In an in vitro culture system, primary hepatocytes usually display a low proliferation capacity, accompanied with a decrease of viability and a loss of hepatocyte-specific functions. Previous studies have demonstrated that the combination introductions of certain hepatocyte-specific transcription factors are able to convert fibroblasts into functional hepatocyte-like cells. However, such combinational usage of transcription factors in primary hepatocytes culture has not yet sufficiently studied. The forkhead box protein A3 (FoxA3) and hepatocyte nuclear factor 4α (Hnf4α) are liver-enriched transcription factors that play vital roles in the differentiation, and maintenance of hepatocytes. Thus, we simultaneously overexpressed the two genes, Foxa3 and Hnf4α, in rat hepatocytes and observed that the combinational augmentation of these two transcription factors have enhanced the proliferation and stabilized the hepatocyte-specific functions of primary hepatocytes over a long-term culture period.
Antiepileptic drugs are versatile drugs with the potential to be used in functional drug formulations with drug repurposing approaches. In the present review, we investigated the anticancer properties of antiepileptic drugs and interlinked cancer and epileptic pathways. Our focus was primarily on those drugs that have entered clinical trials with positive results and those that provided good results in preclinical studies. Many contributing factors make cancer therapy fail, like drug resistance, tumor heterogeneity, and cost; exploring all alternatives for efficient treatment is important. It is crucial to find new drug targets to find out new antitumor molecules from the already clinically validated and approved drugs utilizing drug repurposing methods. The advancements in genomics, proteomics, and other computational approaches speed up drug repurposing. This review summarizes the potential of antiepileptic drugs in different cancers and tumor progression in the brain. Valproic acid, oxcarbazepine, lacosamide, lamotrigine, and levetiracetam are the drugs that showed potential beneficial outcomes against different cancers. Antiepileptic drugs might be a good option for adjuvant cancer therapy, but there is a need to investigate further their efficacy in cancer therapy clinical trials.
Lung cancer remains a formidable global health burden, necessitating a comprehensive understanding of the underlying molecular mechanisms driving its progression. Recently, lncRNAs have become necessary controllers of various biological functions, including cancer development. MALAT1 has garnered significant attention due to its multifaceted role in lung cancer progression. Lung cancer, among other malignancies, upregulates MALAT1. Its overexpression has been associated with aggressive tumor behavior and poor patient prognosis. MALAT1 promotes cellular proliferation, epithelial-mesenchymal transition (EMT), and angiogenesis in lung cancer, collectively facilitating tumor growth and metastasis. Additionally, MALAT1 enhances cancer cell invasion by interacting with numerous signaling pathways. Furthermore, MALAT1 has been implicated in mediating drug resistance in lung cancer, contributing to the limited efficacy of conventional therapies. Recent advancements in molecular biology and high-throughput sequencing technologies have offered fresh perspectives into the regulatory networks of MALAT1 in lung cancer. It exerts its oncogenic effects by acting as a ceRNA to sponge microRNAs, thereby relieving their inhibitory effects on target genes. Moreover, MALAT1 also influences chromatin remodeling and post-translational modifications to modulate gene expression, further expanding its regulatory capabilities. This review sheds light on the multifaceted roles of MALAT1 in lung cancer progression, underscoring its potential as an innovative therapeutic target and diagnostic biomarker. Targeting MALAT1 alone or combined with existing therapies holds promise to mitigate lung cancer progression and improve patient outcomes.
Colorectal Neoplasia Differentially Expressed (CRNDE), a long non-coding RNA that was initially identified as aberrantly expressed in colorectal cancer (CRC) has also been observed to exhibit elevated expression in various other human malignancies. Recent research has accumulated substantial evidence implicating CRNDE as an oncogenic player, exerting influence over critical cellular processes linked to cancer progression. Particularly, its regulatory interactions with microRNAs and proteins have been shown to modulate pathways that contribute to carcinogenesis and tumorigenesis. This review will comprehensively outline the roles of CRNDE in colorectal, liver, glioma, lung, cervical, gastric and prostate cancer, elucidating the mechanisms involved in modulating proliferation, apoptosis, migration, invasion, angiogenesis, and radio/chemoresistance. Furthermore, the review highlights CRNDE's potential as a multifaceted biomarker, owing to its presence in diverse biological samples and stable properties, thereby underscoring its diagnostic, therapeutic, and prognostic applications. This review aims to provide comprehensive insights of CRNDE-mediated oncogenesis and identify CRNDE as a promising target for future clinical interventions.
Andrographolide is a labdane diterpenoid isolated from Andrographis paniculata. The plant extract and andrographolide has long been used in traditional medicine practices mainly for gastrointestinal diseases and improving liver function. Andrographolide has shown various pharmacological properties including anti-inflammatory, antioxidant and anticancer activity. This study evaluated the effect of andrographolide on proliferation of human gastric carcinoma cells in relevance to p53 and Mdm-2 pathways. Andrographolide inhibited the proliferation of SGC7901 and AGS cells in a dose-dependent manner with estimated IC50 values 38 and 44 μM respectively. Effect of andrographolide on p53 activity was ascertained by using a p53 activator (RITA) which showed synergistic inhibition of cell proliferation. While andrographolide when used in combination with a p53 inhibitor (pifithrin-α) showed potent restriction over its response. Andrographolide caused decrease in mitochondrial membrane potential as an indicator of apoptotic activity. Andrographolide activated the expression of p53 protein and gene and downregulated the levels of Mdm-2 (negative regulator of p53). Andrographolide inhibited the colony formation abilities in SGC7901 in a p53-dependent manner followed by induction of mitochondrial intrinsic apoptosis through activation of caspases-9 and -3, cleavage of PARP, and inhibition of pro-apoptotic Bcl-2. Andrographolide induced p53 mediated apoptosis in gastric carcinoma cells which adds to a novel approach in anticancer therapies.
Triple-negative breast cancer (TNBC) stands out as the most formidable variant of breast cancer, predominantly affecting younger women and characterized by a bleak outlook and a high likelihood of spreading. The absence of safe and effective targeted treatments leaves standard cytotoxic chemotherapy as the primary option. The role of protein kinases, frequently altered in many cancers, is significant in the advancement and drug resistance of TNBC, making them a logical target for creating new, potent therapies against TNBC. Recently, an array of promising small molecules aimed at various kinases have been developed specifically for TNBC, with combination studies showing a synergistic improvement in combatting this condition. This review underscores the effectiveness of small molecule kinase inhibitors in battling the most lethal form of breast cancer and sheds light on prospective pathways for crafting novel treatments.
The emergence of the Internet of Things and the proliferation of mobile wireless devices has brought the area of mobile cognitive radio sensor networks (MCRSN) to the research spot light. Notwithstanding the potentials of CRSNs in terms of opportunistic channel usage for bursty traffic, the effect of the mobility of resource-constrained nodes to route stability, mobility-induced spatio-temporal spectral opportunities and primary user (PU) protection still remain open issues that need to be jointly addressed. To this effect, this paper proposes a mobile reliable geographical forwarding routing (MROR) protocol. MROR provides a robust mobile framework for geographical forwarding that is based on a mobility-induced channel availability model. It presents a comprehensive routing strategy that considers PU activity (to take care of routes that have to be built through PU coverage), PU signal protection (by the introduction of a mobility-induced guard (mguard) distance) and the random mobility-induced spatio-temporal spectrum opportunities (for enhancement of throughput). It also addresses the issue of frequent route maintenance that arises when speeds of the mobile nodes are considered as a routing metric. As a result, simulation has shown the ability of MROR to reduce the route failure rate by about 65% as against other schemes. In addition, further results show that MROR can improve both the throughput and goodput at the sink in an energy-efficient manner that is required in CRSNs as against compared works.
The proliferation of home sharing in the extant marketing and tourism literature has only been accelerated in recent times due to the emergence of the sharing economy. This paper contends that it is now an opportune time to pursue a stock take of existing knowledge in order to guide future marketing and tourism research on home sharing. Therefore, the goal of this paper is to review and propose an agenda for home sharing from a marketing and tourism perspective. Through a framework-based systematic review, this paper offers an organized, retrospective view of the antecedents, decisions, and outcomes (ADO) of home sharing in marketing and tourism. The paper also provides a snapshot on the theories, contexts, and methods (TCM) employed to gain this understanding before concluding with a discussion on the extant knowledge gaps and the ways in which these gaps could be addressed through pertinent ideas for future marketing and tourism research on home sharing.
The proliferation of smart devices in the Internet of Things (IoT) networks creates significant security challenges for the communications between such devices. Blockchain is a decentralized and distributed technology that can potentially tackle the security problems within the 5G-enabled IoT networks. This paper proposes a Multi layer Blockchain Security model to protect IoT networks while simplifying the implementation. The concept of clustering is utilized in order to facilitate the multi-layer architecture. The K-unknown clusters are defined within the IoT network by applying techniques that utillize a hybrid Evolutionary Computation Algorithm while using Simulated Annealing and Genetic Algorithms. The chosen cluster heads are responsible for local authentication and authorization. Local private blockchain implementation facilitates communications between the cluster heads and relevant base stations. Such a blockchain enhances credibility assurance and security while also providing a network authentication mechanism. The open-source Hyperledger Fabric Blockchain platform is deployed for the proposed model development. Base stations adopt a global blockchain approach to communicate with each other securely. The simulation results demonstrate that the proposed clustering algorithm performs well when compared to the earlier reported approaches. The proposed lightweight blockchain model is also shown to be better suited to balance network latency and throughput as compared to a traditional global blockchain.
The distinctive regenerative ability of local marine worm (polychaete),Diopatra claparediiGrube, 1878, has the potential as a cellular growth agent. In this study, the growth effect was investigatedin normal cellsand cancer cells. Different concentrations (0-100
Adaptive metabolic responses toward a low oxygen environment are essential to maintain rapid proliferation and are relevant for tumorigenesis. Reprogramming of core metabolism in tumors confers a selective growth advantage such as the ability to evade apoptosis and/or enhance cell proliferation and promotes tumor growth and progression. One of the mechanisms that contributes to tumor growth is the impairment of cancer cell metabolism. In this review, we outline the small-molecule inhibitors identified over the past decade in targeting cancer cell metabolism and the usage of some of these molecules in clinical trials.
MicroRNAs (miRNAs) are the small noncoding RNA molecules which regulate target gene expression posttranscriptionally. They are known to regulate key cellular processes like inflammation, cell differentiation, cell proliferation, and cell apoptosis across various ocular diseases. Due to their easier access, recent focus has been laid on the investigation of miRNA expression and their involvement in several conjunctival diseases. The aim of this narrative review is to provide understanding of the miRNAs and describe the current role of miRNAs as the mediators of the various conjunctival diseases. A literature search was made using PubMed, Scopus, and Web of Science databases for studies involving miRNAs in the conjunctival pathological conditions. Original articles in the last 10 years involving both human and animal models were included. Literature search retrieved 27 studies matching our criteria. Pertaining to the numerous literatures, there is a strong correlation between miRNA and the various pathological conditions that occur in the conjunctiva. miRNAs are involved in various physiological processes such as cell differentiation, proliferation, apoptosis, development, and inflammation by regulating various signaling pathways, genes, proteins, and mediators. Pterygium was the most studied conjunctival disease for miRNA involvement, whereas miRNA research in allergic conjunctivitis is still in its early stages. Our review provides deep insights into the various miRNAs playing an important role in the various conjunctival diseases. miRNAs do have the potential to serve as noninvasive biomarkers with diagnostic, prognostic, and therapeutic implications. However, multitudinous studies are required to validate miRNAs as the reliable biomarkers in conjunctival pathologies and its targeted therapy.
Apert syndrome is a genetic disorder characterised by craniosynostosis and structural discrepancy of the craniofacial region as well as the hands and feet. This condition is closely linked with fibroblast growth factor receptor-2 (FGFR2) gene mutations. Gene therapies are progressively being tested in advanced clinical trials, leading to a rise of its potential clinical indications. In recent years, research has made great progress in the gene therapy of craniosynostosis syndromes and several studies have investigated its influences in preventing/diminishing the complications of Apert syndrome. This article reviewed and exhibited different techniques of gene therapy and their influences in Apert syndrome progression. A systematic search was executed using electronic bibliographic databases including PubMed, EMBASE, ScienceDirect, SciFinder and Web of Science for all studies of gene therapy for Apert syndrome. The primary outcomes measurements vary from protein to gene expressions. According to the findings of included studies, we conclude that the gene therapy using FGF in Apert syndrome was critical in the regulation of suture fusion and patency, occurred via alterations in cellular proliferation. The superior outcome could be brought by biological therapies targeting the FGF/FGFR signalling. More studies in molecular genetics in Apert syndrome are recommended. This study reviews the current literature and provides insights to future possibilities of genetic therapy as intervention in Apert syndrome.
Autophagy is an evolutionarily conserved process that plays a role in regulating homeostasis under physiological conditions. However, dysregulation of autophagy is observed in the development of human diseases, especially cancer. Autophagy has reciprocal functions in cancer and may be responsible for either survival or death. Hepatocellular carcinoma (HCC) is one of the most lethal and common malignancies of the liver, and smoking, infection, and alcohol consumption can lead to its development. Genetic mutations and alterations in molecular processes can exacerbate the progression of HCC. The function of autophagy in HCC is controversial and may be both tumor suppressive and tumor promoting. Activation of autophagy may affect apoptosis in HCC and is a regulator of proliferation and glucose metabolism. Induction of autophagy may promote tumor metastasis via induction of EMT. In addition, autophagy is a regulator of stem cell formation in HCC, and pro-survival autophagy leads to cancer cell resistance to chemotherapy and radiotherapy. Targeting autophagy impairs growth and metastasis in HCC and improves tumor cell response to therapy. Of note, a large number of signaling pathways such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs regulate autophagy in HCC. Moreover, regulation of autophagy (induction or inhibition) by antitumor agents could be suggested for effective treatment of HCC. In this paper, we comprehensively review the role and mechanisms of autophagy in HCC and discuss the potential benefit of targeting this process in the treatment of the cancer. Video Abstract.
Airway remodelling occurs in chronic respiratory diseases (CRDs) such as asthma and chronic obstructive pulmonary disease (COPD). It is characterized by aberrant activation of epithelial reparation, excessive extracellular matrix (ECM) deposition, epithelial-to-mesenchymal transition (EMT), and airway obstruction. The master regulator is Transforming Growth Factor-β (TGF-β), which activates tissue repair, release of growth factors, EMT, increased cell proliferation, and reduced nitric oxide (NO) secretion. Due to its fundamental role in remodelling, TGF-β is an emerging target in the treatment of CRDs. Berberine is a benzylisoquinoline alkaloid with antioxidant, anti-inflammatory, and anti-fibrotic activities whose clinical application is hampered by poor permeability. To overcome these limitations, in this study, berberine was encapsulated in monoolein-based liquid crystalline nanoparticles (BM-LCNs). The potential of BM-LCNs in inhibiting TGF-β-induced remodelling features in human bronchial epithelial cells (BEAS-2B) was tested. BM-LCNs significantly inhibited TGF-β-induced migration, reducing the levels of proteins upregulated by TGF-β including endoglin, thrombospondin-1, basic fibroblast growth factor, vascular-endothelial growth factor, and myeloperoxidase, and increasing the levels of cystatin C, a protein whose expression was downregulated by TGF-β. Furthermore, BM-LCNs restored baseline NO levels downregulated by TGF-β. The results prove the in vitro therapeutic efficacy of BM-LCNs in counteracting TGF-β-induced remodelling features. This study supports the suitability of berberine-loaded drug delivery systems to counteract airway remodelling, with potential application as a treatment strategy against CRDs.
α-Hederin is a natural bioactive molecule very abundant in aromatic and medicinal plants (AMP). It was identified, characterized, and isolated using different extraction and characterization technologies, such as HPLC, LC-MS and NMR. Biological tests have revealed that this natural molecule possesses different biological properties, particularly anticancer activity. Indeed, this activity has been investigated against several cancers (e.g., esophageal, hepatic, breast, colon, colorectal, lung, ovarian, and gastric). The underlying mechanisms are varied and include induction of apoptosis and cell cycle arrest, reduction of ATP generation, as well as inhibition of autophagy, cell proliferation, invasion, and metastasis. In fact, these anticancer mechanisms are considered the most targeted for new chemotherapeutic agents' development. In the light of all these data, α-hederin could be a very interesting candidate as an anticancer drug for chemotherapy, as well as it could be used in combination with other molecules already validated or possibly investigated as an agent sensitizing tumor cells to chemotherapeutic treatments.
Lung cancer is the second most prevalent type of cancer and is responsible for the highest number of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) makes up the majority of lung cancer cases. Zerumbone (ZER) is natural compound commonly found in the roots of Zingiber zerumbet which has recently demonstrated anti-cancer activity in both in vitro and in vivo studies. Despite their medical benefits, ZER has low aqueous solubility, poor GI absorption and oral bioavailability that hinders its effectiveness. Liquid crystalline nanoparticles (LCNs) are novel drug delivery carrier that have tuneable characteristics to enhance and ease the delivery of bioactive compounds. This study aimed to formulate ZER-loaded LCNs and investigate their effectiveness against NSCLC in vitro using A549 lung cancer cells. ZER-LCNs, prepared in the study, inhibited the proliferation and migration of A549 cells. These inhibitory effects were superior to the effects of ZER alone at a concentration 10 times lower than that of free ZER, demonstrating a potent anti-cancer activity of ZER-LCNs. The underlying mechanisms of the anti-cancer effects by ZER-LCNs were associated with the transcriptional regulation of tumor suppressor genes P53 and PTEN, and metastasis-associated gene KRT18. The protein array data showed downregulation of several proliferation associated proteins such as AXL, HER1, PGRN, and BIRC5 and metastasis-associated proteins such as DKK1, CAPG, CTSS, CTSB, CTSD, and PLAU. This study provides evidence of potential for increasing the potency and effectiveness of ZER with LCN formulation and developing ZER-LCNs as a treatment strategy for mitigation and treatment of NSCLC.
Curcumin has demonstrated potential cytotoxicity across various cell lines despite its poor bioavailability and rapid metabolism. Therefore, our group have synthesized curcuminoid analogues with piperidone derivatives, FLDP-5 and FLDP-8 to overcome these limitations. In this study, the analogues were assessed on LN-18 human glioblastoma cells in comparison to curcumin. Results from cytotoxicity assessment showed that FLDP-5 and FLDP-8 curcuminoid analogues caused death in LN-18 cells in a concentration-dependent manner after 24-h treatment with much lower IC50 values of 2.5 µM and 4 µM respectively, which were more potent compared to curcumin with IC50 of 31 µM. Moreover, a significant increase (p cell death process induced by these analogues. These analogues also showed potent anti-migratory effects through inhibition of LN-18 cells' migration and invasion. In addition, cell cycle analysis showed that these analogues are capable of inducing significant (p cell cycle arrest during the 24-h treatment as compared to untreated, which explained the reduced proliferation indicated by MTT assay. In conclusion, these curcuminoid analogues exhibit potent anti-cancer effects with anti-proliferative and anti-migratory properties towards LN-18 cells as compared to curcumin.
Platelet rich concentrate (PRC) is a natural adjuvant that aids in human mesenchymal stromal cell (hMSC) proliferation in vitro; however, its role requires further exploration. This study was conducted to determine the optimal concentration of PRC required for achieving the maximal proliferation, and the need for activating the platelets to achieve this effect, and if PRC could independently induce early differentiation of hMSC. The gene expression of markers for osteocytes (ALP, RUNX2), chondrocytes (SOX9, COL2A1), and adipocytes (PPAR-γ) was determined at each time point in hMSC treated with 15% activated and nonactivated PRC since maximal proliferative effect was achieved at this concentration. The isolated PRC had approximately fourfold higher platelet count than whole blood. There was no significant difference in hMSC proliferation between the activated and nonactivated PRC. Only RUNX2 and SOX9 genes were upregulated throughout the 8 days. However, protein expression study showed formation of oil globules from day 4, significant increase in ALP at days 6 and 8 (P ≤ 0.05), and increased glycosaminoglycan levels at all time points (P < 0.05), suggesting the early differentiation of hMSC into osteogenic and adipogenic lineages. This study demonstrates that the use of PRC increased hMSC proliferation and induced early differentiation of hMSC into multiple mesenchymal lineages, without preactivation or addition of differentiation medium.
It has been previously demonstrated that mechanical stimuli are important for multipotent human bone marrow-derived mesenchymal stromal cells (hMSCs) to maintain good tissue homeostasis and even to enhance tissue repair processes. In tendons, this is achieved by promoting the cellular proliferation and tenogenic expression/differentiation. The present study was conducted to determine the optimal loading conditions needed to achieve the best proliferation rates and tenogenic differentiation potential. The effects of mechanical uniaxial stretching using different rates and strains were performed on hMSCs cultured in vitro. hMSCs were subjected to cyclical uniaxial stretching of 4, 8 or 12 % strain at 0.5 or 1 Hz for 6, 24, 48 or 72 h. Cell proliferation was analyzed using alamarBlue[Formula: see text] assay, while hMSCs differentiation was analyzed using total collagen assay and specific tenogenic gene expression markers (type I collagen, type III collagen, decorin, tenascin-C, scleraxis and tenomodulin). Our results demonstrate that the highest cell proliferation is observed when 4 % strain [Formula: see text] 1 Hz was applied. However, at 8 % strain [Formula: see text] 1 Hz loading, collagen production and the tenogenic gene expression were highest. Increasing strain or rates thereafter did not demonstrate any significant increase in both cell proliferation and tenogenic differentiation. In conclusion, our results suggest that 4 % [Formula: see text] 1 Hz cyclic uniaxial loading increases cell proliferation, but higher strains are required for superior tenogenic expressions. This study suggests that selected loading regimes will stimulate tenogenesis of hMSCs.