Stem Cell Therapy for Erectile Dysfunction of Cavernous Nerve Injury Rats: A Systematic Review and Meta-Analysis

Introduction

Stem cell treatment is a novel therapeutic strategy for erectile dysfunction (ED) patients with bilateral cavernous nerve injury (CNI). The relative animal studies provide important clues to design pre-clinical studies and clinical studies further in the future.

Purpose

This study aims to evaluate the effects and influential factors of stem cell transplantation on ED rats with CNI.

Materials and Methods

We searched PubMed and EBSCO databases published before April 30, 2014 for pre-clinical studies to evaluate the efficacy of stem cell transplantation in the treatment of ED rats with CNI. A systematic review and a planned subgroup analysis were performed to identify whether or not some certain influential factors could bring significant effects on stem cell treatment.

Results

12 studies with 319 rats were enrolled in this meta-analysis. Pooled analysis results confirmed the efficacy of stem cell transplantation. Subgroup analysis results showed that treatment effects were not related to CNI models, follow-up time, stem cell species, stem cell sources, markers and delivery approaches in the transplantation. Uncultured stem cells were poorly effective compared with cultured stem cells. Periprostatic implantation (PPI) with acellular scaffolds could promote cavernous nerve regeneration, but was less effective for smooth muscle cell recovery. Stem cells modified by NGF or BDNF combined with udenafil/bFGF seemed to be more effective than those modified by BDNF alone.

Conclusion

This meta-analysis shows that stem cell therapy can be performed to recover erectile function. Future studies should focus on nerve restoration and vascular cell recovery. The synergistic actions of multiple growth factors following stem cell transplantation should also be considered as beneficial strategies to obtain preferable effects.     

Clinical Efficacy of Stem Cell Therapy for Diabetes Mellitus: A Meta-Analysis

BackgroundStem cell therapy is a promising therapeutic modality for advanced diabetes mellitus (DM). This study presents a meta-analysis of relevant clinical trials to determine the efficacy of stem cell therapy in DM. We aim to critically evaluate and synthesize clinical evidence on the safety and efficiency of different types of stem cell therapy for both T1DM and T2DM.ConclusionsStem cell transplantation can represent a safe and effective treatment for selected patients with DM. In this cohort of trials, the best therapeutic outcome was achieved with CD34⁺ HSC therapy for T1DM, while the poorest outcome was observed with HUCB for T1DM. Diabetic ketoacidosis impedes therapeutic efficacy.     

The safety and efficacy of mesenchymal stem cell therapy in diabetic lower extremity vascular disease: a meta-analysis and systematic review

Background aimsSeveral studies have shown the efficacy of mesenchymal stem cell (MSC) therapy for lower extremity vascular disease (LEVD) in diabetic patients, but the results are not consistent. Therefore, the authors conducted a meta-analysis of randomized controlled trials (RCTs) to examine the safety and efficacy of MSC therapy in diabetic patients with LEVD.MethodsEight available databases were searched in both English and Chinese to identify RCTs comparing MSC therapy-based conventional treatment with conventional treatment alone in diabetic patients with LEVD. Three investigators independently screened the literature, extracted the data and assessed the risk bias. Meta-analysis was performed using RevMan 5.4.1 and Stata 14.0.ResultsA total of 10 studies involving 453 patients were included. Compared with conventional treatment only, patients receiving MSC therapy-based conventional treatment had a higher ulcer healing rate, greater number of reduced ulcers and shorter complete healing time. MSC therapy also increased ankle–brachial index and transcutaneous oxygen pressure. In addition, four of the included studies showed that MSC therapy significantly improved the number of new collateral vessels. Moreover, no more adverse events were recorded in the MSC group.ConclusionsThis meta-analysis suggests that MSC therapy promotes ulcer healing in diabetic LEVD patients with ulcers, improves blood supply and has a favorable safety profile. More large and well-designed RCTs with long-term follow-up are still needed to explore the safety and efficacy of MSC therapy in diabetic patients with LEVD.     

Safety of autologous bone marrow-derived mesenchymal stem cells in erectile dysfunction: an open-label phase 1 clinical trial

Background aimsThe efficacy of phosphodiesterase type 5 inhibitors (PDE5Is), which are commonly used to treat erectile dysfunction (ED), is not satisfactory in patients with denervation of the cavernous nerve due to pelvic surgeries and diabetes mellitus (DM). Pre-clinical studies using bone marrow-derived mesenchymal stem cells (BMSCs) to treat ED have shown promising results. The authors conducted a phase 1 clinical trial with autologous BMSCs in patients with ED due to radical prostatectomy or DM.MethodsTen patients (five with post-prostatectomy ED and five with DM-associated ED) who could not perform sexual activity despite taking the maximum dose of a PDE5I were enrolled. The brief clinical trial protocol was registered with the US National Institutes of Health on ClinicalTrials.gov (NCT02344849). The primary outcome was the safety of stem cell therapy, and the secondary outcome was the improvement of erectile function.ResultsOf the 13 patients screened, 10 were registered in the clinical trial and received autologous BMSCs and nine completed the clinical trial. One patient with post-prostatectomy ED experienced two treatment-emergent adverse events (TEAEs) (pyrexia and back pain), and two patients with DM-associated ED experienced a total of five TEAEs (one case each of viral upper respiratory tract infection, prostatitis and pruritus and two cases of hyperglycemia). Of these patients, one with DM-associated ED experienced two serious TEAEs (two instances of hyperglycemia). All TEAEs were considered not to be related to autologous BMSC therapy. In addition, no clinical significance was identified related to other safety measures, such as laboratory tests and vital signs. The mean International Index of Erectile Function score increased significantly at 1 month versus baseline (24.9 versus 18.1, P = 0.0222).ConclusionsThis phase 1 clinical trial confirmed the safety and potential efficacy of autologous BMSC therapy in patients with ED. The authors’ results need to be confirmed by a phase 2 clinical trial.     

Mesenchymal stem cells alone or ex vivo gene modified with endothelial nitric oxide synthase reverse age-associated erectile dysfunction

Mesenchymal stem cells (MSCs) can be used in adult stem cell-based gene therapy for vascular diseases. To test the hypothesis that MSCs alone or endothelial nitric oxide synthase (eNOS)-modified MSCs can be used for treatment of erectile dysfunction (ED), syngeneic rat MSCs (rMSCs) were isolated, ex vivo expanded, transduced with adenovirus containing eNOS, and injected into the penis of aged rats. Histological analysis demonstrated that rMSCs survived for at least 21 days in corporal tissue after intracavernous injection, and an inflammatory response was not induced. Intracavernous administration of eNOS-modified rMSCs improved the erectile response in aged rats at 7 and 21 days after injection. The increase in erectile function was associated with increased eNOS protein, NOS activity, and cGMP levels. rMSCs alone increased erectile function of aged rats at day 21, but not at day 7, with the transplanted cells exhibiting positive immunostaining for several endothelial and smooth muscle cell markers. This change in rMSC phenotype was accompanied by upregulation of penile eNOS protein expression/activity and elevated cGMP levels. These findings demonstrate that an adenovirus can be used to transduce ex vivo expanded rMSCs to express eNOS and that eNOS-modified rMSCs improve erectile function in the aged rat. Intracavernous injection of unmodified wildtype rMSCs improved erectile function 21 days after injection through mechanisms involving improved endothelium-derived NO/cGMP signaling and rMSC differentiation into penile cells expressing endothelial and smooth muscle markers. These data highlight the potential clinical use of adult stem cell-based therapy for the treatment of ED.     

Mesenchymal stem cell‐derived exosomes ameliorate erection by reducing oxidative stress damage of corpus cavernosum in a rat model of artery injury

Erectile dysfunction (ED) is a common ageing male's disease, and vascular ED accounts for the largest proportion of all types of ED. One of the mechanisms of vascular ED in the clinic is arterial insufficiency, which mainly caused by atherosclerosis, trauma and surgical. Moreover, oxidative stress damage after tissue ischemia usually aggravated the progress of ED. As a new way of acellular therapy, mesenchymal stem cell‐derived exosomes (MSC‐Exos) have great potential in ED treatment. In the current study, we have explored the mechanism of MSC‐Exos therapy in a rat model of internal iliac artery injury‐induced ED. Compared with intracavernous (IC) injection of phosphate‐buffered saline after artery injury, of note, we observed that both mesenchymal stem cells (MSCs) and MSC‐Exos through IC injection could improve the erectile function to varying degrees. More specifically, IC injection MSC‐Exos could promote cavernous sinus endothelial formation, reduce the organization oxidative stress damage, and improve the nitric oxide synthase and smooth muscle content in the corpus cavernosum. With similar potency compared with the stem cell therapy and other unique advantages, IC injection of MSC‐ Exos could be an effective treatment to ameliorate erectile function in a rat model of arterial injury.     

Antioxidant icariside II combined with insulin restores erectile function in streptozotocin‐induced type 1 diabetic rats

Erectile dysfunction (ED) worsens in patients with diabetes mellitus (DM) despite good control of blood glucose level with insulin. Recent studies imply that diabetic vascular stresses (e.g. oxidative stress) persist in spite of glucose normalization, which is defined as metabolic memory. Studies suggest that the interaction between advanced glycation end products (AGEs) and their receptor (RAGE) mediates the development of metabolic memory. To investigate the effects of the antioxidant icariside II plus insulin on erectile function in streptozotocin (STZ)‐ induced type 1 diabetic rats. Fifty 8‐week‐old Sprague‐Dawley rats were randomly distributed into five groups: normal control, diabetic, insulin‐treated diabetic, icariside II‐treated diabetic, and insulin plus icariside II‐treated diabetic. Diabetes was induced by a single intraperitoneal injection of STZ. Eight weeks after induction of diabetes, icariside II was administered by gastric lavage once a day (5 mg/kg) for 6 weeks; and 2–6 units of intermediate‐acting insulin were given to maintain normal glycemia for 6 weeks. The main outcome measures were the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP); histology of penile endothelial cells and smooth muscle cells; neural nitric oxide synthase, AGEs and RAGE expression; malondialdehyde concentration; superoxide dismutase activity; and apoptosis index. Diabetic rats demonstrated a significantly lower ICP/MAP ratio, reduced penile endothelial cells, reduced smooth muscle cells, increased AGEs and RAGE, and increased apoptosis. Insulin and icariside II monotherapy partially restored erectile function and histological changes. However, the combination therapy group showed significantly better erectile parameters, cytological components and biochemistry, similar to those in the normal control group. These results suggest that, although insulin can effectively control glycemic levels, it does not completely alter the pathological changes in erectile tissues. Better efficacy could be expected with tight glycemic control plus the antioxidant icariside II. The proposed combination therapy might have the potential to eliminate metabolic memory by down‐regulating the AGEs‐RAGE‐oxidative stress axis.     

Mesenchymal stem cells and differentiated insulin producing cells are new horizons for pancreatic regeneration in type I diabetes mellitus

BackgroundDiabetes mellitus has become the third human killer following cancer and cardiovascular disease. Millions of patients, often children, suffer from type 1 diabetes (T1D). Stem cells created hopes to regenerate damaged body tissues and restore their function.AimThis work aimed at clarifying and comparing the therapeutic potential of differentiated and non-differentiated mesenchymal stem cells (MSCs) as a new line of therapy for T1D.Methods40 Female albino rats divided into group I (control): 10 rats and group II (diabetic), III and IV, 10 rats in each, were injected with streptozotocin (50 mg/kg body weight). Group III (MSCs) were transplanted with bone marrow derived MSCs from male rats and group IV (IPCs) with differentiated insulin producing cells. Blood and pancreatic tissue samples were taken from all rats for biochemical and histological studies.ResultsMSCs reduced hyperglycemia in diabetic rats on day 15 while IPCs normalizes blood glucose level on day 7. Histological and morphometric analysis of pancreas of experimental diabetic rats showed improvement in MSCs-treated group but in IPCs-treated group, β-cells insulin immunoreactions were obviously returned to normal, with normal distribution of β-cells in the center and other cells at the periphery. Meanwhile, most of the pathological lesions were still detected in diabetic rats.ConclusionMSCs transplantation can reduce blood glucose level in recipient diabetic rats. IPCs initiate endogenous pancreatic regeneration by neogenesis of islets. IPCs are better than MSCs in regeneration of β-cells. So, IPCs therapy can be considered clinically to offer a hope for patients suffering from T1D.     

Stem cells in animal asthma models: a systematic review

Background aimsAsthma control frequently falls short of the goals set in international guidelines. Treatment options for patients with poorly controlled asthma despite inhaled corticosteroids and long-acting β-agonists are limited, and new therapeutic options are needed. Stem cell therapy is promising for a variety of disorders but there has been no human clinical trial of stem cell therapy for asthma. We aimed to systematically review the literature regarding the potential benefits of stem cell therapy in animal models of asthma to determine whether a human trial is warranted.MethodsThe MEDLINE and Embase databases were searched for original studies of stem cell therapy in animal asthma models.ResultsNineteen studies were selected. They were found to be heterogeneous in their design. Mesenchymal stromal cells were used before sensitization with an allergen, before challenge with the allergen and after challenge, most frequently with ovalbumin, and mainly in BALB/c mice. Stem cell therapy resulted in a reduction of bronchoalveolar lavage fluid inflammation and eosinophilia as well as Th2 cytokines such as interleukin-4 and interleukin-5. Improvement in histopathology such as peribronchial and perivascular inflammation, epithelial thickness, goblet cell hyperplasia and smooth muscle layer thickening was universal. Several studies showed a reduction in airway hyper-responsiveness.ConclusionsStem cell therapy decreases eosinophilic and Th2 inflammation and is effective in several phases of the allergic response in animal asthma models. Further study is warranted, up to human clinical trials.     

Yidiyin, a Chinese herbal decoction, improves erectile dysfunction in diabetic patients and rats through the NO-cGMP pathway

The nitric-oxide (NO)-cyclic-guanosine-monophosphate (cGMP) pathway plays a key role in penile erection. Erectile dysfunction (ED) is a complication in male diabetic patients that impacts their quality of 1ife. Recently, Yidiyin, a Chinese herbal decoction, is used to treat diabetic ED, but convincing evidence is lacking, and the potential mechanisms remain uncertain. In the study, diabetic ED patients had low scores on international index of erectile function-5 (IIEF-5), and administration of Yidiyin and hypoglycemic drugs for 16 weeks ameliorated patients' scores on IIEF-5 more than the hypoglycemic drug alone. Moreover, streptozotocin-induced diabetes severely impaired rats' erectile function and the activity of the NO-cGMP pathway in the corpora cavernosum, and treatment with Yidiyin for 4 weeks obviously increased the rats' erectile function, remarkably enhanced the activity of nitric oxide synthase (NOS), and elevated the contents of NO and cGMP. Our findings indicate that Yidiyin improves diabetic ED probably by enhancing the NO-cGMP pathway.     

Amyotrophic lateral sclerosis in pregnancy: clinical outcome during the post-partum period after stem cell transplantation into the frontal motor cortex

Background aimsAmyotrophic lateral sclerosis (ALS) is rare in pregnant patients. Stem cell therapy has been proposed as a potential therapeutic strategy for ALS.MethodsWe describe a young woman with sporadic ALS that started during the second trimester of pregnancy with a rapid progression after delivery and severe motor impairment. Several drugs and stem cell injection by lumbar puncture were performed without changes before the patient was referred to our institution.ResultsAfter bilateral autologous stem cell transplantation into the frontal motor cortices, we observed stabilization in ALS functional rating scale, significant delay of ALS progression and an extension in her life expectancy.ConclusionsStem cell transplantation may alter the clinical course of ALS and improve quality of life in pre-menopausal women.     

Stem cell therapy and diabetic erectile dysfunction: A critical review

Erectile dysfunction (ED) has been identified as one of the most frequent chronic complications of diabetes mellitus (DM). The prevalence of ED is estimated to be about 67.4% in all DM cases worldwide. The pathophysiological process leading to ED involves endothelial, neurological, hormonal, and psychological factors. In DM, endothelial and neurological factors play a crucial role. Damages in the blood vessels and erectile tissue due to insulin resistance are the hallmark of ED in DM. The current treatments for ED include phosphodiesterase-5 inhibitors and penile prosthesis surgery. However, these treatments are limited in terms of just relieving the symptoms, but not resolving the cause of the problem. The use of stem cells for treating ED is currently being studied mostly in experimental animals. The stem cells used are derived from adipose tissue, bone, or human urine. Most of the studies observed an improvement in erectile quality in the experimental animals as well as an improvement in erectile tissue. However, research on stem cell therapy for ED in humans remains to be limited. Nevertheless, significant findings from studies using animal models indicate a potential use of stem cells in the treatment of ED.     

Development and regulation of stem cell‐based therapies in China

BackgroundClinical researches of stem cell‐based therapies are highly active in China, while it was arduous to determine the most effective way of clinical translation of those advanced therapies.MethodsThis article briefly introduced the regulatory framework development, the progress in stem cell clinical researches and clinical trials of commercially developed stem cell‐based products, as well as the clinical review concerns of stem cell‐based products in China.Main findingsThe current regulatory framework of stem cell clinical researches in China was launched in 2015, when regulatory authorities issued “Administrative Measures on Stem Cell Clinical Research” (AMSCCR) detailing the rules of stem cell clinical research. Thereafter, the rapidly growing stem cell clinical researches were rigorously managed and clinical use of stem cell therapy was halted. Meanwhile, commercially developed stem cell‐based products are supervised by Drug Administration Law (DAL).ConclusionThe regulatory framework of stem cell‐based therapy in China has progressed in the last few decades, which is currently regulated according to AMSCCR and DAL. Well‐designed and patient‐focused clinical trial is required for commercially developed stem cell‐based products, and definite clinical benefit evidence is crucial to obtain marketing authorization.

This article briefly introduced the regulatory framework development of stem cell‐based therapy, progress in stem cell‐based clinical studies and clinical review concerns in China.     

Vascular endothelial growth factor restores erectile function through modulation of the insulin-like growth factor system and sex hormone receptors in diabetic rat

Previous studies have shown that intracavernous injection of vascular endothelial growth factor (VEGF) restored erectile function in diabetic rats. However, the mechanism of VEGF in diabetes-related erectile dysfunction (ED) has not been fully investigated. We hypothesize that intracavernous injection of VEGF may reverse diabetes-related ED through modulation of the insulin-like growth factor system and sex hormone receptors. To test this hypothesis the erectile function of treated and control rats was analyzed by measurement of intracavernous pressure (ICP) following electrostimulation of the cavernous nerves. Mean ICP was significantly lower in non-treated diabetic rats compared to controls. After VEGF injection, ICP was significantly higher than in non-treated diabetic rats. IGFBP-3 mRNA and protein expression was significantly higher in non-treated diabetic rat crura than controls, while VEGF-treated animals had control levels. ER-beta and PR mRNA and protein expression was significantly lower in non-treated diabetic rat crura. After VEGF injection, ER-beta and PR mRNA and protein expression was similar to control levels. Expression of AR and ER-alpha was the same in all groups. These findings suggest that orthotopic injection of VEGF may improve the functional recovery of diabetes-related ED through modulation of the insulin-like growth factor system and sex hormone receptors. To our knowledge, this is the first study demonstrating that VEGF treatment restores erectile function through restoration of the insulin-like growth factor system and sex hormone receptor genes at the mRNA and protein levels in diabetic rat crura. These results may be important in understanding the pathogenesis of diabetes-related ED and also in providing better strategies for management of this disease.     

Effects of stem cells on non-ischemic cardiomyopathy: a systematic review and meta-analysis of randomized controlled trials

Background aimsTo assess the impacts of stem cell therapy on clinical outcomes in patients with non-ischemic cardiomyopathy (NICM). The effect of stem cell therapy on prognosis is unclear and controversial.MethodsThe authors performed a systematic review and meta-analysis of the effects of autologous stem cell transplantation in patients with NICM on a composite outcome of all-cause mortality and heart transplantation, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), New York Heart Association (NYHA) classification, 6-minute walk test (6-MWT) distance and serum brain natriuretic peptide (BNP) level, considering studies published before March 19, 2020.ResultsTwelve trials with 623 subjects met inclusion criteria. Compared with the control group, stem cell therapy improved LVEF (weighted mean difference [WMD], 4.08%, 95% confidence interval [CI], 1.93–6.23, P = 0.0002) and 6-MWT distance (WMD, 101.49 m, 95% CI, 45.62–157.35, P = 0.0004) and reduced BNP level (–294.94 pg/mL, 95% CI, –383.97 to –205.90, P < 0.00001) and NYHA classification (–0.70, 95% CI, –0.98 to –0.43, P < 0.00001). However, LVEDD showed no significant difference between the two groups (WMD, –0.09 cm, 95% CI, –0.23 to 0.06, P = 0.25). In 10 studies (535 subjects) employing the intracoronary route for cell delivery, mortality and heart transplantation were decreased (risk ratio [RR], 0.73, 95% CI, 0.52–1.00, P = 0.05). Furthermore, in four studies (248 subjects) with peripheral CD34+ cells, either all-cause mortality (RR, 0.44, 95% CI, 0.23–0.86, P = 0.02) or mortality and heart transplantation (RR, 0.45, 95% CI, 0.27–0.77, P = 0.003) improved in the treatment group compared with the control. The trial sequential analysis suggested the information size of LVEF, 6-WMT and BNP has been adequate for evidencing the benefits of stem cells on NICM. However, to determine the potential survival benefit, more clinical data are required to make the statistical significance in meta-analysis more conclusive.ConclusionsThis meta-analysis demonstrates that stem cell therapy may improve survival, exercise capacity and cardiac ejection fraction in NICM, which suggests that stem cells are a promising option for NICM treatment.     

Relationship between common eNOS gene polymorphisms and predisposition to coronary artery disease: Evidence from a meta-analysis of 155 published association studies

BackgroundRelationship between endothelial nitric oxide synthase (eNOS) polymorphisms and predisposition to coronary artery disease (CAD) are still controversial and ambiguous. So we performed this meta-analysis to more precisely estimate relationship between eNOS polymorphisms and CAD by pooling the results of already published studies.MethodsWe searched Pubmed, Embase, Web of Science and CNKI for eligible studies. We used Review Manager to pool the results of eligible studies.ResultsOne hundred and fifty-five studies were included in this meta-analysis. We found that eNOS rs1799983, rs2070744 and rs869109213 polymorphisms were all significantly associated with CAD in the general population. We also detected similar significant results for eNOS rs1799983, rs2070744 and rs869109213 polymorphisms in both Caucasians and Asians in further subgroup analyses.ConclusionsThis meta-analysis demonstrated that eNOS rs1799983, rs2070744 and rs869109213 polymorphisms might influence predisposition to CAD in both Caucasians and Asians.     

Advanced glycation end-products: a common pathway in diabetes and age-related erectile dysfunction

Abstract

Reactive derivatives of non-enzymatic glucose-protein condensation reactions integrate a heterogeneous group of irreversible adducts called advanced glycation end-products (AGEs). Numerous studies have investigated the role of the AGEs in cardiovascular system; however, its contribution to erectile dysfunction (ED) that is an early manifestation of cardiovascular disease has been less intensively investigated. This review summarizes the most recent advances concerning AGEs effects in the cavernous tissue of the penis and in ED onset, particularly on diabetes and aging, conditions that not only favor AGEs formation, but also increase risk of developing ED. The specific contribution of AGE on intra- and extracellular deposition of insoluble complexes, interference in activity of endothelial nitric oxide (NO) synthase, NO bioavailability, endothelial-dependent vasodilatation, as well as molecular pathways activated by receptor of AGEs are presented. Finally, the interventional actions that prevent AGEs formation, accumulation or activity in the cavernous tissue and that include nutritional pattern modulation, nutraceuticals, exercise, therapeutic strategies (statins, anti-diabetics, inhibitors of phosphodiesterase-5, anti-hypertensive drugs) and inhibitors of AGEs formation and crosslink breakers, are discussed. From this review, we conclude that despite the experiments conducted in animal models pointing to the AGE/RAGE axis as a potential interventional target with respect to ED associated with diabetes and aging, the clinical data have been very disappointing and, until now, did not provide evidence of benefits of treatments directed to AGE inactivation.     

Pericyte-derived extracellular vesicle-mimetic nanovesicles ameliorate erectile dysfunction via lipocalin 2 in diabetic mice

Diabetes mellitus is one of the main causes of erectile dysfunction (ED). Men with diabetic ED do not respond well to oral phosphodiesterase-5 inhibitors owing to neurovascular dysfunction. Pericyte-derived extracellular vesicle-mimetic nanovesicles (PC-NVs) are known to promote nerve regeneration in a mouse model of cavernous nerve injury. Here, we report that administration of PC-NVs effectively promoted penile angiogenesis and neural regeneration under diabetic conditions, thereby improving erectile function. Specifically, PC-NVs induced endothelial proliferation and migration and reduced cell apoptosis under diabetic conditions. In addition, PC-NVs induced neural regeneration in STZ-induced diabetic mice in dorsal root ganglion and major pelvic ganglion explants in vivo and ex vivo under high-glucose conditions. We found that lipocalin 2 (Lcn2) is a new target of PC-NVs in this process, demonstrating that PC-NVs exert their angiogenic and nerve-regeneration effects by activating MAP kinase and PI3K/Akt and suppressing P53 signaling pathway in an Lcn2-dependent manner. Our findings provide new conclusive evidence that PC-NVs can promote neurovascular regeneration and recovery of erectile function under diabetic conditions via an Lcn2-dependent mechanism. Thus, local administration of PC-NVs may be a promising treatment strategy for the treatment of diabetic ED.     

Effects of male silkworm pupa powder on the erectile dysfunction by chronic ethanol consumption in rats

Erectile dysfunction (ED) is a highly prevalent disorder that affects millions of men worldwide. ED is now considered an early manifestation of atherosclerosis, and consequently, a precursor of systemic vascular disease. This study was designed to investigate the effects of male silkworm pupa powder (SWP) on the levels of nitric oxide synthase (NOS) expression, nitrite, and glutathione (GSH); lipid peroxidation; libido; and erectile response of the corpus cavernosum of the rat penis. We induced ED in the study animals by oral administration of 20% ethanol over 8 weeks. The SWP-treated male rats were divided into 3 groups that were orally administered 200, 400, and 800 mg/kg. The libido of the SWP-administered male rats was higher than that of the ethanol control group. In addition, the erectile response of the corpus cavernosum was restored in males on SWP administration, to a level similar to that of the normal group without ED. The testosterone concentration did not increase significantly. The lipid peroxidation in the corpus cavernosum of the male rats administered SWP decreased significantly. In contrast, compared to the ethanol group, SWP-administered male rats showed increased GSH levels in the corpus cavernosum. The level of nitrite and NOS expression in the corpus cavernosum of SWP-administered male rats increased significantly. These results indicated that SWP effectively restored ethanol-induced ED in male rats.     

Effect of Stem Cell Therapy on Bone Mineral Density: A Meta-Analysis of Preclinical Studies in Animal Models of Osteoporosis

Background

Preclinical studies of the therapeutic role of stem cell based therapy in animal models of osteoporosis have largely yielded inconsistent results. We performed a meta-analysis to provide an overview of the currently available evidence.

Methods

Pubmed, Embase and Cochrane Library databases were systematically searched for relevant controlled studies. A random-effect model was used for pooled analysis of the effect of stem cell based therapy on bone mineral density (BMD). Stratified analyses were performed to explore the effect of study characteristics on the outcomes.

Results

Pooled results from 12 preclinical studies (110 animals in stem cell treatment groups, and 106 animals in control groups) indicated that stem cell based treatment was associated with significantly improved BMD (standardized mean difference [SMD] = 1.29, 95% Confidence Interval [CI]: 0.84–1.74, P < 0.001) with moderate heterogeneity (Cochrane’s Q test: P = 0.02, I² = 45%) among the constituent studies. Implantation of bone marrow cells, bone marrow mesenchymal stem cells, adipose-derived stem cells, and human umbilical cord blood-derived CD34+ cells, were all associated with improved BMD as compared to that in the controls (P < 0.05 for all); the only exception being the use of embryonic stem cell transplantation (P > 0.05). Egger’s test detected potential publication bias (P = 0.055); however, ‘trim and fill’ analysis yielded similar results after statistically incorporating the hypothetical studies in the analysis (SMD = 1.24, 95% CI: 0.32–2.16, P < 0.001).

Conclusions

Stem cell transplantation may improve BMD in animal models of osteoporosis. Our meta-analysis indicates a potential therapeutic role of stem cell based therapy for osteoporosis, and serves to augment the rationale for clinical studies.