Angiogenic activity of mitochondria; beyond the sole bioenergetic organelle.

Angiogenesis is a complex process that involves the expansion of the pre-existing vascular plexus to enhance oxygen and nutrient delivery and is stimulated by various factors, including hypoxia. Since the process of angiogenesis requires a lot of energy, mitochondria play an important role in regulating and promoting this phenomenon. Besides their roles as an oxidative metabolism base, mitochondria are potential bioenergetics organelles to maintain cellular homeostasis via sensing alteration in oxygen levels. Under hypoxic conditions, mitochondria can regulate angiogenesis through different factors. It has been indicated that unidirectional and bidirectional exchange of mitochondria or their related byproducts between the cells is orchestrated via different intercellular mechanisms such as tunneling nanotubes, extracellular vesicles, and gap junctions to maintain the cell homeostasis. Even though, the transfer of mitochondria is one possible mechanism by which cells can promote and regulate the process of angiogenesis under reperfusion/ischemia injury. Despite the existence of a close relationship between mitochondrial donation and angiogenic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible role of mitochondria concerning angiogenesis, especially the role of mitochondrial transport and the possible relation of this transfer with autophagy, the housekeeping phenomenon of cells, and angiogenesis.

Amikacin-loaded niosome nanoparticles improve amikacin activity against antibiotic-resistant Klebsiella pneumoniae strains.

Amikacin is an aminoglycoside antibiotic used in drug-resistant bacterial infections. The spread of bacterial infections has become a severe concern for the treatment system because of the simultaneous drug resistance bacteria and SARS-CoV-2 hospitalized patients. One of the most common bacteria in the development of drug resistance is Klebsiella strains, which is a severe threat due to the possibility of biofilm production. In this regard, recent nanotechnology studies have proposed using nanocarriers as a practical proposal to improve the performance of antibiotics and combat drug resistance. Among drug nanocarriers, niosomes are considered for their absorption mechanism, drug coverage, and biocompatibility. In this study, niosomal formulations were synthesized by the thin-layer method. After optimizing the synthesized niosomes, their properties were evaluated in terms of stability and drug release rate. The toxicity of the optimal formulation was then analyzed. The effect of free amikacin and amikacin encapsulated in niosome on biofilm inhibition were compared in multi-drug resistant isolated Klebsiella strains, and the mrkD gene expression was calculated. The MIC and MBC were measured for the free drug and amikacin loaded in the noisome. The particle size of synthesized amikacin-loaded niosomes ranged from 175.2 to 248.3 nm. The results showed that the amount of lipid and the molar ratio of tween 60 to span 60 has a positive effect on particle size, while the molar ratio of surfactant to cholesterol has a negative effect. The highest release rate in amikacin-loaded niosomes is visible in the first 8 h, and then a slower release occurs up to 72 h. The cytotoxicity induced by amikacin-loaded niosome is significantly less than the cytotoxicity of free amikacin in HFF cells (***p < 0.001, **p < 0.01). The mrkD mRNA expression level in the studied strains was significantly reduced after treatment with niosome-containing amikacin compared to free amikacin (***p < 0.001). It was confirmed that in the presence of the niosome, the amikacin antibacterial activity increased while the concentration of the drug used decreased, the formation of biofilm inhibited, and reduced antibiotics resistance in MDR Klebsiella strains.

Revolutionizing Cancer Treatment: Harnessing the Power of Mesenchymal Stem Cells for Precise Targeted Therapy in the Tumor Microenvironment.

In recent years, mesenchymal stem cells (MSCs) have emerged as promising anti-- cancer mediators with the potential to treat several cancers. MSCs have been modified to produce anti-proliferative, pro-apoptotic, and anti-angiogenic molecules that could be effective against a variety of malignancies. Additionally, customizing MSCs with cytokines that stimulate pro-tumorigenic immunity or using them as vehicles for traditional chemical molecules with anti-cancer characteristics. Even though the specific function of MSCs in tumors is still challenged, promising outcomes from preclinical investigations of MSC-based gene therapy for a variety of cancers inspire the beginning of clinical trials. In addition, the tumor microenvironment (TME) could have a substantial influence on normal tissue stem cells, which can affect the treatment outcomes. To overcome the complications of TME in cancer development, MSCs could provide some signs of hope for converting TME into unequivocal therapeutic tools. Hence, this review focuses on engineered MSCs (En-MSCs) as a promising approach to overcoming the complications of TME.

Autophagy modulation effect on homotypic transfer of intracellular components via tunneling nanotubes in mesenchymal stem cells.

BACKGROUND: Recent studies have proved the role of autophagy in mesenchymal stem cell (MSCs) function and regenerative properties. How and by which mechanism autophagy modulation can affect the juxtacrine interaction of MSCs should be addressed. Here, the role of autophagy was investigated in the formation of tunneling nanotubes (TNTs) and homotypic mitochondrial donation. METHODS: MSCs were incubated with 15 µM Metformin (Met) and/or 3 µM 3-methyladenine (3-MA) for 48 h. The formation of TNTs was assessed using bright-field and SEM images. The mitochondria density and ΔΨ values were monitored using flow cytometry analysis. Using RT-PCR and protein array, the close interaction and shared mediators between autophagy, apoptosis, and Wnt signaling pathways were also monitored. The total fatty acid profile was assessed using gas chromatography. RESULT: Data indicated the increase of TNT length and number, along with other cell projections after the induction of autophagy while these features were blunted in 3-MA-treated MSCs (p < 0.05). Western blotting revealed the significant reduction of Rab8 and p-FAK in 3-MA-treated MSCs (p < 0.05), indicating the inhibition of TNT assembly and vesicle transport. Likewise, the stimulation of autophagy increased autophagic flux and mitochondrial membrane integrity compared to 3-MA-treated MSCs. Despite these findings, protein levels of mitochondrial membrane Miro1 and 2 were unchanged after autophagy inhibition/stimulation (p > 0.05). We found that the inhibition/stimulation of autophagy can affect the protein, and transcription levels of several mediators related to Wnt and apoptosis signaling pathways involved in different cell bioactivities. Data confirmed the profound increase of mono and polyunsaturated/saturated fatty acid ratio in MSCs exposed to autophagy stimulator. CONCLUSIONS: In summary, autophagy modulation could affect TNT formation which is required for homotypic mitochondrial donation. Thus, the modulation of autophagy creates a promising perspective to increase the efficiency of cell-based therapies.

The Role of MicroRNAs in the Induction of Pancreatic Differentiation.

Stem cell-based therapy is one of the therapeutic options with promising results in the treatment of diabetes. Stem cells from various sources are expanded and induced to generate the cells capable of secreting insulin. These insulin-producing cells [IPCs] could be used as an alternative to islets in the treatment of patients with diabetes. Soluble growth factors, small molecules, geneencoding transcription factors, and microRNAs [miRNAs] are commonly used for the induction of stem cell differentiation. MiRNAs are small non-coding RNAs with 21-23 nucleotides that are involved in the regulation of gene expression by targeting multiple mRNA targets. Studies have shown the dynamic expression of miRNAs during pancreatic development and stem cell differentiation. MiR- 7 and miR-375 are the most abundant miRNAs in pancreatic islet cells and play key roles in pancreatic development as well as islet cell functions. Some studies have tried to use these small RNAs for the induction of pancreatic differentiation. This review focuses on the miRNAs used in the induction of stem cells into IPCs and discusses their functions in pancreatic ß-cells.

Multi-scale segmentation in GBM treatment using diffusion tensor imaging.

Glioblastoma (GBM) is the commonest primary malignant brain tumor in adults, and despite advances in multi-modality therapy, the outlook for patients has changed little in the last 10 years. Local recurrence is the predominant pattern of treatment failure, hence improved local therapies (surgery and radiotherapy) are needed to improve patient outcomes. Currently segmentation of GBM for surgery or radiotherapy (RT) planning is labor intensive, especially for high-dimensional MR imaging methods that may provide more sensitive indicators of tumor phenotype. Automating processing and segmentation of these images will aid treatment planning. Diffusion tensor magnetic resonance imaging is a recently developed technique (DTI) that is exquisitely sensitive to the ordered diffusion of water in white matter tracts. Our group has shown that decomposition of the tensor information into the isotropic component (p - shown to represent tumor invasion) and the anisotropic component (q - shown to represent the tumor bulk) can provide valuable prognostic information regarding tumor infiltration and patient survival. However, tensor decomposition of DTI data is not commonly used for neurosurgery or radiotherapy treatment planning due to difficulties in segmenting the resultant image maps. For this reason, automated techniques for segmentation of tensor decomposition maps would have significant clinical utility. In this paper, we modified a well-established convolutional neural network architecture (CNN) for medical image segmentation and used it as an automatic multi-sequence GBM segmentation based on both DTI image maps (p and q maps) and conventional MRI sequences (T2-FLAIR and T1 weighted post contrast (T1c)). In this proof-of-concept work, we have used multiple MRI sequences, each with individually defined ground truths for better understanding of the contribution of each image sequence to the segmentation performance. The high accuracy and efficiency of our proposed model demonstrates the potential of utilizing diffusion MR images for target definition in precision radiation treatment planning and surgery in routine clinical practice.

Surgical options for beating-heart aortic valve replacement in patients with patent coronary artery bypass.

BACKGROUND AND AIM OF THE STUDY: The study aim was to assess the surgical options and advantages of beating-heart aortic valve replacement (AVR) in patients with patent coronary artery bypasses. METHODS: In this prospective study, conducted between January and August 2006, four consecutive patients (mean age 77.5 +/- 6.6 years) each with patent coronary artery bypasses, underwent beating-heart AVR using two specific methods of myocardial perfusion based on the origin and status of the grafts, as assessed by preoperative angiography. Pre-operatively, all patients were in NYHA functional class III, and each received an aortic valve bioprosthesis. RESULTS: There were no hospital deaths. The mean duration of ICU stay was 3.2 +/- 1.3 days. One patient presented with transitory atrial fibrillation. At discharge, echocardiography confirmed normally functioning bioprostheses, with no significant transprosthetic gradient. CONCLUSION: Beating-heart AVR with patent coronary artery bypasses using continuous myocardial perfusion is a reliable, simple and effective technique to reduce the risks of graft and myocardial injuries, and to achieve optimal preservation of the hypertrophic myocardium with coronary artery disease.

Association of Serum Fetuin-A Levels with Allograft Outcome in Renal Transplant Recipients.

PURPOSE: To determine serum fetuin-A pattern after renal transplantation and its association with graft outcome. MATERIALS AND METHODS: In 41 renal transplant recipients, serum pretransplant fetuin-A levels and serum fetuin-A concentrations on days 7 and 30 after transplantation were measured using the enzyme-linked immunosorbent as­say (ELISA) method. Also, the association between serum fetuin-A levels with clinical and laboratory parameters was evaluated. RESULTS: A significant decrease in serum fetuin-A levels was noted in the first week after transplantation (P < .001). Subsequently, it started to increase and surpass pretransplant values during the first month (P < .001). Pretransplant fetuin-A levels did not differ among patients with different diethylenetriamine pentaacetic acid (DTPA) results. In addition, serum fetuin-A levels did not significantly correlate with metabolic parameters. CONCLUSION: In this prospective study there was no increase in serum fetuin-A levels during the first month and pretransplant fetuin-A levels are not predictive for allograft outcome in renal transplant recipients.

Does hypertension remain after kidney transplantation?

Hypertension is a common complication of kidney transplantation with the prevalence of 80%. Studies in adults have shown a high prevalence of hypertension (HTN) in the first three months of transplantation while this rate is reduced to 50- 60% at the end of the first year. HTN remains as a major risk factor for cardiovascular diseases, lower graft survival rates and poor function of transplanted kidney in adults and children. In this retrospective study, medical records of 400 kidney transplantation patients of Sina Hospital were evaluated. Patients were followed monthly for the 1st year, every two months in the 2nd year and every three months after that. In this study 244 (61%) patients were male. Mean ± SD age of recipients was 39.3 ± 13.8 years. In most patients (40.8%) the cause of end-stage renal disease (ESRD) was unknown followed by HTN (26.3%). A total of 166 (41.5%) patients had been hypertensive before transplantation and 234 (58.5%) had normal blood pressure. Among these 234 individuals, 94 (40.2%) developed post-transplantation HTN. On the other hand, among 166 pre-transplant hypertensive patients, 86 patients (56.8%) remained hypertensive after transplantation. Totally 180 (45%) patients had post-transplantation HTN and 220 patients (55%) didn't develop HTN. Based on the findings, the incidence of post-transplantation hypertension is high, and kidney transplantation does not lead to remission of hypertension. On the other hand, hypertension is one of the main causes of ESRD. Thus, early screening of hypertension can prevent kidney damage and reduce further problems in renal transplant recipients.