stem cells (MSCs) on bone healing and to assess the role of various chemical stimulants and mediators in healing. Forty female mice were randomly assigned to 4 groups (10 mice each) after the induction of fixed fractures: group I: received fixation only; group II: received phosphate-buffered saline (PBS); group III: received intralesion MSCs (IL-MSCs); and group IV: received intraperitoneal MSCs (IP-MSCs). Serum alkaline phosphatase (ALP) levels and the expression of the osteocalcin (OCN), bone morphogenetic protein-2 (BMP-2), and stromal-derived factor-1 (SDF-1) genes were measured. ALP reached baseline level only in IL-MSCs, whereas OCN reached baseline level in MSCs recipients (IL-MSCs and IP-MSCs). BMP-2 significantly increased in MSCs recipients 3 weeks postfracture and increased in all groups 8 weeks postfracture with significant increases in MSC recipients than the fixation and PBS groups. The highest BMP-2 expression was reached in IL-MSC group. MSCs either locally or systemically improves or accelerates the healing of bone fractures with better results obtained after local injection, as shown by biochemical, radiological, and histological findings. MSCs are effective candidates for bone regeneration.