When metal-organic framework mediated smart drug delivery meets gastrointestinal cancers.

Cancers of the gastrointestinal tract constitute one of the most common cancer types worldwide and a ∼58% increase in the global number of cases has been estimated by IARC for the next twenty years. Recent advances in drug delivery technologies have attracted scientific interest for developing and utilizing efficient therapeutic systems. The present review focuses on the use of nanoscale MOFs (Nano-MOFs) as carriers for drug delivery and imaging purposes. In pursuit of significant improvements to current gastrointestinal cancer chemotherapy regimens, systems that allow multiple concomitant therapeutic options (polytherapy) and controlled release are highly desirable. In this sense, MOF-based nanotherapeutics represent a significant step towards achieving this goal. Here, the current state-of-the-art of interdisciplinary research and novel developments into MOF-based gastrointestinal cancer therapy are highlighted and reviewed.

Super-resolution microscopy demystified.

Super-resolution microscopy (SRM) bypasses the diffraction limit, a physical barrier that restricts the optical resolution to roughly 250 nm and was previously thought to be impenetrable. SRM techniques allow the visualization of subcellular organization with unprecedented detail, but also confront biologists with the challenge of selecting the best-suited approach for their particular research question. Here, we provide guidance on how to use SRM techniques advantageously for investigating cellular structures and dynamics to promote new discoveries.

Relationship between cytotoxic T-lymphocyte antigen 4 -318C/T (rs5742909) gene polymorphism and the risk of acute rejection in renal transplantation.

Results on the relationship between CTLA4 -318C/T (rs5742909) gene polymorphism and risk of acute rejection in renal transplantation are still conflicting. This meta-analysis was performed to update the association between CTLA4 -318C/T and risk of acute rejection in renal transplantation. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. Twelve reports were included in this meta-analysis for the association of CTLA4 -318C/T gene polymorphism with acute rejection risk in renal transplantation, consisting of 728 acute rejection patients and 1628 non-acute rejection controls. The association between CTLA4 -318C/T gene polymorphism and acute rejection risk in renal transplantation for overall populations was not found in this meta-analysis (T allele: OR=0.96, 95% CI: 0.60-1.54, P=.88; TT genotype: OR=0.90, 95% CI: 0.47-1.71, P=.74; CC genotype: OR=1.00, 95% CI: 0.62-1.59, P=.98). Interestingly, T allele was associated with the risk of acute rejection in renal transplantation in African population. In conclusion, CTLA4 -318C/T gene polymorphism is not associated with the risk of acute rejection in renal transplantation in overall populations.

Editorial: Analysis of the Interaction of Dp44mT with Human Serum Albumin and Calf Thymus DNA Using Molecular Docking and Spectroscopic Techniques.

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Sika Deer Antler Collagen Type I-Accelerated Osteogenesis in Bone Marrow Mesenchymal Stem Cells via the Smad Pathway.

Deer antler preparations have been used to strengthen bones for centuries. It is particularly rich in collagen type I. This study aimed to unravel part of the purported bioremedial effect of Sika deer antler collagen type I (SDA-Col I) on bone marrow mesenchymal stem cells. The results suggest that SDA-Col I might be used to promote and regulate osteoblast proliferation and differentiation. SDA-Col I might potentially provide the basis for novel therapeutic strategies in the treatment of bone injury and/or in scaffolds for bone replacement strategies. Finally, isolation of SDA-Col I from deer antler represents a renewable, green, and uncomplicated way to obtain a biomedically valuable therapeutic.

Focus on Extracellular Vesicles: Introducing the Next Small Big Thing.

Intercellular communication was long thought to be regulated exclusively through direct contact between cells or via release of soluble molecules that transmit the signal by binding to a suitable receptor on the target cell, and/or via uptake into that cell. With the discovery of small secreted vesicular structures that contain complex cargo, both in their lumen and the lipid membrane that surrounds them, a new frontier of signal transduction was discovered. These "extracellular vesicles" (EV) were initially thought to be garbage bags through which the cell ejected its waste. Whilst this is a major function of one type of EV, i.e., apoptotic bodies, many EVs have intricate functions in intercellular communication and compound exchange; although their physiological roles are still ill-defined. Additionally, it is now becoming increasingly clear that EVs mediate disease progression and therefore studying EVs has ignited significant interests among researchers from various fields of life sciences. Consequently, the research effort into the pathogenic roles of EVs is significantly higher even though their protective roles are not well established. The "Focus on extracellular vesicles" series of reviews highlights the current state of the art regarding various topics in EV research, whilst this review serves as an introductory overview of EVs, their biogenesis and molecular composition.

Focus on Extracellular Vesicles: Development of Extracellular Vesicle-Based Therapeutic Systems.

Many types of cells release phospholipid membrane vesicles thought to play key roles in cell-cell communication, antigen presentation, and the spread of infectious agents. Extracellular vesicles (EVs) carry various proteins, messenger RNAs (mRNAs), and microRNAs (miRNAs), like a "message in a bottle" to cells in remote locations. The encapsulated molecules are protected from multiple types of degradative enzymes in body fluids, making EVs ideal for delivering drugs. This review presents an overview of the potential roles of EVs as natural drugs and novel drug-delivery systems.

GSTM1 Gene Polymorphism is Implicated in Increased Susceptibility to Prostate Cancer in Caucasians and Asians.

Published reports on the relationship between GSTM1 gene polymorphisms and prostate cancer risk are heterogeneous in their conclusions, and the significance of these polymorphisms is still debated. This meta-analysis was performed to attempt to combine comparable studies, thereby increasing sample size and statistical significance in order to obtain a better evaluation of the association between GSTM1 polymorphisms and prostate cancer risk. The association investigations were identified from PubMed, Cochrane Library, and China Biological Medicine Database on March 1, 2014. Forty-three reports were recruited into this meta-analysis that contained data from 6741 patients and 9053 controls. There was a marked association between the GSTM1 null genotype and prostate cancer risk in the overall population (odds ratio = 1.39, 95% confidence interval: 1.21-1.60, P <00001), caucasians (odds ratio = 1.48, 95% confidence interval: 1.23-1.79, P <0001) and Asians (odds ratio = 1.62, 95% confidence interval: 1.16-2.27, P = .005). However, the GSTM1 null genotype was not associated with prostate cancer risk in Africans (odds ratio = 0.77, 95% confidence interval: 0.53-1.13, P = 0.19) and African Americans (odds ratio = 1.00, 95% confidence interval: 0.69-1.45, P = 0.99). In conclusion, GSTM1 null genotype was a risk factor to predict the prostate cancer risk in the overall population, Caucasians, and Asians. Although compelling, limitations inherent to meta-analysis, study design of the individual studies, and most importantly, possible gene-gene and gene-environment interactions, as well as the potential involvement of glutathione S-transferases in multiple cellular processes make drawing definite conclusions difficult.

Meta-analysis of transforming growth factor ß receptor I 6A/9A gene polymorphism and breast cancer risk: the picture remains murky.

Breast cancer is currently the second most common cancer worldwide and the most frequent malignant tumor among women. However, the exact contribution of various allelic alterations remains unclear. This meta-analysis was conducted to evaluate the association of the transforming growth factor ß receptor I 6A/9A (TßR-I 6A/9A) gene polymorphism with breast cancer risk. Relevant studies were identified from PubMed and Cochrane Library on 1 October 2013, and eligible reports were recruited and synthesized. Eleven reports that included a total of 12 studies were recruited into this meta-analysis for the association of the TßR-I 6A/9A gene polymorphism and breast cancer risk. The results indicated that overall the TßR-I 6A allele was associated with breast cancer risk (OR = 1.33, 95% CI: 1.02-1.73, p = 0.04). However, the TßR-I 6A/6A and 9A/9A genotypes were not associated with an increased risk of developing breast cancer (6A/6A: OR = 1.71, 95% CI: 0.95-3.08, p = 0.07; 9A/9A: OR = 0.82, 95% CI: 0.66-1.02, p = 0.08). In the Caucasian population, no such association could be established. In conclusion, the TßR-I 6A allele might represent a risk factor for breast cancer risk, but significantly larger data sets from a larger number of studies, including studies that allow ethnicity, subgroup analysis and environmental impact evaluation, are required to maximize statistical significance and meta-analysis robustness.

Methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and diabetic nephropathy susceptibility in patients with type 2 diabetes mellitus.

Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme that regulates nucleotide synthesis and DNA methylation. The MTHFR C677T gene polymorphism (rs1801133), a C → T transition at nucleotide 677 in exon 4, is a common gene variant of MTHFR and has been implicated in diabetic nephropathy, albeit with inconsistent results. Here, we performed a meta-analysis to assess the common effect size of this polymorphism on DN susceptibility. Case-control studies on the association of the MTHFR C677T gene polymorphism with DN risk were retrieved from databases up to August 1, 2013, and eligible studies were recruited into the meta-analysis and further analyzed. Of 132 studies, 33 were identified as suitable for this analysis. The results showed that T allele and TT genotype were distinctly associated with DN susceptibility in the overall population and Asians, and might be a risk factor in Caucasians and Africans (T allele: Overall population: p < 0.00001, Asians: p = 0.0002, Caucasians: p = 0.02, Africans: p < 0.00001; TT genotype: Overall population: p < 0.00001, Asians: p = 0.0003, Caucasians: p = 0.008, Africans: p = 0.0003). Furthermore, the analysis suggested that the CC genotype might play a protective role against DN onset in patients with type 2 diabetes for the overall population, Asians, Caucasian and Africans. However, due to the limited sample size in the African population, these results should be interpreted with care. In conclusion, the MTHFR C677T T allele or TT genotype might be a significant genetic molecular marker to determine the risk of DN in patients with type 2 diabetes and help to develop suitable disease prevention and management strategies.

Effect of all-trans retinoic acid treatment on prohibitin and renin-angiotensin-aldosterone system expression in hypoxia-induced renal tubular epithelial cell injury.

BACKGROUND AND OBJECTIVE: All-trans retinoic acid (ATRA) exerts various effects on physiological processes such as cell growth, differentiation, apoptosis and inflammation. Prohibitins (PHB), including prohibitin 1 (PHB1) and prohibitin 2 (PHB2), are evolutionary conserved and pleiotropic proteins implicated in various cellular functions, including proliferation, tumor suppression, apoptosis, transcription, and mitochondrial protein folding. The renin-angiotensin-aldosterone system plays a pivotal role in the regulation of blood pressure and volume homeostasis. All these factors and systems have been implicated in renal interstitial fibrosis. Therefore, the objective of this study was to investigate the effect of ATRA treatment on the renin-angiotensin-aldosterone system and expression of prohibitins to further understand its role in the processes leading to renal interstitial fibrosis. METHODS: The hypoxic and oxidative stress conditions in obstructive renal disease were simulated in a hypoxia/reoxygenation model with renal tubular epithelial cells (RTEC) as a model system. Subsequently, the effect of ATRA on mRNA and protein expression levels was determined and correlations were established between factors involved in the renin-angiotensin-aldosterone system, the prohibitins, cellular redox status, renal interstitial fibrosis and ATRA treatment. RESULTS: Correlation analysis showed that both PHB1 and PHB2 protein levels were negatively correlated with angiotensin I, ACE1, angiotensin II, TGF-ß1, Col-IV, FN, ROS, and MDA (PHB1: r = -0.792, -0.834, -0.805, -0.795, -0.778, -0.798, -0.751, -0.682; PHB2: r = -0.872, -0.799, -0.838, -0.773, -0.769, -0.841, -0.794, -0.826; each p < 0.05), but positively correlated with ACE2, SOD, and GSH (PHB1: r = 0.796, 0.879, 0.824; PHB2: r = 0.785, 0.914, 0.849; each p < 0.05). ACE1 was positively correlated with angiotensin I, angiotensin II, TGF-ß1, Col-IV, FN, ROS, and MDA, and negatively correlated with ACE2, SOD, and GSH (each p < 0.05). ACE2 was negatively correlated with ACE1, angiotensin I, angiotensin II, TGF-ß1, Col-IV, FN, ROS, and MDA, and positively correlated with SOD and GSH (each p < 0.05). CONCLUSION: The results suggest that ATRA acts as a positive regulator of PHB1, PHB2 and ACE2, and as a negative regulator of ACE1, angiotensin I, and angiotensin II in a RTEC model system under hypoxia/reoxygenation conditions.

GSTT1 polymorphism and the risk of developing prostate cancer.

A possible association between glutathione S-transferase theta 1 gene (GSTT1) polymorphism and the risk of developing prostate cancer is currently hotly debated, but evidence from various epidemiologic studies remains unclear. This investigation was performed to assess whether an association between GSTT1 polymorphism and prostate cancer risk exists by using meta-analysis to combine comparable studies, thereby increasing sample size and statistical significance, as well as to identify patterns in various studies. The association reports were identified from the PubMed database and the Cochrane Library on March 1, 2013, and data from eligible studies (from 1999-2012) were synthesized. Thirty-eight reports were included in this meta-analysis on the association of the null genotype of GSTT1 with prostate cancer risk. No solid association between the GSTT1 null genotype and prostate cancer risk could be established for the overall population (odds ratio = 1.11, 95% confidence interval: 0.97, 1.27; P = 0.13). However, the GSTT1 null genotype was distinctly associated with prostate cancer risk in Caucasians (odds ratio = 1.24, 95% confidence interval: 1.03, 1.48, P = 0.02). In conclusion, the GSTT1 null genotype is associated with prostate cancer risk in Caucasians, but not in the overall population.

Association of transforming growth factor-ß1 T869C, G915C, and C509T gene polymorphisms with rheumatoid arthritis risk.

The association of transforming growth factor-ß1 (TGFß1) is an important signaling pathway factor involving extracellular matrix regulation, and its gene polymorphisms with the risk of rheumatoid arthritis (RA) is currently still fiercely debated. Therefore, this meta-analysis was performed to determine if TGFß1 T869C, G915C, and C509T gene polymorphisms correlate with the risk of developing RA. Association reports were identified from PubMed, Cochrane Library and CBM-disc (China Biological Medicine Database) on 1 May 2013, and eligible studies were recruited and synthesized to identifying patterns among study results. T869C TT genotype in the overall population was associated with increased RA risk (OR = 1.28, 95% CI: 1.02-1.60, p = 0.03). In the sub-group analysis, T869C TT genotype was shown to be a risk factor for RA, and T869C C allele or CC genotype a protective factor against RA disease in Asians, but these associations were not found in Caucasians. Furthermore, TGFß1 C509T TT genotype was distinctly associated with RA susceptibility, but the T allele and CC genotype were not. TGFß1 G915C gene polymorphism was not associated with RA susceptibility. In conclusion, the TT genotype of TGFß1 T869C was associated with RA risk in the overall population and Asians. Furthermore, CC genotype or C allele was determined to be protective factors with respect to the RA risk in the overall population and Asians. Nonetheless, additional studies are required to firmly establish a correlation between the aforementioned polymorphisms and RA risk.

LIM homeobox transcription factor 1B expression affects renal interstitial fibrosis and apoptosis in unilateral ureteral obstructed rats.

LIM homeobox transcription factor 1B (LMX1B) is a transcription factor of the LIM homeodomain type and has been implicated in the development of diverse structures such as limbs, kidneys, eyes, and the brain. Furthermore, LMX1B has been implicated in nail-patella syndrome, which is predominantly characterized by malformation of limbs and nails, and in 30% of patients, nephropathy, including renal fibrosis, is observed. Since no reports were available that studied the link between LMX1B expression and renal interstitial fibrosis, we explored if LMX1B affects typical markers of fibrosis, e.g., extracellular matrix components, profibrotic factors, and apoptosis as the final detrimental consequence. We recently showed that LMX1B acts as a negative regulator of transforming growth factor-ßl, collagen type III, fibronectin, cleaved caspase-3, and the cell apoptosis rate in a renal tubular epithelial cell system under hypoxic conditions. Here, we confirmed these results in unilateral ureteral obstructed rats. Furthermore, LMX1B was distinctly expressed throughout the glomerulus and tubule lining, including epithelial cells. Knockdown of LMX1B aggravated the expression of fibrosis markers, oxidative stress, and apoptosis compared with the already increased levels due to unilateral ureteral obstruction, whereas overexpression attenuated these effects. In conclusion, reduced LMX1B levels clearly represent a risk factor for renal fibrosis, whereas overexpression affords some level of protection. In general, LMX1B may be considered to be a negative regulator of the fibrosis index, transforming growth factor-ßl, collagen type III, fibronectin, cleaved caspase-3, cell apoptosis, ROS, and malondialdehyde (r = -0.756, -0.698, -0.921, -0.923, -0.843, -0.794, -0.883, and -0.825, all P < 0.01).

Association of prohibitin-1 and 2 with oxidative stress in rats with renal interstitial fibrosis.

Prohibitins PHB1 and PHB2 are evolutionary conserved and pleiotropic proteins, which have been shown to be important factors in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. Recently, we demonstrated that down-regulation promoted renal interstitial fibrosis (RIF) in ureteral obstructed rats. Furthermore, the hypoxic conditions and oxidative stress have been implicated in obstruction-mediated renal disease. This study was performed to explore the association of PHBs with oxidative stress in a rat model of RIF. PHBs, the pro-fibrotic transforming growth factor-ß1 (TGF-ß1), and the extracellular matrix proteins collagen-IV (Col-IV) and fibronectin (FN) were evaluated, as were markers of oxidative stress [total reactive oxygen species (ROS), malondialdehyde (MDA)] and antioxidative capacity (superoxide dismutase, glutathione), and apoptosis. Our results showed a progressive increase in oxidative stress and concomitant decrease in antioxidants over a period of 4 weeks ureteral obstruction. Concomitantly, profibrotic components increased and PHB expression decreased. Overall, both PHBs were negatively correlated with the extent of observed fibrosis, TGF-ß1, Col-IV, FN, ROS, MDA, and apoptosis.

Association of transforming growth factor-ß1 T869C gene polymorphism with diabetic nephropathy risk.

AIM: A possible association between the transforming growth factor-ß1 (TGF-ß1) T869C gene polymorphism and the risk of developing diabetic nephropathy (DN) remains unclear. This investigation was performed to assess if an association between the TGF-ß1 T869C gene polymorphism and DN risk exists by using meta-analysis to combine comparable studies, thereby increasing sample size and statistical significance, and to identify patterns in various studies. METHODS: The association reports were identified from PubMed, Cochrane Library, and CBM-disc (China Biological Medicine Database) on 1 May 2013, and eligible studies were recruited and synthesized. RESULTS: Fifty reports were recruited into this meta-analysis for the association of the TGF-ß1 T869C gene polymorphism with DN risk. The TT genotype in the overall population was shown to be associated with DN risk (odds ratio (OR) = 0.74, 95% confidence interval (CI): 0.56-0.98, P = 0.04). In the sub-group analysis, CC genotype was associated with DN risk in Asians, Caucasians, and Africans. However, the sample size for Caucasians and Africans was relatively small. Furthermore, T allele was distinctly associated with the risk of developing DN in the Asian population (OR = 0.76, 95% CI: 0.62-0.92, P = 0.005). CONCLUSIONS: The TT genotype of TGF-ß1 T869C in the overall population was associated with DN risk, whereas the CC genotype and T allele were distinctly associated with DN risk in the Asian population. Nonetheless, additional studies are required to firmly establish a correlation between the aforementioned polymorphism and DN risk.

Meta-analysis of the association of glutathione S-transferase T1 null/presence gene polymorphism with the risk of gastric carcinoma.

A possible association of glutathione S-transferase T1 (GSTT1) null/presence gene polymorphism and an increased risk of developing gastric carcinoma is still unclear and hotly debated. This investigation was performed to assess the association of the GSTT1 null/presence gene polymorphism with the risk of gastric carcinoma via a meta-analysis to increase sample size and statistical significance. PubMed, Cochrane Library and CBM-disc (China Biological Medicine Database) were searched on March 1, 2013, association reports were identified, and eligible studies were recruited and synthesized. Fifty-two reports were found to be suitable for this meta-analysis for the association of the GSTT1 null genotype with gastric carcinoma risk. The results showed that there was a significantly increased gastric carcinoma risk when the GSTT1 null genotype was present in the overall population (OR 1.21, 95 % CI 1.11-1.32, P < 0.0001), Caucasians (OR 1.25, 95 % CI 1.05-1.48, P = 0.01), East-Asians (OR 1.18, 95 % CI 1.06-1.31, P = 0.003), and Chinese (OR 1.24, 95 % CI 1.07-1.44, P = 0.005). However, no statistically relevant association could be established for the Indian ethnic group (OR 1.33, 95 % CI 0.94-1.90, P = 0.11). In conclusion, the GSTT1 null genotype is associated with an increased gastric carcinoma risk in the overall population, Caucasians, East-Asians, and Chinese.

LIM homeobox transcription factor 1B is associated with pro-fibrotic components and apoptosis in hypoxia/reoxygenation renal tubular epithelial cells.

LIM homeobox transcription factor 1B (LMX1B) is a transcription factor of the LIM-homeodomain type, which plays an important role in foetal development during formation of the extremities, kidneys, eyes, and the brain. Furthermore, LMX1B has been implicated in nail-patella syndrome, which is predominantly characterized by malformation of limbs and nails, and in 30 % of patients, nephropathy, including renal fibrosis, is observed. Since no reports were available that studied the link between LMX1B expression and pro-fibrotic components and apoptosis in hypoxic renal tubular epithelial cells (RTEC), we explored if LMX1B was associated with extracellular matrix components, profibrotic factors, and apoptosis induced by hypoxia/reoxygenation (H-R). In this cell system under hypoxic conditions, when the expression of LMX1B was inhibited in H-R RTEC, the expression of transforming growth factor-ßl, collagen-III, fibronectin, cleaved caspase-3, and cell apoptosis rate was increased. Consequently, overexpression of LMX1B was associated with reduced cell apoptosis, whilst downregulation of LMX1B was associated with increased cell apoptosis in H-R RTEC.

Prohibitin attenuates oxidative stress and extracellular matrix accumulation in renal interstitial fibrosis disease.

Prohibitin is an evolutionary conserved and pleiotropic protein that has been implicated in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. Both prohibitin over- and under-expression have been implicated in various diseases and cell types. We recently demonstrated that prohibitin down-regulation results in increased renal interstitial fibrosis (RIF). Here we investigated the role of oxidative stress and prohibitin expression in RIF in unilateral ureteral obstructed rats. Lentivirus-based delivery vectors were used to knockdown or over-express prohibitin. Our results show that increased prohibitin expression was negatively correlated with the RIF index, reactive oxygen species, malon dialdehyde, transforming growth factor ß1, collagen IV, fibronectin, and cell apoptosis index. In conclusion, we postulate that prohibitin acts as a positive regulator of mechanisms that counteract oxidative stress and extracellular matrix accumulation and therefore has an antioxidative effect.

Prohibitin is associated with antioxidative protection in hypoxia/reoxygenation-induced renal tubular epithelial cell injury.

Prohibitin is an evolutionary conserved and pleiotropic protein that has been implicated in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. We recently demonstrated that prohibitin downregulation results in increased renal interstitial fibrosis. Here we investigated the role of oxidative stress and prohibitin expression in a hypoxia/reoxygenation injury system in renal tubular epithelial cells with lentivirus-based delivery vectors to knockdown or overexpress prohibitin. Our results show that increased prohibitin expression was negatively correlated with reactive oxygen species, malon dialdehyde, transforming-growth-factor-ß1, collagen-IV, fibronectin, and apoptosis (r = -0.895, -0.764, -0.798, -0.826, -0.817, -0.735; each P < 0.01), but positively correlated with superoxide dismutase, glutathione and mitochondrial membrane potential (r = 0.807, 0.815, 0.739; each P < 0.01). We postulate that prohibitin acts as a positive regulator of mechanisms that counteract oxidative stress and extracellular matrix accumulation and therefore has an antioxidative effect.