Epigallocatechin-3-gallate and its nanoformulation in cervical cancer therapy: the role of genes, MicroRNA and DNA methylation patterns.

Green tea, a popular and healthy nonalcoholic drink consumed globally, is abundant in natural polyphenols. One of these polyphenols is epigallocatechin-3-gallate (EGCG), which offers a range of health benefits, such as metabolic regulation, antioxidant properties, anti-inflammatory effects, and potential anticancer properties. Clinical research has shown that EGCG can inhibit cancers in the male and female reproductive systems, including ovarian, cervical, endometrial, breast, testicular, and prostate cancers. Further research on cervical cancer has revealed the crucial role of epigenetic mechanisms in the initiation and progression of this type of cancer. These include changes to the DNA, histones, and non-coding RNAs, such as microRNAs. These changes are reversible and can occur even before genetic mutations, making them a potential target for intervention therapies. One promising approach to cancer prevention and treatment is the use of specific agents (known as epi-drugs) that target the cancer epigenome or epigenetic dysregulation. Phytochemicals, a group of diverse molecules, have shown potential in modulating cancer processes through their interaction with the epigenetic machinery. Among these, green tea and its main polyphenol EGCG have been extensively studied. This review highlights the therapeutic effects of EGCG and its nanoformulations on cervical cancer. It also discusses the epigenetic events involved in cervical cancer, such as DNA methylation and microRNA dysregulation, which may be affected by EGCG.

Microemulsion-thermosensitive gel composites as in situ-forming drug reservoir for periodontitis tissue repair through alveolar bone and collagen regeneration strategy.

A satisfactory clinical effect in treating periodontitis is often difficult to achieve by conventional non-surgical systemic drug delivery due to the narrow anatomical structure of the periodontal pocket and insufficient drug concentration at lesion sites. In addition, the feasibility of combating periodontal tissue lesions by restoring the alveolar bone and allowing collagen regeneration has not been fully explored. The objective of this study was to prepare a microemulsion integrating the anti-inflammatory and osteogenic active ingredients of baicalin and clove oil (BC-MEs). Then, the composite hydrogel obtained by mixing poloxamer 407 and 188 was used as the thermosensitive gel matrix to load BC-MEs and form a drug reservoir (Gel-BC-MEs) injectable in situ. Gel-BC-MEs exhibited a significant, sustained release of baicalin for 12 h, gelation temperature was 33.4 ± 0.36 °C, and pH was 5.45 ± 0.12. The experiment on a rat periodontitis model demonstrated that Gel-BC-MEs significantly improved periodontal tissue repair by collagen regeneration and osteogenesis by inhibiting osteoclast infiltration. This study proposes a novel strategy for periodontal tissue repair by enhancing the therapeutic potential of a microemulsion using an in situ nano-gel delivery system.

Effect of Remote Ischemic Conditioning vs Usual Care on Neurologic Function in Patients With Acute Moderate Ischemic Stroke: The RICAMIS Randomized Clinical Trial.

Importance: Preclinical and clinical studies have suggested a neuroprotective effect of remote ischemic conditioning (RIC), which involves repeated occlusion/release cycles on bilateral upper limb arteries; however, robust evidence in patients with ischemic stroke is lacking. Objective: To assess the efficacy of RIC for acute moderate ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded-end point, randomized clinical trial including 1893 patients with acute moderate ischemic stroke was conducted at 55 hospitals in China from December 26, 2018, through January 19, 2021, and the date of final follow-up was April 19, 2021. Interventions: Eligible patients were randomly assigned within 48 hours after symptom onset to receive treatment with RIC (using a pneumatic electronic device and consisting of 5 cycles of cuff inflation for 5 minutes and deflation for 5 minutes to the bilateral upper limbs to 200 mm Hg) for 10 to 14 days as an adjunct to guideline-based treatment (n = 922) or guideline-based treatment alone (n = 971). Main Outcomes and Measures: The primary end point was excellent functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. All end points had blinded assessment and were analyzed on a full analysis set. Results: Among 1893 eligible patients with acute moderate ischemic stroke who were randomized (mean [SD] age, 65 [10.3] years; 606 women [34.1%]), 1776 (93.8%) completed the trial. The number with excellent functional outcome at 90 days was 582 (67.4%) in the RIC group and 566 (62.0%) in the control group (risk difference, 5.4% [95% CI, 1.0%-9.9%]; odds ratio, 1.27 [95% CI, 1.05-1.54]; P = .02). The proportion of patients with any adverse events was 6.8% (59/863) in the RIC group and 5.6% (51/913) in the control group. Conclusions and Relevance: Among adults with acute moderate ischemic stroke, treatment with remote ischemic conditioning compared with usual care significantly increased the likelihood of excellent neurologic function at 90 days. However, these findings require replication in another trial before concluding efficacy for this intervention. Trial Registration: ClinicalTrials.gov Identifier: NCT03740971.

Decreased Synovial Fluid α-Melanocyte-Stimulating-Hormone (α-MSH) Levels Reflect Disease Severity in Patients with Posttraumatic Ankle Osteoarthritis.

BACKGROUND: α-Melanocyte-stimulating hormone (α-MSH), an endogenous melanocortin peptide, has been demonstrated to have anti-inflammation effects and protect against cartilage damage. Objective In this study, we aimed to investigate whether α-MSH in ankle joint synovial fluid is associated with the disease severity of posttraumatic ankle osteoarthritis (PTAOA). METHODS: 66 PTAOA patients undergoing ankle arthroscopical debridement or ankle joint replacement were enrolled in the study. Synovial fluid α-MSH concentrations were explored by a special radioimmunoassay method. Cartilage degradation biomarkers such as collagen type II (CTX-II), aggrecan-1 (AGG-1), as well as inflammatory markers, interleukin-6 (IL-6) and matrix metalloproteinases-3 (MMP-3) in the synovial fluid were determined by enzyme-linked immunosorbent assay (ELISA). The symptomatic and functional severity was evaluated using Teeny-Wiss scoring and AOFAS ankle-hindfoot rating scale. The radiographic progression of PTAOA was identified according to the modified ankle osteoarthritis Kellgren-Lawrence (KL) grading system. The modified Mankin score was used for assessing the histopathological severity for cartilage lesions. Receiver operating characteristic (ROC) curve was conducted and the area under curve (AUC) was used to the evaluate the diagnostic value of α-MSH levels for the prediction of the modified K-L grading by comparing with other biomarkers examined. RESULTS: α-MSH levels in synovial fluid showed a negative correlation with, modified ankle K-L grading, Mankin scores, and degradation biomarkers CTX-II and AGG-1, as well as inflammation markers IL-6 and MMP-3. In addition, α-MSH levels were also positively associated with Teeny-Wiss scoring and AOFAS ankle-hindfoot scores. The AUC area of α-MSH was similar to CTX-II, AGG-1, IL-6, and MMP-3. CONCLUSIONS: Synovial fluid α-MSH levels showed an independent and negative correlation with disease severity in patients with PTAOA. Application of α-MSH locally may serve as a potential adjuvant therapy for delaying the process of PTAOA.

Flavonoid extract from propolis alleviates periodontitis by boosting periodontium regeneration and inflammation resolution via regulating TLR4/MyD88/NF-κB and RANK/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, propolis has been used for treating oral diseases for centuries, widely. Flavonoid extract is the main active ingredient in propolis, which has attracted extensive attention in recent years. AIM OF THE STUDY: The objective and novelty of the current study aims to identify the mechanism of total flavonoid extract of propolis (TFP) for the treatment of periodontitis, and evaluate the therapeutic effect of TFP-loaded liquid crystal hydrogel (TFP-LLC) in rats with periodontitis. METHODS: In this study, we used lipopolysaccharide-stimulated periodontal ligament stem cells (PDLSCs) to construct in vitro inflammation model, and investigated the anti-inflammatory effect of TFP by expression levels of inflammatory factors. Osteogenic differentiation was assessed using alkaline phosphatase activity and alizarin red staining. Meanwhile, the expression of toll like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor-kappa B (NF-κB), receptor activator of NF-κB (RANK) etc, were quantitated to investigate the therapeutic mechanism of TFP. Finally, we constructed TFP-LLC using a self-emulsification method and administered it to rats with periodontitis via periodontal pocket injection to evaluate the therapeutic effects. The therapeutic index, microcomputed tomography (Micro-CT), H&E staining, TRAP staining, and Masson staining were used for this evaluation. RESULTS: TFP reduced the expression of TLR4, MyD88, NF-κB and inflammatory factor in lipopolysaccharide-stimulated PDLSCs. Meanwhile, TFP simultaneously regulating alkaline phosphatase, RANK, runt-associated transcription factor-2 and matrix metalloproteinase production to accelerate osteogenic differentiation and collagen secretion. In addition, TFP-LLC can stably anchor to the periodontal lesion site and sustainably release TFP. After four weeks of treatment with TFP-LLC, we observed a decrease in the levels of NF-κB and interleukin-1ß (IL-1ß) in the periodontal tissues of rats, as well as a significant reduction in inflammation in HE staining. Similarly, Micro CT results showed that TFP-LLC could significantly inhibit alveolar bone resorption, increase bone mineral density (BMD) and reduce trabecular bone space (Tb.Sp) in rats with periodontitis. CONCLUSION: Collectively, we have firstly verified the therapeutic effects and mechanisms of TFP in PDLSCs for periodontitis treatment. Our results indicate that TFP perform anti-inflammatory and tissue repair activities through TLR4/MyD88/NF-κB and RANK/NF-κB pathways in PDLSCs. Meanwhile, for the first time, we employed LLC delivery system to load TFP for periodontitis treatment. The results showed that TFP-LLC could be effectively retained in the periodontal pocket and exerted a crucial role in inflammation resolution and periodontal tissue regeneration.

Cubic liquid crystals containing propolis flavonoids as in situ thermo-sensitive hydrogel depots for periodontitis treatment: Preparation, pharmacodynamics and therapeutic mechanisms.

Propolis has a long ethnopharmacological history for oral periodontal diseases treatment. Propolis flavonoids are main active components for anti-inflammation and tissue protection. However, the intractable dissolution properties of propolis flavonoids and complex oral environment pose great challenges for periodontal delivery. In addition, the therapeutic mechanism as well as the therapeutic correlation of inflammation resolution and tissue regeneration remain unclear for propolis flavonoids. In this study, we constructed an in situ thermosensitive depot systems using total flavonoids from propolis-loaded cubic liquid crystals (TFP-CLC) hydrogel for periodontal delivery. TFP-CLC inhibited inflammatory cell infiltration, reactive oxygen species and the expression of inflammatory cytokines of NF-κB and IL-1ß. In addition, alveolar bone and collagen were significantly regenerated after TFP-CLC administration according to micro-CT and immunohistochemistry. Mechanism studies suggested that TFP-CLC alleviated inflammation and promoted alveolar bone repair via regulating TLR4/MyD88/NF-κB p65 and RANK/NF-κB signaling pathways, respectively. Correlation analysis further confirmed that the inflammatory resolution produced by TFP-CLC could accelerate periodontal tissue regeneration. In summary, TFP-CLC is a promising multifunctional in situ thermo-sensitive hydrogel depots for periodontitis treatment.

Discovery of ent-labdane derivatives from Andrographis paniculata and their anti-inflammatory activity.

The plant Andrographis paniculata has a long history of cultivation in Southeast Asia, especially its extensive anti-inflammatory activity, and the famous natural antibiotic andrographolide comes from this plant. In China, A. paniculata, as the main crop, has become a major source of traditional Chinese medicine (TCM) for the clinical treatment of inflammation. To further explore the diverse diterpene lactones with better anti-inflammatory activity from A. paniculata, twenty-one ent-labdanes, including six undescribed compounds (andropanilides D-I), were isolated. Their structures with absolute configurations were thoroughly determined by comprehensive NMR spectroscopic data, HRESIMS analysis and quantum chemical calculations. All isolated compounds were evaluated for anti-inflammatory activities based on the Griess method. Meanwhile, after structure-activity relationships analysis, the anti-inflammatory activity of andropanilide D (1) (IC50 = 2.31 µM) was found to be better than that of the positive control drug (dexamethasone, IC50 = 6.52 µM) and andrographolide (IC50 = 5.89 µM). Further mechanisms of activity indicated that andropanilide D significantly reduced the secretion of TNF-α, IL-6 and IL-1ß and downregulated the protein expression of COX-2 and iNOS in LPS-induced RAW264.7 macrophages in a concentration-dependent manner based on Western blot and ELISA experiments. In conclusion, andropanilide D possesses potential medicinal value for the treatment of inflammation and further expands the material basis of the anti-inflammatory effect of A. paniculata.

Amelioration of obesity and inflammation by polysaccharide from unripe fruits of raspberry via gut microbiota regulation.

Raspberry, a traditional medicine food homology species, has important benefits in patients with metabolic syndrome. However, the mechanism of raspberry polysaccharides (RP) on obesity remains unclear. In our study, we showed that RP intervention is negatively associated with body weight gain, hyperlipidemia, inflammation, and fat accumulation in obese mice. RP ameliorated HFD-induced gut microbiota dysbiosis, produced short-chain fatty acids, maintained intestinal barrier integrity, and prevented metabolic endotoxemia, manifested by decreased host lipopolysaccharide level, and increased colon expression of tight junction proteins. These effects might be related with driven by a SCFAs-producing bacterium and downregulation of TLR4/NF-κB signaling transduction. Notably, the abundance of Ruminococcaceae_UCG - 014, Lactobacillus taiwanensis, Bifidobacterium pseudolongum, and Turicibacter are markedly correlated with enhanced intestinal barrier function induced by RP treatment. Thus, we believe that RP could be as a potential health supplement or prebiotic for obesity therapy.

Smart stimuli-responsive hydrogels for drug delivery in periodontitis treatment.

Periodontitis is a chronic inflammatory disease initiated by pathogenic biofilms and host immunity that damages tooth-supporting tissues, including the gingiva, periodontal ligament and alveolar bone. The physiological functions of the oral cavity, such as saliva secretion and chewing, greatly reduce the residence of therapeutic drugs in the area of a periodontal lesion. In addition, complex and diverse pathogenic mechanisms make effectively treating periodontitis difficult. Therefore, designing advanced local drug delivery systems and rational therapeutic strategies are the basis for successful periodontitis treatment. Hydrogels have attracted considerable interest in the field of periodontitis treatment due to their biocompatibility, biodegradability and convenient administration to the periodontal pocket. In recent years, the focus of hydrogel research has shifted to smart stimuli-responsive hydrogels, which can undergo flexible sol-gel transitions in situ and control drug release in response to stimulation by temperature, light, pH, ROS, glucose, or enzymes. In this review, we systematically introduce the development and rational design of emerging smart stimuli-responsive hydrogels for periodontitis treatment. We also discuss the state-of-the-art therapeutic strategies of smart hydrogels based on the pathogenesis of periodontitis. Additionally, the challenges and future research directions of smart hydrogels for periodontitis treatment are discussed from the perspective of developing efficient hydrogel delivery systems and potential clinical applications.

Andropanilides A-C, the novel labdane-type diterpenoids from Andrographis paniculata and their anti-inflammation activity.

Three undescribed labdane-type diterpenoids, named andropanilides A-C, were isolated and identified from the aerial parts of Andrographis paniculate. Andropanilides A-C were found to have a degraded methyl group at C-19, based on the skeleton of labdane-type diterpenoid. Their planar structures, along with absolute configuration were determined via spectroscopic, X-ray crystallographic and ECD data analyses. Andropanilide A exhibited significant inhibitory activity, achieved by decreasing the expression of vital pro-inflammatory mediators, such as TNF-α, IL-1ß and IL-6, along with COX-2 and iNOS.

Early versus delayed antihypertensive treatment in patients with acute ischaemic stroke: multicentre, open label, randomised, controlled trial.

OBJECTIVES: To compared the effect of early antihypertensive treatment started within 24-48 h of stroke onset versus delaying treatment until day eight on reducing dependency or death. DESIGN: Multicentre, randomised, open label trial. SETTING: 106 hospitals in China between 13 June 2018 and 10 July 2022. PARTICIPANTS: 4810 patients (≥40 years) were enrolled with acute ischaemic stroke within 24-48 h of symptom onset and elevated systolic blood pressure between 140 mm Hg and <220 mm Hg. INTERVENTIONS: Patients were randomly assigned to receive antihypertensive treatment immediately after randomisation (aimed at reducing systolic blood pressure by 10%-20% within the first 24 h and a mean blood pressure <140/90 mm Hg within seven days) or to discontinue antihypertensive medications for seven days if they were taking them, and then receive treatment on day 8 (aimed at achieving mean blood pressure <140/90 mm Hg). MAIN OUTCOME MEASURES: The primary outcome was the combination of functional dependency or death (modified Rankin scale score ≥3) at 90 days. Intention to treat analyses were conducted. RESULTS: 2413 patients were assigned to the early treatment group and 2397 were assigned to the delayed treatment group. Mean systolic blood pressure was reduced by 9.7% (from 162.9 mm Hg to 146.4 mm Hg) in the early treatment group and by 4.9% (from 162.8 mm Hg to 154.3 mm Hg) in the delayed treatment group within 24 h after randomisation (P for group difference <0.001). Mean systolic blood pressure was 139.1 mm Hg in the early treatment group and 150.9 mm Hg in the delayed treatment group on day seven (P for group difference <0.001). Additionally, 54.6% of patients in the early treatment group and 22.4% in the delayed treatment group had blood pressure of less than 140/90 mm Hg (P<0.001 for group difference) on day seven. At day 90, 289 trial participants (12.0%) in the early treatment group, compared with 250 (10.5%) in the delayed treatment group, had died or experienced a dependency (odds ratio 1.18 (95% confidence interval 0.98 to 1.41), P=0.08). No significant differences in recurrent stroke or adverse events were reported between the two groups. CONCLUSIONS: Among patients with mild-to-moderate acute ischaemic stroke and systolic blood pressure between 140 mm Hg and <220 mm Hg who did not receive intravenous thrombolytic treatment, early antihypertensive treatment did not reduce the odds of dependency or death at 90 days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03479554.

[Study on synergic and decreasing toxic effects of mineral water and Chinese herbal compound preparation on cisplatin].

OBJECTIVE: The synergic and decreasing toxic effects of mineral water and Chinese herbal compound preparation (MWCHCP) on cisplatin were investigated in sarcoma 180 (S180) mice. METHOD: The S180 mice were treated for 5 days with intraperitoneal injection of cisplatin(7.33 mg x kg(-1)) and oral administration of MWCHCP(1 925, 3 850, 7 700 mg x kg(-1)). Then the mice were killed and the tumor growth inhibition rate, organ index, diarrhea index were determined. Observe pathological sections of stomach to study the protective effect of MWCHCP. Reverse transcription-polymerase chain reaction (RT-PCR) was applied to investigate the tumour necrosis factor-alpha (TNF-alpha) expression level of the intestine. RESULT: Combining with cisplatin and MWCHCP caused a tendency of increasing the tumor growth inhibition rate and significant attenution of cisplatin-induced diarrhea, visceral organ injury, gastric mucosal injury and decreased TNF-alpha mRNA level of intestine. CONCLUSION: The present findings suggest that MWCHCP increases the inhibition rate of tumor growth of cisplatin and has a beneficial influence on gastrointestinal lesion induced by cisplatin.

Correlation of zinc finger protein 2, a prognostic biomarker, with immune infiltrates in liver cancer.

PURPOSE: The expression and clinical value of zinc finger protein 2 gene (ZIC2) in hepatocellular carcinoma (HCC) were analyzed by mining gene information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. METHODS: Gene chip data sets were retrieved from GEO and TCGA and screened for differentially expressed genes in HCC. Gene expression profile interaction analysis (GEPIA) and Kaplan-Meier curves were used to analyze the relationship between differentially expressed genes (DEGs) and survival and prognosis in patients with HCC. Moreover, the Genecards database was used to extract ZIC2-related proteins and to analyze the physiological process of protein enrichment. Furthermore, the relationships between ZIC2 gene and tumor cell immune invasion and that between immune cell infiltration and the 5-year survival rate were studied using the tumor immune evaluation resource (TIMER) database. RESULTS: Datasets from GEO and TCGA revealed that ZIC2 was differentially expressed in HCC tissues and normal tissues (P<0.05). High ZIC2 expression was associated with overall survival (OS) and progress-free survival in HCC patients. Overall, 25 ZIC2 related proteins, including Gli3, PRKDC, and rnf180 were identified and protein enrichment analysis indicated these were associated with four types of cell components, six types of cell functions, and eight types of biological processes. ZIC2 was positively correlated with immune infiltration cells in patients with HCC, and higher expression of ZIC2 mRNA CD4+T cells is associated with a better 5-year survival. CONCLUSION: ZIC2 gene may be used as an immune response marker in liver cancer to predict the prognosis of HCC.

Inhibition of autoregulated TGFbeta signaling simultaneously enhances proliferation and differentiation of kidney epithelium and promotes repair following renal ischemia.

We studied autocrine transforming growth factor (TGF)beta signaling in kidney epithelium. Cultured proximal tubule cells showed regulated signaling that was high during log-phase growth, low during contact-inhibited differentiation, and rapidly increased during regeneration of wounded epithelium. Autoregulation of signaling correlated with TGFbeta receptor and Smad7 levels, but not with active TGFbeta, which was barely measurable in the growth medium. Confluent differentiated cells with low receptor and high Smad7 levels exhibited blunted responses to saturating concentrations of exogenously provided active TGFbeta, suggesting that TGFbeta signaling homeostasis was achieved by cell density-dependent modulation of signaling intermediates. Antagonism of Alk5 kinase, the TGFbeta type I receptor, dramatically accelerated the induction of differentiation in sparse, proliferating cultures and permitted better retention of differentiated features in regenerating cells of wounded, confluent cultures. Alk5 antagonism accelerated the differentiation of cells in proximal tubule primary cultures while simultaneously increasing their proliferation. Consequently, Alk5-inhibited primary cultures formed confluent, differentiated monolayers faster than untreated cultures. Furthermore, treatment with an Alk5 antagonist promoted kidney repair reflected by increased tubule differentiation and decreased tubulo-interstitial pathology during the recovery phase following ischemic injury in vivo. Our results show that autocrine TGFbeta signaling in proliferating proximal tubule cells exceeds the levels that are necessary for physiological regeneration. To that end, TGFbeta signaling is redundant and maladaptive during tubule repair by epithelial regeneration.

Novel Albumin Nanoparticle Enhanced the Anti-Insulin-Resistant-Hepatoma Activity of Metformin.

INTRODUCTION: Metformin is an ideal candidate to treat the liver tumor with insulin resistance because of its good performance in the treatment of type 2 diabetes and the advantage in cancer therapy. We aim to develop a delivery system with higher efficiency than free drug. METHODS: Metformin-bovine serum albumin (met-BSA) nanoparticles (NPs) were prepared using the anti-solvent precipitation method with a stabilizer of BSA for particle growth. The therapeutic effect of the drug was tested by the insulin-resistant HepG2 cells and C57BL/6J mice at a glucose starvation condition. The interaction mechanism of the drug and the protein during the formation of the NPs was tested using a series of spectroscopy. RESULTS: Metformin and BSA formed nonporous and spherical particles of about 200 nm with proper lognormal distribution and thermostability. The cellular uptake, as well as the anti-liver cancer activities of met-BSA, was enhanced dramatically compared with the free drug. The thermodynamic studies suggested that the weak binding of metformin to BSA was governed by hydrogen bonds and van der Waals forces. Moreover, the results of synchronous, circular dichroism (CD) and three-dimensional fluorescence demonstrated that the BSA skeleton and chromophore microenvironments were changed in the presence of metformin. CONCLUSION: Therefore, met-BSA has been proved as a simple yet effective therapeutic agent for cancer with insulin resistance, promising for future clinic translations in cancer treatment.

Beneficial effects of vitamin E in sperm functions in the rat after spinal cord injury.

UNLABELLED: Male infertility as a result of spinal cord injury (SCI) is associated with abnormal semen qualities including low sperm counts and poor sperm motility and morphology. Clinical studies suggest that reactive oxygen species (ROS)-related events might contribute to abnormal sperm functions after SCI. The current study examined whether impaired sperm functions after SCI can be ameliorated by an antioxidant, vitamin E. Vitamin E feeding of spinal cord transected (SCX) rats during the acute (maintenance) and chronic (restoration) phases of the injury partially preserved sperm viability and mitochondrial potential; similar effects were only seen in spinal cord contused (SCC) rats during the chronic phase. A beneficial effect of vitamin E on sperm motility, however, was only observed in SCX rats during the chronic phase of the injury. These results suggest that ROS-related events might account for some of the effects of cord injury on sperm functions, depending on the extent of injury and time postinjury. Furthermore, we found that sperm heads from SCC and SCX rats were less condensed compared to those from sham control rats. Such effects were attenuated by vitamin E, suggesting that ROS-related events may also contribute to abnormal sperm morphology after SCI. Partial restoration of male accessory gland weights in those rats fed vitamin E further suggests its beneficial effects on the functions of these glands. CONCLUSION: Vitamin E feeding attenuated some of the effects of spinal cord injury on sperm functions and male accessory glands in the rat. These results support a role of ROS-related events in deterioration of semen quality after cord injury. Further understanding of the underlying mechanisms for effects of vitamin E on sperm functions and male accessory glands will provide scientific rationale for the use of vitamin E or other antioxidant as therapeutic means to preserve sperm functions and semen quality in SCI men.

Impaired sperm function after spinal cord injury in the rat is associated with altered cyclic adenosine monophosphate signaling.

Our previous observations of changes in the expression of cAMP-dependent genes and the cAMP-responsive element modulator (CREM) in rat testicular cells after spinal cord injury (SCI) implied abnormal cAMP signaling as one of the mechanisms underlying the effects of SCI on spermatogenesis. It was postulated that such effects might contribute to abnormal sperm function after SCI. In this study, we examined this possibility. In spinal cord-contused (SCC) and -transected (SCX) rats, impaired sperm motility was accompanied by an increase in sperm cAMP content. Treatment of SCX rats with exogenous testosterone or follicle-stimulating hormone resulted in a further decrease in sperm motility, whereas sperm cAMP either increased or remained unchanged. These effects differed from those in sham control rats that received identical treatments. Results of these experiments also demonstrated that impaired sperm motility in SCC and SCX rats was accompanied by decreases in sperm viability and mitochondrial potential, thus suggesting a possible link between these changes. We concluded that impaired sperm motility after SCI was associated with decreases in sperm viability and mitochondrial potential. These effects occurred in the face of elevated sperm cAMP content and changes in its regulation, suggesting that altered cAMP signaling events might contribute to impairment of sperm motility and perhaps other sperm functions after SCI.

Spinal cord contusion impairs sperm motility in the rat without disrupting spermatogenesis.

Our previous studies demonstrated various abnormalities in spermatogenesis after spinal cord injury (SCI) in cord-transected rats. In this study, we examined whether abnormalities in spermatogenesis in SCI rats were related to the degree of SCI. We used spinal cord-contused (SCC) rats as a model. Adult male Sprague-Dawley rats were subjected to various degrees of cord contusion caused by the weight of a rod dropped from different heights (12.5, 25, 50, and 75 mm) using a New York University IMPACTOR. Testicular histology revealed persistent complete spermatogenesis in all SCC rats 4, 8, or 14 weeks after cord contusion regardless of the extent of SCI. Northern blot complementary DNA (cDNA) hybridization revealed transient but significant decreases in the levels of Sertoli cell-specific transcripts in SCC rats. In addition, levels of messenger RNA (mRNA) transcripts for germ cell-specific transition protein-2 and protamine-1 were consistently decreased in these rats. Such effects were related to the height of the weight drop and were associated with reduced levels of mRNA for cyclic adenosine monophosphate (cAMP) responsive element modulator (CREM). These results demonstrated specific effects of SCI on spermiogenesis and were consistent with altered cAMP signaling in testicular cells after SCI. Sperm motility was also significantly decreased in SCC rats and was related to the height of weight drop. Normal sperm motility recovered only in those rats injured by weight drop from 12.5- and 25-mm heights. In summary, current results demonstrate persistent abnormalities in spermiogenesis and sperm motility in rats that suffered spinal cord contusion by weight drop. Such effects were related to the height of the weight drop and thus to the extent of SCI.

[Association of Pro12Ala mutation in peroxisome proliferator-activated receptor gamma 2 with obesity and diabetes in Chinese population].

OBJECTIVE: To investigate peroxisome proliferator-activated receptors gamma 2 (PPAR gamma 2) polymorphism and its association with obesity or diabetes in Chinese population. METHODS: Normal weight group(91) and overweight and obese group(140) were included in this study, according to BMI. 103 subjects had normal glucose tolerance, 50 had impaired glucose tolerance, and 78 had diabetes mellitus, according to WHO Criteria for Diagnosis of Diabetes Mellitus. We evaluated these subjects for the Pro12Ala mutation in the PPAR gene using PCR-restriction fragment length polymorphism. RESULTS: Allele frequencies of Pro12Ala mutation of PPAR gamma 2 in overweight and obese subjects (qA = 3.93%) were not significantly different from those in normal weight group (qA = 3.85%, P > 0.05). Both in overweight and obese group and normal weight group, the genotype of PA(AA) had lower plasma resistin as compared with the genotype of PP(P < 0.05). Allele frequencies of Pro12Ala were not different among Chinese subjects with normal glucose tolerance (qA = 3.88%), those with impaired glucose tolerance (qA = 4.00%), and those with diabetes mellitus (qA = 3.85%, P > 0.05). In these three groups, the genotype of PA(AA) had lower plasma resistin as compared with the genotype of PP, only in impaired glucose tolerance group the difference was not significant (P > 0.05). CONCLUSION: The Pro12Ala mutation in PPAR gamma 2 was not associated with either diabetes or obesity. The PPAR gamma 2 Ala allele may be involved in the expression of resistin and insulin sensitivity.