A State-of-the-Art Review on the Recent Advances of Mesenchymal Stem Cell Therapeutic Application in Systematic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with an unknown etiology that has widespread clinical and immunological manifestations. Despite the increase in knowledge about the pathogenesis process and the increase in treatment options, however, the treatments fail in half of the cases. Therefore, there is still a need for research on new therapies. Mesenchymal stem cells (MSCs) are powerful regulators of the immune system and can reduce the symptoms of systemic lupus erythematosus. This study aimed to review the mechanisms of immune system modulation by MSCs and the role of these cells in the treatment of SLE. MSCs suppress T lymphocytes through various mechanisms, including the production of transforming growth factor-beta (TGF-B), prostaglandin E2 (PGE2), nitric oxide (NO), and indolamine 2 and 3-oxygenase (IDO). In addition, MSCs inhibit the production of their autoantibodies by inhibiting the differentiation of lymphocytes. The production of autoantibodies against nuclear antigens is an important feature of SLE. On the other hand, MSCs inhibit antigen delivery by antigen-presenting cells (APCs) to T lymphocytes. Studies in animal models have shown the effectiveness of these cells in treating SLE. However, few studies have been performed on the effectiveness of this treatment in humans. It can be expected that new treatment strategies for SLE will be introduced in the future, given the promising results of MSCs application.

Protective effects of calorie restriction and 17-ß estradiol on cardiac hypertrophy in ovariectomized obese rats.

Obesity and menopause lead to cardiovascular diseases. Calorie restriction (CR) can modulate estrogen deficiency and obesity-related cardiovascular diseases. The protective effects of CR and estradiol on cardiac hypertrophy in ovariectomized obese rats were explored in this study. The adult female Wistar rats were divided into sham and ovariectomized (OVX) groups that received a high-fat diet (60% HFD) or standard diet (SD) or 30% CR for 16 weeks, and then, 1mg/kg E2 (17-ß estradiol) was injected intraperitoneally every 4 days for four weeks in OVX-rats. Hemodynamic parameters were evaluated before and after each diet. Heart tissues were collected for biochemical, histological, and molecular analysis. HFD consumption led to weight gain in sham and OVX rats. In contrast, CR and E2 led to body weight loss in these animals. Also, heart weight (HW), heart weight/body weight (HW/BW) ratio, and left ventricular weight (LVW) were enhanced in OVX rats that received SD and HFD. E2 reduced these indexes in both diet conditions but reduction effects of CR were seen only in HFD groups. HFD and SD feeding increased hemodynamic parameters, ANP (atrial natriuretic peptide) mRNA expression, and TGF-ß1(transforming growth factor-beta 1) protein level in the OVX animals, while CR and E2 reduced these factors. Cardiomyocyte diameter and hydroxyproline content were increased in the OVX-HFD groups. Nevertheless, CR and E2 decreased these indicators. The results showed that CR and E2 treatment reduced obesity-induced-cardiac hypertrophy in ovariectomized groups (20% and 24% respectively). CR appears to have almost as reducing effects as estrogen therapy on cardiac hypertrophy. The findings suggest that CR can be considered a therapeutic candidate for postmenopausal cardiovascular disease.

Beneficial effects of time and energy restriction diets on the development of experimental acute kidney injury in Rat: Bax/Bcl-2 and histopathological evaluation.

People's lifestyles and, especially, their eating habits affect their health and the functioning of the organs in their bodies, including the kidneys. One's diet influences the cells' responses to stressful conditions such as acute kidney injury (AKI). This study aims to determine the preconditioning effects of four different diets: energy restriction (ER) diet, time restriction (TR) eating, intermittent fasting (IF), and high-fat diet (HF) on histopathological indices of the kidney as well as the molecules involved in apoptosis during AKI. Adult male rats underwent ER, TR, IF, and HF diets for eight weeks. Then, AKI was induced, and renal function indices, histopathological indices, and molecules involved in apoptosis were measured. In animals with AKI, urinary albumin excretion, serum urea, creatinine and, Bax/Bcl-2 ratio increased in the kidney, while renal eGFR decreased. ER and TR diets improved renal parameters and prevented an increase in the Bax/Bcl-2 ratio. The IF diet improved renal parameters but had no effect on the Bax/Bcl-2 ratio. On the other hand, the HF diet worsened renal function and increased the Bax/Bcl-2 ratio. Histopathological examination also showed improved kidney conditions in the ER and TR groups and more damage in the HF group. This study demonstrated that ER and TR diets have renoprotective effects on AKI and possibly cause the resistance of kidney cells to damage by reducing the Bax/Bcl-2 ratio and improving apoptotic conditions.

The effect of two types of diet on apoptosis indexes, lipid profile and histopathological outcome in acute kidney injury during exercise.

BACKGROUND: Exercise and some pre-AKI diets have been shown to improve injury, apoptosis, and lipid profile. In this study, the effect of two different diets along with exercise training on acute kidney injury (AKI) was investigated.  MATERIALS AND METHODS: Laboratory rats were randomly divided into four groups of control, standard diet + exercise, exercise + calorie restriction (CR) and exercise + time restriction (TR). Each group was divided into two subgroups of AKI and no AKI. The animals received endurance training and diet regimens before AKI. Fasting blood glucose, serum creatinine, Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl2) and histopathological outcome of renal tissue as well as serum lipid profile of animals were assessed 24 h after AKI.  RESULTS: The percentage of changes in renal Bcl2 and Bax after AKI in the group with previous exercise was lower than the group without previous exercise (p < 0.01). After induction of AKI, serum lipid profile changed in non-exercised rats (p < 0.001). Also, after injury, fasting blood glucose levels increased in non-exercised rats (p < 0.05). After injury, the start of both CR and TR diets during exercise caused less change in Bcl2 and Bax of non-exercised rats compared to exercised rats (p < 0.001). CR diet along with exercise improved lipid profile, and also CR diet along exercise decreased fasting blood glucose levels (p < 0.001). Also, both the CR and TR diets during exercise caused fewer changes in histopathological outcome after AKI. CONCLUSION: Exercise alone decreased changes in apoptotic and histopathological indexes, fasting blood glucose, as well as lipid profile of rats after AKI. Reduction of apoptosis and improvement of histopathological outcome after AKI appeared more when CR and TR diets were commenced during exercise. The reduction of lipid profile changes was more pronounced in the group that received CR diet during exercise.

Effects of caloric and time restriction diets on kidney health in rat model of postmenopausal acute kidney injury: An apoptosis and histopathological study.

Objectives: Lifestyle and eating habits affect the health and function of the body's organs, including the kidneys. The current study was carried out to determine the effects of two types of diet programs, including time restriction (TR) and calorie restriction (CR) on the histopathological changes and apoptotic molecules during acute kidney injury (AKI) in postmenopausal rats. Materials and Methods: In this study the female rats were divided into two groups of ovariectomized (OVX) and ovary-intact (sham), then they were placed on TR and CR diets for 8 weeks; afterward, AKI was induced by injection of glycerol. Functional indices, histopathological changes, Bax, and Bcl2 were measured before and after AKI. Results: After AKI, creatinine, serum urea, urinary albumin excretion, kidney tissue Bax, and Bax/Bcl2 ratio increased, while glomerular filtration rate (GFR) and kidney tissue Bcl2 decreased compared with before AKI. Histopathological indices (inflammation, cellular necrosis, cell vacuolization, tubular dilatation, intratubular cast, and congestion) also confirmed renal injury. TR and CR diets improved renal injury indices and prevented an increase in the Bax/Bcl2 ratio. However, in some indices, the effects of two diets on OVX animals were not observed. In addition, none of the diets could decrease kidney weight/body weight ratio (KW/BW). The histopathological finding also showed improvement of renal status in both groups, especially in the CR diet. Conclusion: The results indicated that TR and CR diets had renoprotective effects against AKI by reducing the Bax/Bcl2 ratio and improving apoptosis. The effects of CR were more than TR.

The effects of two different dietary regimens during exercise on outcome of experimental acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a syndrome characterized by rapid loss of excretory function of kidney. Both exercise and some diets have been shown to increase silent information regulator (SIRT1) expression leading to reduction of kidney injury. In this study, the effect of two different diets during exercise on kidney function, oxidative stress, inflammation and also SIRT1 in AKI was investigated. MATERIALS AND METHODS: A number of rats were randomly divided into four groups; control without exercise, control with exercise, exercise + calorie restriction (CR), and exercise + time restriction (TR). Each group was divided into two subgroups of without AKI and with AKI (six rats in each group). Endurance exercise and diets were implemented before AKI. Serum urea and creatinine, urinary albumin, kidney malondialdehyde (MDA), total antioxidant capacity (TAC), transforming growth factor (TGF-ß1), and SIRT1 levels, glomerular filtration rate (GFR) and relative kidney weight were measured before and 24 h after AKI induction. RESULTS: After induction of kidney injury, serum urea and creatinine, urinary albumin, kidney MDA and TGF-ß1 levels increased in rats with both previous exercise and no previous exercise, while GFR, and kidney TAC and SIRT1 levels significantly decreased. These changes after AKI were less in the group with previous exercise than in the group that had no exercise (p <0.001). The TR diet during exercise caused a less increase in serum urea (p <0.01) and creatinine (p <0.01), and urinary albumin (p <0.001) levels after the injury compared to the just exercise group. Also, both CR and TR diets during exercise caused less change in MDA (p <0.001) and TAC (p <0.05, p <0.001, respectively) levels compared to just exercise group. CONCLUSIONS: The results showed that exercise alone had no effect on preventing function impairment of kidney, oxidative stress, inflammation and also SIRT1 alteration following AKI, although these indexes were less among those with exercise than those without exercise. However, when the CR and TR diets were implemented during exercise, strong renoprotective effects appeared, and the protective effect of TR diet was greater.

Protective effects of combining SERMs with estrogen on metabolic parameters in postmenopausal diabetic cardiovascular dysfunction: The role of cytokines and angiotensin II.

INTRODUCTION: The beneficial effects of the administration of selective estrogen receptor modulators (SERMs) and estrogen (E2), alone or in combination with each other, have been reported in postmenopausal diabetic cardiovascular dysfunction. In the present study, we determined the mechanism of action of SERMs and E2 on inflammatory balance, angiotensin II (Ang II) serum levels, and glycemic profile in a postmenopausal diabetic rat model. METHODS: Ovariectomized rats with type 2 diabetes received daily SERMs (tamoxifen and raloxifene) and E2 for one month. After treatment, cardiovascular risk indices, glycemic profile, and serum Ang II, TNF-α and IL-10 levels were measured. RESULTS: Type 2 diabetes caused an abnormal glycemic profile, which was exacerbated by ovariectomy. All treatments inhibited the effects of diabetes and ovariectomy on the glycemic profile, with combined treatments (SERMs + E2) showing stronger effects. Cardiovascular risk indices that became abnormal by diabetes and worsened by ovariectomy were improved in all treatment modalities. Also, combined treatment reduced serum Ang II, TNF-α, and the ratio of TNF-α to IL-10, indicating an improvement in inflammatory balance. CONCLUSION: Our study showed the administration of SERMs and E2, alone or in combination, could be an effective alternative in the treatment of menopausal diabetes, and generally, the beneficial effects of combined treatments were more effective than the effects of E2 or SERMs alone. It appears that E2 or SERMs benefit the cardiovascular system by improving inflammatory balance and reducing Ang II levels.

Substitution of calorie restriction for protective effects of estrogen on cardiometabolic risk factors and oxidative stress in obese postmenopausal rat model.

Estrogen has an anti-obesity effect and plays an important role in improving cardiometabolic disorders. Weight loss and reduction in calorie intake impede the development of obesity-related cardiometabolic risk factors. Therefore, we investigated the substitution of calorie restriction for effects of estrogen on cardiometabolic risk factors and oxidative stress in obese postmenopausal rat model. In this study, adult female Wistar rats were allocated into Sham and ovariectomized (OVX) groups and were given standard diet (SD) or 60% high-fat diet (HFD) or 30% calorie restriction (CR) for 16 weeks, following this, animals received E2 (17-ß estradiol; 1 mg/kg; i.p.) every four days for 4 weeks. Results showed that HFD elevated the body weight, BMI, food intake, and blood glucose (BG) level in both sham and OVX groups. In addition, HFD had negative effects on lipid profile and oxidative stress in these groups. Whereas CR decreased these indices in both Sham and OVX groups fed an HFD, it could not diminish the BG level in the OVX-HFD group. E2 treatment in OVX animals with or without CR reduced body weight, BMI, food intake, and BG level, and also had positive effects on lipid profile alterations and oxidative stress reduction. In comparison, no significant differences were observed regarding the effects of E2 with CR between two groups for body weight, lipid profile, BG, and oxidative stress in the OVX-HFD rats. Overall, CR prevents and ameliorates cardiometabolic risk factors induced by obesity in postmenopausal conditions and is also a good candidate for E2 substitution.

Comparison of the effects of different dietary regimens on susceptibility to experimental acute kidney injury: The roles of SIRT1 and TGF-ß1.

OBJECTIVES: Mortality due to acute kidney injury (AKI) is high despite its reversibility, and studies on efficient treatments for accelerating the recovery of or preventing AKI are of great significance. The amount of daily calorie intake and how it is taken affect body organs and how cells respond to it. The aim of this study was to determine the effects of four types of diets: calorie restriction (CR), time-restriction eating (TR), intermittent fasting (IF), and high-fat diet (HF), on renal injury indicators in male rats. METHODS: Adult rats were placed on CR, TR, IF, and HF diets for 8 wk, after which AKI was induced in them by injection of glycerol. Renal injury indicators and biochemical parameters were measured before and after AKI induction. RESULTS: After AKI, urinary albumin excretion, urea, serum creatinine, and transforming growth factor (TGF)-ß1 increased, whereas creatinine clearance and SIRT1 decreased. CR and TR diets improved renal indicators, decreased TGF-ß1 and malondialdehyde (MDA), and increased SIRT1, total antioxidant capacity, and creatinine clearance after AKI induction. Although IF improved renal indicators, it only led to a decrease in MDA and TGF-ß1. On the other hand, the HF diet worsened renal indicators, increased TGF-ß1, and decreased SIRT1 in the kidney. Moreover, CR and TR improved metabolism indicators, and HF led to the abnormalization of these factors. CONCLUSIONS: The results of the present study showed that CR and TR can be introduced as a treatment method to prevent AKI. These diets can increase the resistance of kidney cells against injuries, possibly by increasing SIRT1, decreasing TGF-ß1, and improving antioxidant status; and they have renoprotective effects.

Activators of SIRT1 in the kidney and protective effects of SIRT1 during acute kidney injury (AKI) (effect of SIRT1 activators on acute kidney injury).

Acute kidney injury (AKI) is a complex disorder and a clinical condition characterized by acute reduction in renal function. If AKI is not treated, it can lead to chronic kidney disease, which is associated with a high risk of death. SIRT1 (silent information regulator 1) is an NAD-dependent deacetylase. This enzyme is responsible for the processes of DNA repair or recombination, chromosomal stability, and gene transcription. This enzyme also plays a protective role in many diseases, including AKI. In this study, we review the mechanisms that mediate the protective effects of SIRT1 on AKI, including SIRT1 activators.

Renoprotective effects of estrogen on acute kidney injury: the role of SIRT1.

Acute kidney injury (AKI) is a common syndrome associated with high morbidity and mortality, despite progress in medical care. Many studies have shown that there are sex differences and different role of sex hormones particularly estrogens in kidney injury. In this regard, the incidence and rate of progression of kidney diseases are higher in men compared with women. These observations suggest that female sex hormone may be renoprotective. Silent information regulator 2 homolog 1 (SIRT1) is a histone deacetylase, which is implicated in multiple biologic processes in several organisms. In the kidneys, SIRT1 inhibits renal cell apoptosis, inflammation, and fibrosis. Studies have reported a link between SIRT1 and estrogen. In addition, SIRT1 regulates ERα expression and inhibition of SIRT1 activity suppresses ERα expression. This effect leads to inhibition of estrogen-responsive gene expression. In this text, we review the role of SIRT1 in mediating the protective effects of estrogen in the onset and progression of AKI.

The effects of alone and combination tamoxifen, raloxifene and estrogen on lipid profile and atherogenic index of ovariectomized type 2 diabetic rats.

INTRODUCTION: The cardiovascular dysfunctions in postmenopausal diabetic women increase relative to premenopausal women. In this study we evaluated protective effects of selective estrogen receptor modulators (SERMs), alone and in combination with estrogen (E2) in diabetic rats with menopausal model. METHODS: Female rats groups are included: Sham-Control (CTL), Diabetes (DM), and ovariectomized rats divided to DM, DM + Vehicle (Veh), DM + Tamoxifen (TAM), DM + Raloxifene (RLX), DM + Veh + Oil, DM + Oil, DM + E2, DM + E2 + Veh, DM + TAM + E2, DM + RLX + E2. DM was induced by high fat diet and followed by a light dose of streptozotocin. SERMs and E2 were administrated for four weeks after establishment of type 2 diabetes mellitus (T2DM). RESULTS: Our results depicts that, T2DM increased triglyceride, total cholesterol, low-density lipoprotein, and fasting blood glucose. Also it decreased high-density lipoprotein, which had exacerbated by ovariectomy. These changes were reversed by using SERMs, E2 and SERMs+E2, although combinatory treatment is more effective than individual treatment. Additionally the cardiovascular indices were also significantly disrupted in ovariectomized diabetic rats, but all therapeutic groups equally improved these disturbances, whereas in TAM + E2 group, the atherogenic index was more decreased than TAM group. CONCLUSION: We concluded that SERMs treatment, individual or in combination with E2 in menopausal model can be efficient substitute for E2 replacement therapy. This study suggests cellular mechanisms of SERMs in future studies.

The effect of blood flow restriction along with low-intensity exercise on cardiac structure and function in aging rat: Role of angiogenesis.

AIMS: Low-intensity aerobic training along with limbs blood flow restriction can improve mass and strength of skeletal muscle, but its effects on aging heart structure and performance is unidentified. We investigated the effects of this model of training on myocardial function, histology and angiogenesis in old male rats. MAIN METHODS: Animals randomly were divided into control (Ctl), sham-operated (Sh), limbs blood flow restriction (BFR), sham-operated plus 10 weeks low intensity treadmill exercise (Sh + Ex), and BFR plus exercise (BFR + Ex) groups. Finally, blood pressure, heart physiological and stereological parameters, myocardial oxygen consumption index and expression of vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and kdr) were assessed. KEY FINDINGS: BFR + Ex group had significantly lower heart rate (P < 0.05 vs. Ctl and Sh groups), rate-pressure product (RPP) and left ventricular end diastolic pressure (P < 0.05 and P < 0.01 vs. untrained groups, respectively). BFR + Ex group also had greater +dp/dt max (P < 0.01) and -dp/dt max (P < 0.05) than untrained groups. A significant increase in volumes of left ventricle and myocytes (P < 0.05, vs. Ctl and Sham), ventricular hypertrophy index and capillaries length density (P < 0.05 vs. untrained groups) were observed in BFR + Ex group. The level of VEGF and Flt-1 proteins and their mRNAs increased in the BFR + Ex group compared to Ctl, Sh and BFR (P < 0.01) and Sh + Ex (P < 0.05) groups. The kdr mRNA and its protein level were significantly higher in the BFR + Ex group. SIGNIFICANCE: Findings suggest that BFR plus exercise through improving the angiogenesis, physiological cardiac remodeling and oxygen demand/supply matching can promote cardiac performance in the elderly rats.

Mild exercise along with limb blood-flow restriction modulates the electrocardiogram, angiotensin, and apelin receptors of the heart in aging rats.

OBJECTIVES: Considering the lack of information, the effects of mild endurance exercise plus blood flow restriction (BFR) on electrocardiographic parameters, hypertrophy index, and expression of angiotensin II receptors type 1 (AT1R) and type 2 (AT2R) and apelin receptor (APJ) were assessed in hearts of old male rats. MATERIALS AND METHODS: Animal were grouped as control (CTL), Sham (Sh), lower extremities blood flow restriction (BFR), exercise (Ex), Sham + exercise (Sh + Ex), and blood flow restriction + exercise (BFR + Ex). RESULTS: Exercise plus BFR significantly decreased the corrected QT (QTc) interval (P<0.01 vs CTL and Sh groups) and increased the heart hypertrophy index (P<0.05 vs CTL and BFR groups). Exercise alone increased expression of the APJ (P<0.01, vs CTL, Sh, and BFR groups) and AT2 receptors (P<0.001, vs Sh, CTL, BFR, and BFR + exercise groups), whereas it reduced expression of AT1R (P<0.01 in comparison with CTL, Sh, and BFR groups). Exercise plus BFR caused a significant increase in APJ (P<0.05 vs Ex, Sh+Ex and P<0.001 vs CTL, Sh, and BFR groups) and also expression of AT1R (P<0.001 vs Ex, Sh + Ex, CTL, Sh, and P<0.01 vs BFR groups). Accompaniment of exercise with BFR destroyed the effect of exercise on the expression of AT2R. CONCLUSION: Mild endurance exercise plus BFR can alter the expression of angiotensin II and apelin receptors that leads to cardiac hypertrophy and improves the ventricular conductivity of aging rats.