The mammalian target of rapamycin (mTOR) is the major controller of a number of important cellular activities, including protein synthesis, cell expansion, multiplication, autophagy, lysosomal ...function, and cellular metabolism. When mTOR interacts with specific adaptor proteins, it forms two complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The mTOR signaling system regulates gene transcription and protein manufacturing to control proliferation of cell, differentiation of immune cell, and tumor metabolism. Due to its vital role in case of microbial infections, inflammations and cancer development and progression, mTOR has been considered as a key therapeutic target for the development of targeted medication. As autophagy dysfunction is linked to changes in both innate and adaptive immune responses, bacterial clearance defects, and goblet and Paneth cell malfunction, all of these changes are linked to inflammatory bowel diseases (IBD) and colorectal cancer (CRC) pathogenesis. Preclinical and clinical data have shown that the inhibition and induction of autophagy have significant potential to be translated into the clinical applications. In IBD and several CRC models, mTORC1 inhibitors have been found effective. In the recent years, a number of novel mTOR inhibitors have been investigated in clinical trials, and a number of drugs have shown considerably enhanced efficacy when combined with mTOR inhibitors. The future developments in the mTOR targeting medications can benefit patients in individualized therapy. Advanced and innovative medicines that are more effective and have lower drug resistance are still in high demand. New findings could be relevant in medicine development, pharmacological modification, or future mTOR inhibitor research. Therefore, the goal of this review is to present a comprehensive account of current developments on the mTOR pathway and its inhibitors, with an emphasis on the management of microbial infections, the treatment of inflammatory bowel disease, and the management of colon cancer.
The extracellular matrix (ECM) is a complex mixture of structural proteins, proteoglycans, and signaling molecules that are essential for tissue integrity and homeostasis. While a number of recent ...studies have explored the use of decellularized ECM (dECM) as a biomaterial for tissue engineering, the complete composition, structure, and mechanics of these materials remain incompletely understood. In this study, we performed an in-depth characterization of skin-derived dECM biomaterials for human skin equivalent (HSE) models. The dECM materials were purified from porcine skin, and through mass spectrometry profiling, we quantified the presence of major ECM molecules, including types I, III, and VI collagen, fibrillin, and lumican. Rheological analysis demonstrated the sol-gel and shear-thinning properties of dECM materials, indicating their physical suitability as a tissue scaffold, while electron microscopy revealed a complex, hierarchical structure of nanofibers in dECM hydrogels. The dECM materials were compatible with advanced biofabrication techniques, including 3D printing within a gelatin microparticle support bath, printing with a sacrificial material, or blending with other ECM molecules to achieve more complex compositions and structures. As a proof of concept, we also demonstrate how dECM materials can be fabricated into a 3D skin wound healing model using 3D printing. Skin-derived dECM therefore represents a complex and versatile biomaterial with advantageous properties for the fabrication of next-generation HSEs.
(1) Background: 2-Methoxyestradiol (2ME) is a metabolite of estrogens and possesses promising anti-proliferative and cytotoxic activities. However, it suffers unfavorable pharmacokinetic ...characteristics such as absorption after oral administration. The aim of this study was to prepare an optimized 2ME self-nanoemulsifying drug delivery system (2ME-SNEDDS) and evaluate its cytotoxicity and pro-apoptotic activities in MCF-7 breast cancer cells. (2) Methods: For optimization of the 2ME-SNEDDS, a three-component system was used in the D-optimal mixture experimental study. MCF-7 cells were incubated with the 2ME-SNEDDS and subjected to an assessment of growth inhibition, cell cycle progression, annexin V staining, caspase-3 concentration, Bax, Bcl-2, and cyclin D1 mRNA expression, and reactive oxygen species (ROS) generation. (3) Results: The optimized formula had a globule size of 94.97 ± 4.35 nm. Zeta potential was found to be -3.4 ± 1.2 mV with a polydispersity index (PDI) of 0.34. In addition, 96.3 ± 4.3% of 2ME was released from the 2ME-SNEDDS within 24 h using the activated analysis bag technique. Moreover, the prepared 2ME-SNEDDS exhibited a significant enhancement of the anti-proliferative activity against MCF-7 cells in comparison to raw 2ME. This was associated with cyclin D1 expression down-regulation and the accumulation of cells in the G0/G1 and G2/M phases. The pro-apoptotic activities of the 2ME-SNEDDS were confirmed by annexin V staining, which indicated enhanced early and late cell death. This accompanied modulation of the mRNA expression of Bax and Bcl-2 in favor of apoptosis. The 2ME-SNEDDS significantly enhanced cleaved caspase-3 concentration in comparison to raw 2ME. In addition, the 2ME-SNEDDS significantly increased the generation of ROS in MCF-7 cells. (4) Conclusions: The 2ME-SNEDDS exhibits enhanced cytotoxicity and pro-apoptotic activity in MCF-7 cells. This is mediated by, at least partially, ROS generation.
Background
Diffusion-weighted MR imaging (DWI) is sensitive to changes in the microstructural organization of tissue that may influence water diffusion. It has been utilized in various forms to ...evaluate head and neck tumors. The apparent diffusion coefficient (ADC) value is a quantitative parameter for distinguishing malignant from benign thyroid nodule. Determination of different pathologic types of the thyroid nodules is crucial for appropriate therapeutic approach. Our point was to assess the utility of apparent diffusion coefficient values in discriminating different subtypes of benign and malignant solitary thyroid nodules using diffusion MRI with pathological correlation.
Results
This prospective study included 73 patients who had thyroid nodules. The size of the investigated lesions ranged from 0.6 to 3 cm. Most nodules were benign (79.45%), and most of these benign nodules were adenomatous nodules. There was a significant difference in ADC values of benign and malignant thyroid nodules (
P
0.0001), with the mean ADC value for the benign group (1.7 ± 0.12 × 10
-3
) higher than that for malignant nodule (0.71 ± 0.15 × 10). The sensitivity, specificity, and accuracy of ADC in differentiating between benign and malignant thyroid nodules were 97.5, 94.4, and 99.2%, respectively. We noticed a significant overlap in the ADC value of pathological subtypes and upon reviewing the pathological results, we found insignificant differences in the ADC values of the various subtypes of malignant and benign nodules, with
P
value ranging from 0.054 to 0.062 between different pathological subtypes. A significant difference was only noted between non-complicated cysts and solid nodules
P
0.0001. In our series, an ADC value of 0.92 × 10
-3
mm
2
/s or less could be used as an indicator of malignancy, with a sensitivity of 97.5%, a specificity of 94.4%, and an accuracy of 99.2%.
Conclusion
Diffusion MRI including ADC values are helpful in differentiation between benign and malignant thyroid nodules but not helpful in differentiating between different subtypes of benign and malignant nodules.
Myiasis is the parasitic infestation of human by the larvae (maggots) of dipterous fly that grow within the host while feeding on its tissue. Cutaneous myiasis is the most considerably encountered ...clinical form. Moreover, wound (traumatic) myiasis is the main clinical manifestation of cutaneous myiasis. In this research, we aimed to study the type of infesting larvae that are responsible for wound myiasis in the patients in Minia city, Egypt. Three cases of wound myiasis have been noticed among 280 patients with wounds at different parts of bodies. Two of them were diabetic patients. The third one had a history of hypertension with right side hemiplegia 2 years ago. All of them were elderly. The larvae removed from cases 1 and 3 were identified macroscopically and microscopically as the third-stage larvae of Sarcophaga haemorrhoidalis. The larvae removed from case 2 were the third-stage larvae of Phormia regina, which is very rare worldwide. In addition to the open and obsolete wound, diabetes mellitus and low socio-economic circumstances were shown to be attributed as important predisposing risk factors that led to the occurrence of myiasis in these patients.
BACKGROUND: Polyamine intake from milk is considered essential for post‐natal maturation of the immune system and small intestine. The present study aimed to determine polyamine content in human milk ...after preterm delivery and the association with mothers' dietary intake. In comparison, the polyamine levels were compared with those in term breast milk and some corresponding formulas. METHODS: Transitional breast milk was collected from 40 mothers delivering after 24–36 weeks of gestation, and from 12 mothers delivering after full term. Food intake was assessed in mothers delivering preterm babies using a 3‐day diary. Polyamines were analysed by high‐performance liquid chromatography. RESULTS: The dietary intake of polyamines was significantly associated with breast milk content but weaker for spermine than for spermidine and putrescine. Total polyamine level was higher in preterm than term milk and lower in the corresponding formulas. Putrescine, spermidine and spermine contents mean (SEM) in preterm milk were 165.6 (25), 615.5 (80) and 167.7 (16) nmol dL⁻¹, respectively, with the levels of putrescine and spermidine being 50% and 25% higher than in term milk. The content of spermine did not differ. CONCLUSIONS: Dietary intake of polyamines has an impact on the content in breast milk. The difference between human milk after preterm and term delivery might be considered when using donor human milk for preterm infants. The corresponding formulas had lower contents. Further studies are important for determining the relationship between tissue growth and maturation and optimal intake.
Laparoscopic cholecystectomy (LC) is one of the first laparoscopic procedures performed by surgical trainees. This study aims to determine preoperative and/or intraoperative predictors of difficult ...LC and to compare complications of LC performed by trainees with that performed by trained surgeons. A cohort of 180 consecutive patients with cholelithiasis who underwent LC was analyzed. We used univariate and binary logistic regression analyses to predict factors associated with difficult LC. We compared the rate of complications of LCs performed by trainees and that performed by trained surgeons using Pearson’s chi-square test. Patients with impacted stone in the neck of the gallbladder (GB) (OR, 5.0; 95% CI, 1.59–15.77), with adhesions in the Triangle of Calot (OR, 2.9; 95% CI, 1.27–6.83), or with GB rupture (OR, 3.4; 95% CI, 1.02–11.41) were more likely to experience difficult LC. There was no difference between trainees and trained surgeons in the rate of cystic artery injury (p=.144) or GB rupture (p=.097). However, operative time of LCs performed by trained surgeons was significantly shorter (median, 45 min; IQR, 30–70 min) compared with the surgical trainees’ operative time (60 min; IQR, 50–90 min). Surgical trainees can perform difficult LC safely under supervision with no increase in complications albeit with mild increase in operative time.
Phosphocitrate (PC) inhibits osteoarthritis (OA) in Hartley guinea pigs. However, the underlying molecular mechanisms remain poorly understood.
This study sought to examine the biological effect of ...PC on OA chondrocytes and test the hypothesis that PC may exert its OA disease modifying effect, in part, by inhibiting the expression of genes implicated in OA disease process and stimulating the production of extracellular matrices.
OA chondrocytes were cultured in the absence or presence of PC. Total RNA was extracted and subjected to microarray analyses. The effect of PC on proliferation and chondrocyte-mediated calcification were examined in monolayer culture. The effect of PC on the production of extracellular matrices was examined in micromass culture.
PC downregulated the expression of numerous genes classified in proliferation and apoptosis while upregulating the expression of many genes classified in transforming growth factor-β (TGF-β) receptor signaling pathway and ossification. PC also downregulated the expressions of many genes classified in inflammatory response and Wnt receptor signaling pathways. Consistent with its effect on the expression of genes classified in proliferation, ossification, and skeletal development, PC inhibited the proliferation of OA chondrocytes and chondrocyte-mediated calcification while stimulating the production of extracellular matrices.
PC may exert its OA disease modifying effect, in part, through a crystal-independent mechanism or by inhibiting the expressions of many genes implicated in OA disease process, and at the same time, stimulating the expression of genes implicated in chondroprotection and production of extracellular matrices.
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