Foreskin Research Articles

Phase-field dislocation dynamics simulations of temperature-dependent glide mechanisms in niobium

In this work, we present a three-dimensional ab-initio informed phase-field-dislocation dynamics model combined with Langevin dynamics to investigate glide mechanisms of edge and screw dislocations at finite temperatures in Nb. Over a temperature range of 150 K to 600 K, calculations reveal that the screw dislocation changes its mode of glide at two distinct temperatures. At 200–220 K, the glide mechanism changes from single kink pair motion to multiple kink pair motion. The kink pair enthalpies quantitatively agree with those extracted from experimental tests on Nb single crystals. Between 300 K and 350 K the glide mode transitions to overlapping kink pairs and glide is smooth (non-jerky). The screw to edge mobility ratio is seen to peak at 350 K and plateau thereafter. These two temperatures coincide with temperatures at which yield strengths in Nb are observed to become thermally insensitive and athermal, respectively.

3D human foreskin model for testing topical formulations of sildenafil citrate

Sildenafil citrate is an approved drug used for the treatment of erectile dysfunction and premature ejaculation. Despite a widespread application, sildenafil citrate shows numerous adverse cardiovascular effects in high-risk patients. Local transdermal drug delivery of this drug is therefore being explored as an interesting and noninvasive alternative administration method that avoids adverse effects arised from peak plasma drug concentrations. Although human and animal skin represents the most reliable models to perform penetration studies, they involve a series of ethical issues and restrictions. For these reasons new in vitro approaches based on artificially reconstructed human skin or “human skin equivalents” are being developed as possible alternatives for transdermal testing. There is little information, however, on the efficiency of such new in vitro methods on cutaneous penetration of active ingredients. The objective of the current study was to investigate the sildenafil citrate loaded in three commercial transdermal vehicles using 3D full-thickness skin equivalent and compare the results with the permeability experiments using porcine skin. Our results demonstrated that, while the formulation plays an imperative role in an appropriate dermal uptake of sildenafil citrate, the D coefficient results obtained by using the 3D skin equivalent are comparable to those obtained by using the porcine skin when a simple drug suspension is applied (1.17 × 10-10 ± 0.92 × 10-10 cm2/s vs 3.5 × 102 ± 3.3 × 102 cm2/s), suggesting that in such case, this 3D skin model can be a valid alternative for ex-vivo skin absorption experiments.

Direct interaction with the BRD4 carboxyl-terminal motif (CTM) and TopBP1 is required for human papillomavirus 16 E2 association with mitotic chromatin and plasmid segregation function.

Human papillomavirus 16 (HPV16) is a causative agent in around 3%-4% of all human cancers, and currently, there are no anti-viral therapeutics available for combating this disease burden. In order to identify new therapeutic targets, we must increase our understanding of the HPV16 life cycle. Previously, we demonstrated that an interaction between E2 and the cellular protein TopBP1 mediates the plasmid segregation function of E2, allowing distribution of viral genomes into daughter nuclei following cell division. Here, we demonstrate that E2 interaction with an additional host protein, BRD4, is also essential for E2 segregation function, and that BRD4 exists in a complex with TopBP1. Overall, these results enhance our understanding of a critical part of the HPV16 life cycle and presents several therapeutic targets for disruption of the viral life cycle.

The characteristics and biological activity enhancements of melatonin encapsulations for skin care product applications

Melatonin (MLT) exhibits antioxidant, ultraviolet protection, anti-inflammatory, and anti-aging properties. However, its effectiveness is limited by instability, a short half-life, and incompatible absorption. In this research, we encapsulated melatonin (MLT) in transfersomes (MT) and niosomes (MN) to enhance their properties and investigate their effects through in vitro cell assays using murine macrophages cells and human foreskin fibroblasts cells. The vesicle morphology, vesicle size, polydispersity index, zeta potential, entrapment efficiency (EE%), attenuated total reflectance-Fourier transform spectroscopy (ATR-FTIR) spectra, along with in vitro release, permeation profiles, and stability study were also evaluated. The results showed that both encapsulations displayed spherical morphology at the nanometric scale, their great physical stability and provided an EE% range of 58–78%. The MLT incorporation into the vesicle was confirmed by the ATR-FTIR spectra. Additionally, the encapsulation’ release profiles fitted with the Higuchi model, indicating controlled release of melatonin. Furthermore, MT showed greater permeability than MN and MS including melatonin deposition. In cell assays, MT exhibited significantly higher nitric oxide inhibition and stimulation of collagen compared to MN and MS. Therefore, MT demonstrated the highest possibility for anti-inflammatory and collagen-stimulating activities that could be applied in pharmaceutical or anti-aging cosmetic products.

Active Components of Leontopodium alpinum Callus Culture Extract for Blue Light Damage in Human Foreskin Fibroblasts.

Leontopodium alpinum is a source of raw material for food additives and skin health. The purpose of this study was to investigate the application of Leontopodium alpinum callus culture extract (LACCE) to prevent blue light damage to the skin. We screened and identified the blue light-damage-protecting activities and mechanisms of ten components of LACCE, including chlorogenic acid (A), isoquercitrin (B), isochlorogenic acid A (C), cynaroside (D), syringin (E), isochlorogenic acid (F), cynarin (G), rutin (H), leontopodic acid A (I), and leontopodic acid B (J), using a novel blue light-induced human foreskin fibroblast (HFF-1) cell injury model. The study examined the cytotoxicity of ten ingredients using the cell counting kit-8 (CCK-8) assay, and selecting concentrations of 5, 10, and 20 μM for experiments with a cell viability above 65%. We explored the effects and mechanisms of action of these LACCE components in response to blue light injury using Western blotting and an enzyme-linked immunosorbent assay. We also measured ROS secretion and Ca2+ influx. Our study revealed that leontopodic acid A effectively boosted COI-1 expression, hindered MMP-1 expression, curbed ROS and Ca2+ endocytosis, and reduced OPN3 expression. These results provide theoretical support for the development of new raw materials for the pharmaceutical and skincare industries.

Exosomes derived from human dermal fibroblasts protect against UVB‑induced skin photoaging.

Exosomes are used as innovative treatment options for repairing skin defects, such as aging, atopic dermatitis and wounds. However, the effects of exosomes obtained from human foreskin fibroblasts BJ‑5ta (BJ‑5ta Exo) on ultravioletB (UVB)‑mediated photoaging have not been previously reported, at least to the best of our knowledge. Therefore, the present study aimed to investigate the anti‑photoaging effects of BJ‑5ta Exo on UVB radiation in human skin fibroblasts and SKH‑1 hairless mice. The results revealed that BJ‑5ta Exo decreased the production of reactive oxygen species and inhibited the decrease in the expression levels of superoxide dismutase 1 and 2, glutathione peroxidase and catalase following UVB exposure. In addition, BJ‑5ta Exo attenuated the decrease in nuclear factor erythroid 2‑related factor 2 levels induced by UVB rays, indicating its scavenging activity against oxidative stress. Moreover, BJ‑5ta Exo inhibited the UVB‑induced increase in the levels of γH2AX, p53/21 and cleaved PARP, whereas it promoted DNA double‑strand break repair through radiation sensitive 52 and effectively activated the TGF‑β1/Smad pathway. BJ‑5ta Exo also protected against UVB‑induced senescence, as indicated by the downregulation in the levels of senescence‑associated β‑galactosidase and p16. In a mouse model of photoaging, BJ‑5ta Exo prevented the UVB‑induced increase in transepidermal water loss, wrinkle formation and MMP‑1 expression, while also suppressing the UVB‑mediated decrease in collagen typeI and elastin levels in the dorsal skin. Overall, the findings of the present study suggest that BJ‑5ta Exo represent an effective anti‑photoaging agent, which can be used as a component in cosmetic products.

The dissociation of (a+c) misfit dislocations at the InGaN/GaN interface.

In hexagonal materials, (a+c) dislocations are typically observed to dissociate into partial dislocations. Edge (a+c) dislocations are introduced into (0001) nitride semiconductor layers by the process of plastic relaxation. As there is an increasing interest in obtaining relaxed InGaN buffer layers for the deposition of high In content structures, the study of the dissociation mechanism of misfit (a+c) dislocations laying at the InGaN/GaN interface is then crucial for understanding their nucleation and glide mechanisms. In the case of the presented plastically relaxed InGaN layers deposited on GaN substrates, we observe a trigonal network of (a+c) dislocations extending at the interface with a rotation of 3° from <1 00> directions. High-resolution microscopy studies show that these dislocations are dissociated into two Frank-Shockley 1/6<2 03> partial dislocations with the I1 BSF spreading between them. Atomistic simulations of a dissociated edge (a+c) dislocation revealed a 3/5-atom ring structure for the cores of both partial dislocations. The observed separation between two partial dislocations must result from the climb of at least one of the dislocations during the dissociation process, possibly induced by the mismatch stress in the InGaN layer.

Extremophilic Solutions: The Role of Deinoxanthin in Counteracting UV-Induced Skin Harm.

This research delved into the protective capacities of deinoxanthin, a carotenoid present in Deinococcus radiodurans, against UVA- and UVB-mediated skin damage using human fibroblast foreskin cells (HFF-1). Using the MTT assay, HFF-1 cells treated with 10 µM DNX displayed 20% and 31.7% higher viability than the positive (Vitamin C-treated) and negative (DNX-untreated) control groups, respectively, upon 100 mJ/cm2 UVB exposure. At 24 J/cm2 UVA, 20 µM DNX-treated cells showed 80.6% viability, exceeding the positive and negative control groups by 28.6% and 33.6%, respectively. Flow cytometry analysis revealed that cells treated with DNX and exposed to 24 J/cm2 UVA exhibited a 69.32% reduction in apoptotic processes compared to untreated cells. Similarly, when exposed to 100 mJ/cm2 UVB, DNX-treated cells demonstrated a 72.35% decrease in apoptotic processes relative to their untreated counterparts. DNX also displayed dose-dependent inhibition on tyrosinase activity. The study emphasized DNX's antioxidative capacity, evident in its modulation of superoxide dismutase activity and measurements of Malondialdehyde and intracellular reactive oxygen species levels. DNX-treated cells exhibited higher hydroxyproline levels, suggesting healthier collagen production. Additionally, the wound-healing assay method confirmed an accelerated healing rate in DNX-treated cells. Conclusively, DNX offers significant protection against UV-induced skin damage, emphasizing its potential for skincare and therapeutics.

Mechanism of thermally-activated prismatic slip in Mg

Prismatic slip of the screw <a> dislocation in magnesium at temperatures ≳ 150 K is understood to be governed by double-cross-slip of the stable basal screw through the unstable prism screw and back to the basal screw, with the activation energy controlled by the formation energy of two basal-basal kinks. However, atomistic studies of the double-kink process predict activation energies roughly twice those derived experimentally. Here, a new mechanism of prism glide is proposed, analyzed theoretically, and demonstrated qualitatively and quantitatively via direct molecular dynamics (MD) simulations. The new mechanism is intrinsically 3d, and involves the nucleation of a single kink at the junction where a 3d prismatic dislocation loop transitions from the basal screw segment to non-screw prismatic character. The relevant kink energies are calculated using recently-developed Neural-Network Potentials (NNPs) for Mg that show good agreement versus DFT for basal and prism <a> dislocations, enabling a parameter-free analytic model for the activation barrier. Direct MD simulations show both operation of the precise proposed mechanism and a stress-dependent activation barrier that agrees reasonably with the analytic model. Predictions of dislocation velocity compare very well with in-situ TEM data, and macroscopic strength versus temperature can also be understood. Overall, the new intrinsically 3d mechanism for dislocation glide due to single kink nucleation rather than double-kink nucleation explains key features of the prismatic slip in Mg and may have broader applicability in other metals where kink nucleation processes control thermally-activated flow.

The effect of fitting the reference photon dose-response on the clonogenic survival predicted with the Mayo Clinic Florida microdosimetric kinetic model in case of accelerated ions.

The Mayo Clinic Florida microdosimetric kinetic model (MCF MKM) is a recently developed clonogenic survival model. Since the MCF MKM relies on novel strategies to a priori determine the cell-specific model parameters, the only experiment-specific input values are the α and ß terms of the linear-quadratic model (LQM) of clonogenic survival for the reference photon exposure. Because the two LQM terms are anti-correlated, the fitting process of the reference photon survival curve was found to significantly influence the MCF MKM calculations. This article reports this effect for two clinically relevant cell lines (human brain glioblastoma A-172, human healthy foreskin fibroblasts AG01522) and ions (1H and 12C ions).

Chitosan coated copper/silver oxide nanoparticles as carriers of breast anticancer drug: Cyclin D1/P53 expressions and cytotoxicity studies

Developing new treatment strategies for cancer is necessary and inevitable. The aim of this study is the synthesis of a novel nanocomposite (NC) based on chitosan coated copper/silver oxide nanoparticles ((CuO-Ag2O-NCs) ant evaluation of its effect on breast cancer and cyclin D1/P53 expression. A thermal process (500 °C) was used for synthesis of NCs. Characterization was done by powder X-ray Diffraction (XRD), Fourier transforms infrared spectroscopy (FTIR) and field emission electron microscopy (FESEM). The prepared CuO-Ag2O-NCs were also tested against breast cancer cells (MCF-7) and Human foreskin fibroblasts (HFF) cell lines. Also, the expression ofCylclin D1 andP53 genes was measured in MCF-7 cells under CuO-Ag2O-NCs treatment. The XRD showed both CuO and Ag2O phases without no purity or negligible contaminants. The FTIR spectrum also confirmed proper synthesis (peaks at 485, 531and 579 cm−1: CuO vibrations, 721 and 1440 cm−1: Ag2O). FESEM images demonstrated polymorphic particles in which rod-shaped particles were the distinguished ones. Anticancer test indicated significant inhibitory effect of nanoparticle on the growth of MCF-7 cells in a dose-dependent manner. The viability evaluation of MCF-7 cells demonstrated an IC50 value of 173.9, 30.11 and 5.462 µg/mL at 24, 48 and 72 h after treatment, respectively. Prepared NCs had lower toxicity on HFF cell lines in comparison with MCF-7 cells. The results showed that bothcyclin D1andP53expressions enhanced after 48 h of incubation. Results showed that the CuO-Ag2O-NCs induced apoptosis cancer cells compared to control cells. According to results, acquired nanostructures had potent anticancer activity via change in gene expression and apoptosis induction.

MEHP activates JNK to inhibit the migration of human foreskin fibroblasts

This study aimed to investigate the impact of mono(2-ethylhexyl) phthalate (MEHP) on the proliferation, apoptosis, and migration of human foreskin fibroblast cells (HFF-1) and the role of the JNK signaling pathway in cell migration. HFF-1 cells were randomly assigned to the control group with 0 MEHP exposure (M0) or the experimental groups with 25, 50, 100, 200, and 400 μmol/L MEHP exposure (M25, M50, M100, M200, and M400, respectively). After 24 and 48 h of MEHP exposure, the proliferation of HFF-1 cells in any group had no significant change. However, compared with the M0 group, the M200 and M400 groups presented substantially increased apoptosis of HFF-1 cells. Moreover, cell migration ability significantly decreased in all groups (p < 0.05). Additionally, the transcription and phosphorylated protein activation of JNK kinase in HFF-1 cells were substantially upregulated with the increase in MEHP exposure. Subsequently, HFF-1 cells were randomly divided into three groups: the DMSO blank control group, the 100 μM MEHP experimental group (M100), and the 100 μM MEHP plus 10 μM SP600125 (specific JNK inhibitor) experimental group (S10). The activation of JNK protein in HFF-1 cells was substantially downregulated in the S10 group. HFF-1 cells were also divided into the blank control group (M0). They were treated with 100 μM MEHP and varying concentrations of SP600125 (5, 10, and 15 μM for S5, S10, and S15, respectively). As the concentration of the antagonist increased, the migration ability of HFF-1 cells was returned to normal. Finally, the ROS in HFF-1 cells increased under MEHP exposure. This finding indicates that the regulation of cell migration by the JNK signaling pathway may be important in the occurrence of hypospadias.

Simulated microgravity attenuates skin wound healing by inhibiting dermal fibroblast migration via F-actin/YAP signaling pathway.

Skin and its cell components continuously subject to extrinsic and intrinsic mechanical forces and are mechanical sensitive. Disturbed mechanical homeostasis may lead to changes in skin functions. Gravity is the integral mechanical force on the earth, however, how gravity contributes to the maintenance of skin function and how microgravity in space affects the wound healing are poorly understood. Here, using microgravity analogs, we show that simulated microgravity (SMG) inhibits the healing of cutaneous wound and the accumulation of dermal fibroblasts in the wound bed. In vitro, SMG inhibits the migration of human foreskin fibroblast cells (HFF-1), and decreases the F-actin polymerization and YAP (yes-associated protein) activity. The SMG-inhibited migration can be recovered by activating YAP or F-actin polymerization using lysophosphatidic acid (LPA) or jasplakinolide (Jasp), suggesting the involvement of F-actin/YAP signaling pathway in this process. In SMG rats, LPA treatment improves the cutaneous healing with increased dermal fibroblasts in the wound bed. Together, our results demonstrate that SMG attenuates the cutaneous wound healing by inhibiting dermal fibroblast migration, and propose the crucial role of F-actin/YAP mechano-transduction in the maintenance of skin homeostasis under normal gravity, and YAP as a possible therapeutic target for the skin care of astronauts in space.

Vascular endothelial growth factor a modified mRNA engineered cellular electrospun membrane complexes promotes mouse skin wound repair.

Artificial skin substitutes are one of the most promising areas of wound healing research; however, graft survival largely depends on how the treatment is performed. Early angiogenesis is essential for wound healing and graft survival and vascular endothelial growth factor A (VEGFA) is an important cytokine that stimulates angiogenesis. Here, we first investigated the effects of different ratios of collagen (BC) and gelatin blended with poly (l-lactide-co-caprolactone) (PLCL) on nanofibrous membranes. The Young's modulus and cell proliferation were significantly higher in the 50% BC group than that in all other groups. Then, cellular electrospun membrane complexes (CEMC) were successfully constructed from nanoscaffolds and fibroblasts extracted from human foreskin and engineered with controlled autocrine VEGFA by transfecting VEGFA modified mRNA (modRNA). Engineered CEMC significantly promoted wound healing in vivo and contributed to stable vascular network formation in the grafted area, thereby increasing the survival rate of the engineered skin. This study provides a potential solution for wound healing while establishing the value of different RNA modification methods for various engineered skins in the future, thereby advancing engineered skin development.

Unripe Carica papaya Fresh Fruit Extract Protects against Methylglyoxal-Mediated Aging in Human Dermal Skin Fibroblasts.

The glycolytic metabolite methylglyoxal (MGO) initiates the formation of advanced glycation end products and oxidative stress, leading to cellular senescence and skin aging. This study focuses on the anti-aging properties of unripe Carica papaya L. (UCP) fresh fruit extract on MGO-induced human dermal fibroblast senescence. We pretreated human foreskin fibroblasts with UCP before incubating them with MGO (400 μM) for 72 h. We used the glycation inhibitor aminoguanidine hydrochloride (AG) as the positive control. Senescent fibroblasts were detected using senescence-associated beta-galactosidase activity and collagen type I expression (COL1A1). We investigated the changes in the Akt, JNK/p38 mitogen-activated protein kinase (MAPK), c-Jun, and nuclear factor kappa B (NF-κB) signaling pathways using Western blotting. UCP significantly suppressed MGO-induced senescent fibroblasts (from 20.90±2.00% to 11.78±2.04%) when compared with the baseline level at 7.10±0.90% (P<0.05). While COL1A1 was diminished by 43.35±1.56% (P<0.001) in the MGO-treated fibroblasts, UCP and AG could recover COL1A1 to 63.22±4.78% and 64.39±3.34%, respectively. MGO triggered overactivation of Akt, JNK/p38 MAPK, c-Jun, and NF-κB by 2.10±0.09, 8.10±0.37, 6.60±0.29, 2.18±0.23, and 3.74±0.37 folds, respectively. UCP and AG significantly abolished these changes. Consistently, MGO increased matrix metalloproteinase-1 (MMP-1) levels by 2.58±0.04 folds, which was significantly suppressed by UCP and AG pretreatment to 1.87±0.11 and 1.69±0.07 folds, respectively. In summary, UCP controlled MGO-induced fibroblast senescence by suppressing the JNK/c-Jun/MMP and p38/NF-κB/COL1A1 pathways, similar to the action of the glycation inhibitor AG. Therefore, UCP can be considered a functional fruit for preventing and delaying skin aging.

Anti-melanogenic effect of exosomes derived from human dermal fibroblasts (BJ-5ta-Ex) in C57BL/6 mice and B16F10 melanoma cells.

Exosomes are involved in intercellular communication by transferring cargo between cells and altering the specific functions of the target cells. Recent studies have demonstrated the therapeutic effects of exosomes in several skin diseases. However, understanding of the effects of exosomes on anti-pigmentation is limited. Therefore, we investigated whether BJ-5ta exosomes (BJ-5ta-Ex) derived from human foreskin fibroblasts regulate melanogenesis and delineated the underlying mechanism. Interestingly, treatment with BJ-5ta-Ex induced decreased melanin content, tyrosinase (TYR) activity, and expression of melanogenesis-related genes, including microphthalmia-related transcription factor (MITF), TYR, tyrosinase-related protein-1 (TRP1), and tyrosinase-related protein-2 (TRP2). In addition, BJ-5ta-Ex downregulated the cAMP/PKA and GSK-3β/β-catenin signaling pathways and upregulated the MAPK/ERK signaling pathway. Notably, treatment with BJ-5ta-Ex inhibited α-melanocyte-stimulating hormone-induced melanosome transport and decreased the expression of key proteins involved in melanosome transport, namely, rab27a and melanophilin (MLPH). To further confirm the depigmenting effects of BJ-5ta-Ex, we conducted experiments using a three-dimensional reconstituted human full skin model and ultraviolet B (UVB)-irradiated mouse model. Treatment with BJ-5ta-Ex improved tissue brightness and reduced the distribution of melanosomes. In UVB-irradiated mouse ears, BJ-5ta-Ex reduced the number of active melanocytes and melanin granules. These results demonstrate that BJ-5ta-Ex can be useful for the clinical treatment of hyperpigmentation disorders.

Phytohormones regulate asexual Toxoplasma gondii replication.

The protozoan Toxoplasma gondii (T. gondii) is a zoonotic disease agent causing systemic infection in warm-blooded intermediate hosts including humans. Duringthe acute infection, the parasite infects host cells and multiplies intracellularly in the asexual tachyzoite stage. In this stage of the life cycle, invasion, multiplication, and egress are themost critical events in parasite replication. T. gondii features diverse cell organelles to support these processes, including the apicoplast, an endosymbiont-derived vestigial plastid originating from an alga ancestor. Previous studies have highlighted that phytohormones can modify the calcium-mediated secretion, e.g., of adhesins involved in parasite movement and cell invasion processes. The present study aimed to elucidate the influence of different plant hormones on the replication of asexual tachyzoites in a human foreskin fibroblast (HFF) host cell culture. T. gondii replication was measured by the determination of T. gondii DNA copies via qPCR. Three selected phytohormones, namely abscisic acid (ABA), gibberellic acid (GIBB), and kinetin (KIN) as representatives of different plant hormone groups were tested. Moreover, the influence of typical cell culture media components on the phytohormone effects was assessed. Our results indicate that ABA is able to induce a significant increase of T. gondii DNA copies in atypical supplemented cell culture medium when applied in concentrations of 20 ng/μl or 2 ng/μl, respectively. In contrast, depending on the culture medium composition, GIBB may potentially serve as T. gondii growth inhibitor and may be further investigated as a potential treatment for toxoplasmosis.

Chemical analysis of endophytic fungi isolated from mangrove trees in Playa San Pedro Nature Reserve, Buenaventura, Valle del Cauca, Colombia

Endophytic fungi are well known for their association with a wide variety of plant species, likewise, mangrove plants are well known for harboring a vast variety of fungi with a valuable diversity of bioactive compounds originating from the secondary metabolism that is synthesized in part as a response to the chemical defense against microorganisms, hostile environments, and antagonistic insects. The objective of the present study was to analyze the chemical composition of endophytic fungi isolated from mangrove trees in Buenaventura, Colombia. Analyses of DNA sequences from the internal transcribed spacer ribosomal nuclear region (ITS) were conducted to determine the fungi’s identity. The results revealed 17 isolates, belonging to eight fungal families. All isolates were subjected to thin-layer chromatography analysis, observing different phytochemical nuclei eluted in the system (7: 3 hexane: acetone), of these, 23 compounds were recognized using gas chromatography coupled to mass spectrometry; cytotoxicity tests were carried out in human foreskin fibroblast cell line, which did not show a trend in cell viability. The selected endophytic fungi derived from mangrove trees reveal the presence of different chemical compounds, representing an alternative resource of great interest in bioprospecting and bioremediation.

Arginine Is a Novel Drug Target for Arginine Decarboxylase in Human Colorectal Cancer Cells.

Colorectal cancer (CRC) has been proven to be highly reliant on arginine availability. Limiting arginine-rich foods or treating patients with arginine-depleting enzymes arginine deiminase (ADI) or arginase can suppress colon cancer. However, arginase and ADI are not the best drug candidates for CRC. Ornithine, the product of arginase, can enhance the supply of polyamine, which favors CRC cell growth, while citrulline, the product of ADI, faces the problem of arginine recycling due to the overexpression of argininosuccinate synthetase (ASS). Biosynthetic arginine decarboxylase (ADC), an enzyme that catalyzes the conversion of arginine to agmatine and carbon dioxide, may be a better choice as it combines both arginine depletion and suppression of intracellular polyamine synthesis via its product agmatine. ADC has anti-tumor potential yet has received much less attention than the other two arginine-depleting enzymes. In order to gain a better understanding of ADC, the preparation and the anti-cancer properties of this enzyme were explored in this study. When tested in vitro, ADC inhibited the proliferation of three colorectal cancer cell lines regardless of their ASS cellular expression. In contrast, ADC had a lesser cytotoxic effect on the human foreskin fibroblasts and rat primary hepatocytes. Further in vitro studies revealed that ADC induced S and G2/M phase cell-cycle arrest and apoptosis in HCT116 and LoVo cells. ADC-induced apoptosis in HCT116 cells followed the mitochondrial apoptotic pathway and was caspase-3-dependent. With all results obtained, we suggest that arginine is a potential target for treating colorectal cancer with ADC, and the anti-cancer properties of ADC should be more deeply investigated in the future.

Polyurethane-based nanofibrous mat containing porphyrin with photosensitivity and bactericidal properties can promote cutaneous tissue healing in rats

The regeneration of cutaneous tissue is one of the most challenging issues in human regenerative medicine. To date, several studies have been done to promote cutaneous tissue healing with minimum side effects. The healing potential of polyurethane (PU)/Poly (caprolactone)–poly (ethylene glycol)–poly (caprolactone) (PCEC)/chitosan (CS) (PCS) nanofibrous mat with cationic photosensitizer meso tetrakis (N-methyl pyridinium-4-yl) porphyrin tetratosylate salt (TMP) was examined. The CS tripolyphosphate nanoparticles (CSNPs) were prepared and loaded by TMP to provide an efficient drug release system (TMPNPs) for delivery of TMP to promote wound healing. In in vitro setting, parameters such as bactericidal effects, cytocompatibility, and hemolytic effects were examined. The healing potential of prepared nanofibrous mats was investigated in a rat model of full-thickness cutaneous injury. PCS/TMP/TMPNPs nanofibers can efficiently release porphyrin in the aqueous phase. The addition of TMPNPs and CS to the PU backbone increased the hydrophilicity, degradation, and reduced mechanical properties. The culture of human fetal foreskin fibroblasts (HFFF2) on PCS/TMP/TMPNPs scaffold led to an increased survival rate and morphological adaptation analyzed by MTT and SEM images. Irradiation with a red laser (635 nm, 3 J/cm2) for the 30 s reduced viability of S. aureus and E. Coli bacteria plated on PCS/TMP and PCS/TMP/TMPNPs nanofibrous mats compared to PU/PCEC (PC) and PU/PCEC/CS (PCS) groups, indicating prominent antibacterial effects of PCS/TMP and PCS/TMP/TMPNPs nanofibrous (p < 0.05). Data indicated that PCS/TMP/TMPNPs mat enhanced healing of the full-thickness excisional wound in a rat model by the reduction of inflammatory response and fibrotic changes compared to the PC, and PCS groups (p < 0.05). Immunofluorescence imaging indicated that levels of Desmoglein were increased in rats that received PCS/TMP/TMPNPs compared to the other groups. It is found that a PU-based nanofibrous mat is an appropriate scaffold to accelerate the healing of injured skin.Graphical abstract