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Rapid treatment of full-thickness skin loss using ovine tendon collagen type I scaffold with skin cells

Mh Busra F, Rajab NF, Tabata Y, Saim AB, B H Idrus R, Chowdhury SR

J Tissue Eng Regen Med, 2019 05;13(5):874-891.
PMID: 30811090 DOI: 10.1002/term.2842

The full-thickness skin wound is a common skin complication affecting millions of people worldwide. Delayed treatment of this condition causes the loss of skin function and integrity that could lead to the development of chronic wounds or even death. This study was aimed to develop a rapid wound treatment modality using ovine tendon collagen type I (OTC-I) bio-scaffold with or without noncultured skin cells. Genipin (GNP) and carbodiimide (EDC) were used to cross-link OTC-I scaffold to improve the mechanical strength of the bio-scaffold. The physicochemical, biomechanical, biodegradation, biocompatibility, and immunogenicity properties of OTC-I scaffolds were investigated. The efficacy of this treatment approach was evaluated in an in vivo skin wound model. The results demonstrated that GNP cross-linked OTC-I scaffold (OTC-I_GNP) had better physicochemical and mechanical properties compared with EDC cross-linked OTC-I scaffold (OTC-I_EDC) and noncross-link OTC-I scaffold (OTC-I_NC). OTC-I_GNP and OTC-I_NC demonstrated no toxic effect on cells as it promoted higher cell attachment and proliferation of both primary human epidermal keratinocytes and human dermal fibroblasts compared with OTC-I_EDC. Both OTC-I_GNP and OTC-I_NC exhibited spontaneous formation of bilayer structure in vitro. Immunogenic evaluation of OTC-I scaffolds, in vitro and in vivo, revealed no sign of immune response. Finally, implantation of OTC-I_NC and OTC-I_GNP scaffolds with noncultured skin cells demonstrated enhanced healing with superior skin maturity and microstructure features, resembling native skin in contrast to other treatment (without noncultured skin cells) and control group. The findings of this study, therefore, suggested that both OTC-I scaffolds with noncultured skin cells could be promising for the rapid treatment of full-thickness skin wound.

Matched MeSH terms: Heterografts
Three-Dimensional Radiological Assessment of Alveolar Bone Volume Preservation Using Bovine Bone Xenograft

Al Qabbani A, Al Kawas S, A Razak NH, Al Bayatti SW, Enezei HH, Samsudin AR, et al.

J Craniofac Surg, 2018 Mar;29(2):e203-e209.
PMID: 29303859 DOI: 10.1097/SCS.0000000000004263

INTRODUCTION: Alveolar bone is critical in supporting natural teeth, dental implants as well as a removable and fixed prosthesis. Alveolar bone volume diminishes when its associated natural tooth is lost.
OBJECTIVE: The aim of this study is to evaluate the effectiveness of bovine bone granules on alveolar bone socket augmentation for ridge preservation following atraumatic tooth extraction.
MATERIALS AND METHODS: Twenty medically fit patients (12 males and 8 females aged between 18 and 40 years) who needed noncomplicated tooth extraction of 1 mandibular premolar tooth were divided randomly and equally into 2 groups. In control group I, the empty extraction socket was left untreated and allowed to heal in a conventional way. In group II, the empty extraction socket wound was filled with lyophilized bovine bone xenograft granules 0.25 to 1 mm of size, 1 mL/vial. A resorbable pericardium membrane was placed to cover the defect. Clinical and 3-dimensional radiological assessments were performed at day 0, 3 months, and 9 months postoperative.
RESULTS: There were no clinical differences in general wound healing between the groups. Comparisons within the groups showed a significant difference of bone resorption of 1.49 mm (95% confidence interval, 0.63-2.35) at 3 months, and further resorption of 1.84 mm (P ≤ 0.05) at 9 months in the control group. No significant changes of bone resorption were observed in group II during the same time interval. Comparison between groups showed a significant difference of bone resorption at 3 and 9 months (2.40 and 2.88 mm, respectively).
CONCLUSION: The use of lyophilized demineralized bovine bone granules in socket preservation to fill in the extraction socket seems essential in preserving the alveolar bone dimension as it showed excellent soft and hard tissue healing. This study concludes that the alveolar bone socket exhibited a dynamic process of resorption from the first day of tooth extraction. Evidence shows the possibility of using bovine bone granules routinely in socket volume preservation techniques following tooth extraction.

Matched MeSH terms: Heterografts
Fulltext Anti-tumour activity and toxicological studies of combination treatment of Orthosiphon stamineus and gemcitabine on pancreatic xenograft model

Yehya AHS, Subramaniam AV, Asif M, Kaur G, Abdul Majid AMS, Oon CE

World J Gastroenterol, 2022 Aug 28;28(32):4620-4634.
PMID: 36157930 DOI: 10.3748/wjg.v28.i32.4620

BACKGROUND: Pancreatic cancer is the most aggressive cancer type. Gemcitabine is the first line chemo-drug used for pancreatic cancer but exerts a broad spectrum of organ toxicities and adverse effects in patients.
AIM: To evaluate the anti-tumour activity and toxicological effects of Orthosiphon stamineus extract formulation (ID: C5EOSEW5050ESA trademarked as Nuva-staticTM), and gemcitabine combination on pancreatic xenograft model.
METHODS: Mice were randomly divided into six groups of 6 mice each (n = 6) and given different treatments for 28 d. The study design consisted of a 2 x 3 factorial treatment structure, with gemcitabine (yes/no) by oral (at 1200 and 400 mg/kg per day). Human pancreatic cancer cells were injected subcutaneously into the flanks of athymic nude mice. C5EOSEW5050ESA (200 or 400 mg/kg per day) was administered orally, while gemcitabine (10 mg/kg per 3 d) was given intraperitoneally either alone or in combination treatment. Histopathological analyses of vital organs, tumour tissues, and incidence of lethality were analysed. Analyses of tumour necrosis and proliferation were determined by haematoxylin-eosin staining and immunohistochemistry for Ki-67, respectively.
RESULTS: No signs of toxicity or damage to vital organs were observed in all treatment groups compared to the untreated group. C5EOSEW5050ESA at 200 mg/kg and gemcitabine combination had no additive antitumor effects compared to a single treatment. Remarkably, a comparably greater response in a reduction in tumour growth, Ki-67 protein expression, and necrosis was demonstrated by 400 mg/kg of C5EOSEW5050ESA and gemcitabine combination than that of the individual agents.
CONCLUSION: These results highlighted the synergistic activity of C5EOSEW5050ESA with gemcitabine to reduce pancreatic tumour growth in mice compared to a single treatment. Thus, this study provides valuable insights into using C5EOSEW5050ESA as a complementary treatment with gemcitabine for pancreatic cancer.

Matched MeSH terms: Heterografts
Mechanisms of the In Vivo Antitumor Activity of Polyalthia longifolia Leaf Extract Against HeLa Cell Xenograft Tumor: A Microscopic-Based Histological and Immunohistochemical Microanalyses

Cilwyn-Shalitha B, Sasidharan S

Microsc Microanal, 2023 Jun 09;29(3):1153-1167.
PMID: 37749670 DOI: 10.1093/micmic/ozad023

The present study investigated the effects of Polyalthia longifolia leaf extract against the growth of HeLa cell xenograft tumor in nude mice and its underlying mechanism. The nude mice xenografted with HeLa cells were treated with 5% DMSO (vehicle control), 20 mg/kg/body weight of etoposide (positive control), and 500 and 1000 mg/kg/body weight of leaf extract, respectively. Antitumor activity was evaluated with apoptosis, proliferation, and angiogenesis using microscopic-based histological and immunohistochemical microanalyses. The tumor tissue histological and immunohistochemical analyses showed that the HeLa tumor cell death was associated with apoptosis and decreased (p < 0.05) expression of Ki-67 in tumor tissues. The extract also inhibits tumor angiogenesis by downregulating (p < 0.05) the expression of VEGF and CD31 in tumor tissues after treatment for 35 days. Conclusively, the P. longifolia leaf extract effectively inhibited HeLa cell xenograft growth in nude mice. The possible mechanism was related to induction of apoptosis, inhibition of tumor HeLa cell proliferation by decreasing the Ki-67 protein expression, and prevention of tumor angiogenesis by reducing VEGF and CD31 protein expression in HeLa cells.

Matched MeSH terms: Heterografts
Fulltext Toxicological studies of Orthosiphon stamineus (Misai Kucing) standardized ethanol extract in combination with gemcitabine in athymic nude mice model

Yehya AHS, Asif M, Kaur G, Hassan LEA, Al-Suede FSR, Abdul Majid AMS, et al.

J Adv Res, 2019 Jan;15:59-68.
PMID: 30581613 DOI: 10.1016/j.jare.2018.05.006

Pancreatic cancer has the highest mortality rate among cancers due to its aggressive biology and lack of effective treatment. Gemcitabine, the first line anticancer drug has reduced efficacy due to acquired resistance. The current study evaluates the toxicological effects of Orthosiphon stamineus (O.s) and its marker compound (rosmarinic acid) in combination with gemcitabine. O.s (200 or 400 mg/kg/day) and rosmarinic acid (32 mg/kg/day) were administered orally and gemcitabine (10 mg/kg/3 days) intraperitoneally either alone or in combination treatment for fourteen days. Parameters including blood serum biochemistry, hematology, myeloid-erythroid ratio, incident of lethality, and histopathological analysis of liver, kidney, and spleen tissues were studied. Neither, individual drugs/extract nor chemo-herbal combinations at tested doses induced any toxicity and damage to organs in nude mice when compared to control group. Toxicological data obtained from this study will help to select the best doses of chemo-herbal combination for future pancreatic xenograft tumor studies.

Matched MeSH terms: Heterografts
Epidermal Regeneration of Cultured Autograft, Allograft, and Xenograft Keratinocytes Transplanted on Full-Thickness Wounds in Rabbits

Hanifi N, Halim AS, Aleas CF, Singh J, Marzuki M, Win TT, et al.

Exp Clin Transplant, 2015 Jun;13(3):273-8.
PMID: 26086837

Skin grafting has been evolving as an important application in reconstructive surgery. Mixed reports about the survival of allogeneic and xenogeneic keratinocytes require further substantiation to determine the role of these cells in wound healing.

Matched MeSH terms: Heterografts
miR-608 regulates apoptosis in human lung adenocarcinoma via regulation of AKT2

Othman N, Nagoor NH

Int J Oncol, 2017 Dec;51(6):1757-1764.
PMID: 29075783 DOI: 10.3892/ijo.2017.4174

Lung cancer remains a major health problem with a low 5-year survival rate of patients. Recent studies have shown that dysregulation of microRNAs (miRNAs) are prevalent in lung cancer and these aberrations play a significant role in the progression of tumour progression. In the present study, bioinformatics analyses was employed to predict potential miR-608 targets, which are associated with signaling pathways involved in cancer. Luciferase reporter assay identified AKT2 as a novel target of miR-608, and suppression of its protein levels was validated through western blot analysis. Zebrafish embryos were microinjected with cells transfected with miR-608 to elucidate the role of miR-608 in vivo, and immunostained with antibodies to detect activated caspase-3. We present the first evidence that miR-608 behaves as a tumour suppressor in A549 and SK-LU-1 cells through the regulation of AKT2, suggesting that selective targeting of AKT2 via miR-608 may be developed as a potential therapeutic strategy for miRNA-based non-small cell lung cancer (NSCLC) therapy.

Matched MeSH terms: Heterografts
Fulltext Alpinia zerumbet (Pers.): Food and Medicinal Plant with Potential In Vitro and In Vivo Anti-Cancer Activities

Zahra MH, Salem TAR, El-Aarag B, Yosri N, El-Ghlban S, Zaki K, et al.

Molecules, 2019 Jul 08;24(13).
PMID: 31288458 DOI: 10.3390/molecules24132495

BACKGROUND/AIM: Plants play an important role in anti-cancer drug discovery, therefore, the current study aimed to evaluate the biological activity of Alpinia zerumbet (A. zerumbet) flowers.
METHODS: The phytochemical and biological criteria of A. zerumbet were in vitro investigated as well as in mouse xenograft model.
RESULTS: A. zerumbet extracts, specially CH2Cl2 and MeOH extracts, exhibited the highest potent anti-tumor activity against Ehrlich ascites carcinoma (EAC) cells. The most active CH2Cl2 extract was subjected to bioassay-guided fractionation leading to isolatation of the naturally occurring 5,6-dehydrokawain (DK) which was characterized by IR, MS, 1H-NMR and 13C-NMR. A. zerumbet extracts, specially MeOH and CH2Cl2 extracts, exhibited significant inhibitory activity towards tumor volume (TV). Furthermore, A. zerumbet extracts declined the high level of malonaldehyde (MDA) as well as elevated the levels of superoxide dismutase (SOD) and catalase (CAT) in liver tissue homogenate. Moreover, DK showed anti-proliferative action on different human cancer cell lines. The recorded IC50 values against breast carcinoma (MCF-7), liver carcinoma (Hep-G2) and larynx carcinoma cells (HEP-2) were 3.08, 6.8, and 8.7 µg/mL, respectively.
CONCLUSION: Taken together, these findings open the door for further investigations in order to explore the potential medicinal properties of A. zerumbet.

Matched MeSH terms: Heterografts
Fulltext Human non-small cell lung cancer expresses putative cancer stem cell markers and exhibits the transcriptomic profile of multipotent cells

Zakaria N, Yusoff NM, Zakaria Z, Lim MN, Baharuddin PJ, Fakiruddin KS, et al.

BMC Cancer, 2015;15:84.
PMID: 25881239 DOI: 10.1186/s12885-015-1086-3

Despite significant advances in staging and therapies, lung cancer remains a major cause of cancer-related lethality due to its high incidence and recurrence. Clearly, a novel approach is required to develop new therapies to treat this devastating disease. Recent evidence indicates that tumours contain a small population of cells known as cancer stem cells (CSCs) that are responsible for tumour maintenance, spreading and resistant to chemotherapy. The genetic composition of CSCs so far is not fully understood, but manipulation of the specific genes that maintain their integrity would be beneficial for developing strategies to combat cancer. Therefore, the goal of this study isto identify the transcriptomic composition and biological functions of CSCs from non-small cell lung cancer (NSCLC).

Matched MeSH terms: Heterografts
Fulltext Oncogenic S1P signalling in EBV-associated nasopharyngeal carcinoma activates AKT and promotes cell migration through S1P receptor 3

Lee HM, Lo KW, Wei W, Tsao SW, Chung GTY, Ibrahim MH, et al.

J Pathol, 2017 05;242(1):62-72.
PMID: 28240350 DOI: 10.1002/path.4879

Undifferentiated nasopharyngeal carcinoma (NPC) is a cancer with high metastatic potential that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the functional contribution of sphingosine-1-phosphate (S1P) signalling to the pathogenesis of NPC. We show that EBV infection or ectopic expression of the EBV-encoded latent genes (EBNA1, LMP1, and LMP2A) can up-regulate sphingosine kinase 1 (SPHK1), the key enzyme that produces S1P, in NPC cell lines. Exogenous addition of S1P promotes the migration of NPC cells through the activation of AKT; shRNA knockdown of SPHK1 resulted in a reduction in the levels of activated AKT and inhibition of cell migration. We also show that S1P receptor 3 (S1PR3) mRNA is overexpressed in EBV-positive NPC patient-derived xenografts and a subset of primary NPC tissues, and that knockdown of S1PR3 suppressed the activation of AKT and the S1P-induced migration of NPC cells. Taken together, our data point to a central role for EBV in mediating the oncogenic effects of S1P in NPC and identify S1P signalling as a potential therapeutic target in this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Matched MeSH terms: Heterografts
Knockdown of c-MET induced apoptosis in ABCB1-overexpressed multidrug-resistance cancer cell lines

Hung TH, Li YH, Tseng CP, Lan YW, Hsu SC, Chen YH, et al.

Cancer Gene Ther, 2015 May;22(5):262-70.
PMID: 25908454 DOI: 10.1038/cgt.2015.15

Inappropriate c-MET signaling in cancer can enhance tumor cell proliferation, survival, motility, and invasion. Inhibition of c-MET signaling induces apoptosis in a variety of cancers. It has also been recognized as a novel anticancer therapy approach. Furthermore, reports have also indicated that constitutive expression of P-glycoprotein (ABCB1) is involved in the HGF/c-MET-related pathway of multidrug resistance ABCB1-positive human hepatocellular carcinoma cell lines. We previously reported that elevated expression levels of PKCδ and AP-1 downstream genes, and HGF receptor (c-MET) and ABCB1, in the drug-resistant MES-SA/Dx5 cells. Moreover, leukemia cell lines overexpressing ABCB1 have also been shown to be more resistant to the tyrosine kinase inhibitor imatinib mesylate. These findings suggest that chemoresistant cancer cells may also develop a similar mechanism against chemotherapy agents. To circumvent clinical complications arising from drug resistance during cancer therapy, the present study was designed to investigate apoptosis induction in ABCB1-overexpressed cancer cells using c-MET-targeted RNA interference technology in vitro and in vivo. The results showed that cell viability decreased and apoptosis rate increased in c-MET shRNA-transfected HGF/c-MET pathway-positive MES-SA/Dx5 and MCF-7/ADR2 cell lines in a dose-dependent manner. In vivo reduction of tumor volume in mice harboring c-MET shRNA-knockdown MES-SA/Dx5 cells was clearly demonstrated. Our study demonstrated that downregulation of c-MET by shRNA-induced apoptosis in a multidrug resistance cell line.

Matched MeSH terms: Heterografts
Fulltext EBV-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma

Lung RW, Hau PM, Yu KH, Yip KY, Tong JH, Chak WP, et al.

J Pathol, 2018 Apr;244(4):394-407.
PMID: 29230817 DOI: 10.1002/path.5018

Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein-Barr virus (EBV) infection. In NPC, miR-BARTs, the EBV-encoded miRNAs derived from BamH1-A rightward transcripts, are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV-encoded miRNAs in a panel of NPC patient-derived xenografts and an EBV-positive NPC cell line by small RNA sequencing. Among the 40 miR-BARTs, predominant expression of 22 miRNAs was consistently detected in these tumors. Among the abundantly expressed EBV-miRNAs, BART5-5p, BART7-3p, BART9-3p, and BART14-3p could negatively regulate the expression of a key DNA double-strand break (DSB) repair gene, ataxia telangiectasia mutated (ATM), by binding to multiple sites on its 3'-UTR. Notably, the expression of these four miR-BARTs represented more than 10% of all EBV-encoded miRNAs in tumor cells, while downregulation of ATM expression was commonly detected in all of our tested sequenced samples. In addition, downregulation of ATM was also observed in primary NPC tissues in both qRT-PCR (16 NP and 45 NPC cases) and immunohistochemical staining (35 NP and 46 NPC cases) analysis. Modulation of ATM expression by BART5-5p, BART7-3p, BART9-3p, and BART14-3p was demonstrated in the transient transfection assays. These findings suggest that EBV uses miRNA machinery as a key mechanism to control the ATM signaling pathway in NPC cells. By suppressing these endogenous miR-BARTs in EBV-positive NPC cells, we further demonstrated the novel function of miR-BARTs in inhibiting Zta-induced lytic reactivation. These findings imply that the four viral miRNAs work co-operatively to modulate ATM activity in response to DNA damage and to maintain viral latency, contributing to the tumorigenesis of NPC. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Matched MeSH terms: Heterografts

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