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[This corrects the article DOI: 10.3389/fphar.2023.1194578.].
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Diabetic vascular complication including diabetic retinopathy is a major morbidity in Saudia Arabia. The polyol pathway aka aldose reductase (AR) pathway has gained significant association with diabetic retinopathy with regard to chronically enhanced glucose metabolism. Considerable research has been put forth to develop more effective therapeutic strategies to overcome the overwhelming challenges of vascular complications associated with diabetes. In this regard, constituents of Cichorium intybus can offer strong AR inhibitory potential because of their strong antidiabetic properties. Therefore, aim of this study was to investigate the AR inhibitory as well as antiglycation potential of C. intybus extract/compounds. The preliminary in vitro results showed that methanolic extract of C. intybus could significantly inhibit AR enzyme and advanced glycation end product formation. Eventually, based on previous studies and reviews, we selected one hundred fifteen C. intybus root constituents and screened them through Lipinski's rule of five and ADMET analysis. Later, after molecular docking analysis of eight compounds, five best were selected for molecular dynamics simulation to deduce their binding affinity with the AR enzyme. Finally, three out of five compounds were further tested in vitro for their AR inhibitory potential and antiglycation properties. Enzyme assay and kinetic studies showed that all the three tested compounds were having potent AR inhibitory properties, although to a lesser extent than ellagic acid and tolrestat. Similarly, kaempferol showed strong antiglycation property equivalent to ellagic acid, but greater than aminoguanidine. Intriguingly, significant reduction in sorbitol accumulation in RBCs by the tested compounds substantiated strong AR inhibition by these compounds. Moreover, decrease in sorbitol accumulation under high glucose environment also signifies the potential application of these compounds in diabetic retinopathy and other vascular complications. Thus, in sum, the in silico and in vitro studies combinedly showed that C. intybus root is a treasure for therapeutic compounds and can be explored further for drug development against diabetic retinopathy.
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Prostate cancer incidences are rising worldwide at an alarming rate. Drug resistance and relapse are two major challenges in the treatment of prostate cancer. Therefore, new multimodal, safe, and effective therapeutic agents are urgently required which could effectively mitigate the menace of tumor recurrence and chemo-resistance. Plant-derived products are increasingly being utilized due to their antioxidant, antibacterial, and anti-tumor potential. In the current study, 3-acetyl-11-keto-ß-boswellic acid, a triterpenoid isolated from plant Boswellia, was utilized to ascertain its chemotherapeutic potential against human prostate cancer cells. Various in vitro assays including cell viability, nuclear staining, mitochondria potential, reactive oxygen species (ROS) generation, and quantification of apoptosis, were performed for the evaluation of the cytotoxic potential of AKBA. We observed that AKBA (10-50 µM) dose-dependently suppressed cell proliferation and caused programmed cell death in PC3 cells via both intrinsic and extrinsic pathway. Intriguingly, AKBA was also found to chemosensitize PC3 cells in synergistic combination with doxorubicin. To the best of our knowledge, this is the first study to document the synergistic chemosensitizing impact of AKBA when combined with doxorubicin in prostate cancer cells.This showcases the potential of AKBA in combinatorial therapy or adjuvant therapy for the management of prostate cancer. In sum, our results suggested that AKBA is a promising drug-like molecule against prostate cancer. Our investigation introduces a novel perspective, elucidating a previously unexplored dimension, and uncovering a compelling chemosensitizing phenomenon along with a strong synergistic effect arising from the concurrent application of these two agents.
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BACKGROUND: Oxidative stress refers to non-homeostatic elevation within intracellular reactive oxygen species (ROS) levels and is associated with several neuro-related pathological conditions. Diclofenac is a commonly prescribed non-steroidal anti-inflammatory drug (NSAID) for treating aches and pain by reducing inflammation. Diclofenac is also associated with the induction of apoptotic cell death by altering the homeostatic balance within mitochondria. In the present report, the neuroprotective effects of BNC formulation constituted by Bacopa monnieri leaves, Nigella sativa and Curcuma longa rhizome seeds were investigated. METHODS: The synthesized formulation was characterized using FT-IR and LC-MS along with organoleptic evaluation. Thereafter neuroprotective efficacy of BNC formulation was subsequently investigated against Diclofenac-induced oxidative stress in SH-SY5Y cells. The cells were pretreated with synthesized formulation and subsequently evaluated for amelioration in Diclofenac-induced cytotoxicity, and ROS augmentation. The neuroprotective effect of synthesized formulation was further explored by evaluating the changes in nuclear morphology, and apoptosis alleviation with concomitant regulatory effects on caspase-3 and -9 activation. RESULTS: Diclofenac was found to be considerably cytotoxic against human neuroblastoma SHSY5Y cells. Intriguingly, Diclofenac-mediated toxicity was reduced significantly in SH-SY5Y cells pretreated with BNC formulation. Augmented ROS levels within Diclofenac-treated SHSY5Y cells were also reduced in the BNC formulation pretreated SH-SY5Y cells. Furthermore, BNC formulation pretreated SH-SY5Y cells also exhibited reduced dissipation of mitochondrial membrane potential, caspase-3 and -9, along with apoptosis after Diclofenac treatment. CONCLUSION: These findings indicated that, indeed, Diclofenac induces considerable ROSmediated apoptosis in SH-SY5Y cells, which further intriguingly ameliorated Diclofenacmediated cytotoxic effects on SH-SY5Y cells. This manuscript further collected information about available National and International patents published or granted in preparation of and thereof applications against motor and non-motor brain dysfunctions.
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ETHNOPHARMACOLOGICAL USES: Black cohosh, also known as Cimicifuga sp., is one of the most widely used ethnomedicine for the treatment of major health issues in women. Some reports show that Cimicifuga sp. exhibit anti-cancer, anti-viral, anti-microbial, anti-pyretic, and anti-inflammatory properties. PURPOSE OF THIS REVIEW: The objective of this comprehensive review is to furnish current and exhaustive knowledge pertaining to the pharmacological, phytochemical, and therapeutic properties of Cimicifuga sp. MATERIALS AND METHODS: In this review, all the available information was collected on Cimicifugasp. via computerized search using Google Scholar, PubMed, Research Gate, Sci-Hub, supplementary resources (books, government reports, and Ph.D. theses). RESULT: The phytochemical investigation on Cimicifuga sp. has shown phytoconstituents such as triterpenoid glycosides, phenylpropanoid, flavonoids, saponin, lignan, nitrogenous compounds, alkaloids, 4α-Methyl steroids and some other component like monoterpene lactones cimicifugolides A-C etc. Cimicifuga conveys a wide scope of research on in-vitro and in-vivo pharmacological potential, like anti-cancer, anti-microbial, anti-viral, anti-inflammatory, estrogenic, anti-oxidant, anti-neoplastic, anti-depressant, anti-Alzheimer, and anti-climacteric properties. CONCLUSION: This article discusses the medicinal and traditional histories of various Cimicifuga species. Because quality control and safety assessments of Cimicifuga species are currently lacking, only a limited portion of the plant may be used as medication. The majority of current research focuses on triterpene glycosides. Although there are a variety of additional molecules that may have novel biological functions, systematic investigations of these compounds are lacking. The Cimicifuga plant has to go through a lot of studies before it can be completely used in clinics as a viable medicinal contender.
Subject(s)
Actaea , Cimicifuga , Female , Humans , Anti-Inflammatory Agents , Antiviral Agents , Ethnopharmacology , Glycosides , Molecular Structure , Phytochemicals/pharmacology , Phytochemicals/therapeutic use , Phytotherapy , Plant Extracts/pharmacology , Plant Extracts/therapeutic useABSTRACT
In the current study, we report the synthesis of methotrexate-conjugated zinc oxide nanoparticles (MTX-ZnONPs) and their high efficacy against lung cancer cells. Conjugation of MTX with ZnONPs was authenticated by UV-vis spectroscopy, dynamic light scattering (DLS), Fourier-transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). This drug-nanoconjugate also showed high drug-loading efficiency. The therapeutic efficacy of MTX-ZnONPs was further tested in vitro against A549 cells, and the results of MTT and LDH release assays showed that MTX-ZnONPs, in addition to free MTX, were efficient in exerting cytotoxic effect on A549 cells; however, the effectiveness of MTX-ZnONPs was found to be considerably enhanced at very low doses compared to that of free MTX. Moreover, ZnONPs alone significantly inhibited the cell viability of A549 cells at a much higher concentration compared to MTX-ZnONPs and MTX. Furthermore, the cytomorphology of A549 cells was characterized by cellular shrinkage and detachment from the surface in all the treatment groups. Similarly, A549 cells, in all the treatment groups, showed fragmented and condensed nuclei, indicating the initiation of apoptosis. Mitochondrial membrane potential (ψm) in A549 cells showed a gradual loss in all the treatment groups. Results of the qualitative and quantitative analyses depicted increased reactive oxygen species (ROS) levels in A549 cells. The results of the caspase activity assay showed that MTX-ZnONPs andfree MTX caused significant activation of caspase-9, -8, and -3 in A549 cells; however, the effect of MTX-ZnONPs was more profound at very low doses compared to that of free MTX. Thus, our results showed high efficacy of MTX-ZnONPs, suggesting efficient intracellular delivery of the drug by ZnONPs as nanocarriers.
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The Wnt signaling pathway is reported to be associated with lung cancer progression, metastasis and drug resistance, and thus it is an important therapeutic target for lung cancer. Plants have been shown as reservoirs of multiple potential anticancer agents. In the present investigation, the ethanolic leaf extract of Artemisia vulgaris (AvL-EtOH) was initially analyzed by means of gas chromatography-mass spectrometry (GC-MS) to identify the important phytochemical constituents. The GC-MS analysis of AvL-EtOH exhibited 48 peaks of various secondary metabolites such as terpenoids, flavonoids, carbohydrates, coumarins, amino acids, steroids, proteins, phytosterols, and diterpenes. It was found that the treatment with increasing doses of AvL-EtOH suppressed the proliferation and migration of lung cancer cells. Furthermore, AvL-EtOH induced prominent nuclear alteration along with a reduction in mitochondrial membrane potential and increased ROS (reactive oxygen species) generation in lung cancer cells. Moreover, AvL-EtOH-treated cells exhibited increased apoptosis, demonstrated by the activation of caspase cascade. AvL-EtOH also induced downregulation of Wnt3 and ß-catenin expression along with cell cycle protein cyclin D1. Thus, the results of our study elucidated the potential of bioactive components of Artemisia vulgaris in the therapeutic management of lung cancer cells.
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Background: Dates palm (Phoenix dactylifera L.) fruits are among the most widely used fruits in the Middle East and African nations. Numerous researchers confirmed the presence of phytochemicals in P. dactylifera L. fruit and its by-products with broad-ranging biological activities. Objectives: In the present work, phytochemical and biological assessments of two different cultivars of date fruit (Shishi M1 and Majdool M2 grown in the Ha'il region of Saudi Arabia) have been carried out. Methods: Date fruits were extracted and analyzed by gas chromatography-mass spectrometry (GS-MS),liquid chromatography-mass spectrometry (LC-MS) and Fourier-transform infrared spectroscopy (FT-IR)techniques. The lyophilized methanolic extracts were analyzed for their in-vitro antiproliferative andcytotoxicity against colon cancer (HCT116) cell line. To identify the possible constituents responsible for the bioactivity, in-silico molecular docking and molecular dynamics (MD) simulation studies were carried out. Results: Both cultivars exhibited in-vitro anticancer activity (IC50 = 591.3 µg/mL and 449.9 µg/mL for M1 and M2, respectively) against colon cancer HCT-116 cells. The computational analysis results indicated procyanidin B2 and luteolin-7-O-rutinoside as the active constituents. Conclusion: Based on these results, we conclude that these cultivars could be a valuable source for developing health promoter phytochemicals, leading to the development of the Ha'il region, Saudi Arabia.
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The successful chemotherapeutic regime required for the clinical management of different cancers largely depends on the efficient drug delivery within the cancer cells. Exosomes have emerged as an enticing candidate for exploring their role as delivery vehicles. Exosomes are reported to be intrinsically nanosized vesicles competent for efficient delivery across the cellular membrane. In the present study, we assessed the feasibility of an autologous exosome-based drug delivery platform for delivering 5-Fluorouracil (5-FU) against human colon cancer HCT116 cells. Autologous exosomes have shown probable tropism toward the tumor microenvironment, which makes them the most competitive vehicle for drug delivery. It was observed that the autologous exosomes loaded with 5-FU showed an enhanced rate of drug release under acidic conditions. The result of the cell viability assay showed that treatment of 5-FU-loaded exosomes (equivalent to 5 µg 5-FU) resulted in enhanced cytotoxic effect in HCT116 cells as compared to an equivalent amount of free 5-FU (5 µg), which elucidated the efficient delivery of the 5-FU by exosomes inside the cancer cells. Subsequently, 5-FU-loaded exosomes led to increased nuclear condensation and fragmentation along with increased ROS production. In addition, 5-FU-loaded exosomes caused enhanced dissipation of mitochondrial membrane potential and caspase-3 activation, resulting in increased apoptosis induction. Our study also revealed that 5-FU-loaded exosomes upsurged the arrest in the cell cycle at the G0/G1 stage in HCT-116 cells and it was found to be associated with decreased CDK4 and Cyclin D1 expression concomitantly with the upregulation of CDK inhibitor, p21Cip1 expression. Thus, the findings from the present study highlight the advantages of autologous exosomes as a natural drug carrier which could efficiently deliver chemotherapeutic drugs to cancer cells.
Subject(s)
Antineoplastic Agents , Colonic Neoplasms , Exosomes , Humans , Fluorouracil , Exosomes/metabolism , Exosomes/pathology , Apoptosis , Colonic Neoplasms/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
Protein tyrosine phosphatase-1B (PTP-1B) is a well-known therapeutic target for diabetes and obesity as it suppresses insulin and leptin signaling. PTP-1B deletion or pharmacological suppression boosted glucose homeostasis and insulin signaling without altering hepatic fat storage. Inhibitors of PTP-1B may be useful in the treatment of type 2 diabetes, and shikonin, a naturally occurring naphthoquinone dye pigment, is reported to inhibit PTP-1B and possess antidiabetic properties. Since the cell contains a large number of phosphatases, PTP-1B inhibitors must be effective and selective. To explore more about the mechanism underlying the inhibitor's efficacy and selectivity, we investigated its top four pharmacophores and used site-directed mutagenesis to insert amino acid mutations into PTP-1B as an extension of our previous study where we identified 4 pharmacophores of shikonin. The study aimed to examine the site-directed mutations like R24Y, S215E, and S216C influence the binding of shikonin pharmacophores, which act as selective inhibitors of PTP-1B. To achieve this purpose, docking and molecular dynamics simulations of wild-type (WT) and mutant PTP-1B with antidiabetic compounds were undertaken. The simulation results revealed that site-directed mutations can change the hydrogen bond and hydrophobic interactions between shikonin pharmacophores and many residues in PTP-1B's active site, influencing the drug's binding affinity. These findings could aid researchers in better understanding PTP-1B inhibitors' selective binding mechanism and pave the path for the creation of effective PTP-1B inhibitors.
Subject(s)
Diabetes Mellitus, Type 2 , Humans , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/genetics , Phosphoric Monoester Hydrolases/therapeutic use , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Protein Binding , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic useABSTRACT
Adenium obesum commonly known as "desert rose" belongs to the family Apopcynaceae and has previously been reported for its anti-influenza, antimicrobial, and cytotoxic efficacies and well-known for their ethno-medicinal applications. In the present study, ethanolic extracts of A. obesum (AOE) were analyzed by gas chromatography-mass spectrometry (GC-MS) to identify the important phytochemical compounds. The GC-MS analysis of AOE detected the presence of 26 phytochemical compounds. This plant is traditionally used for the treatment of various diseases. In this report, the antioxidant, anti-inflammatory, and anticancer activities of ethanolic leaf extract from A. obesum (AOE) were studied. The antioxidant potential of ethanolic extract of AOE was examined by different antioxidant assays, such as antioxidant capacity by the DPPH, ABTS, superoxide, hydroxyl radical scavenging, and lipid peroxidation inhibition assays. The antioxidant activities of various reaction mixtures of AOE were compared with a reference or standard antioxidant (ascorbic acid). In addition, we also evaluated the anticancer activity of AOE, and it was observed that AOE was found to be cytotoxic against A549 lung cancer cells. It was found that AOE inhibited the viability of A549 lung cancer cells by inducing nuclear condensation and fragmentation. Furthermore, ethanolic AOE demonstrated the anti-inflammatory potential of AOE in murine alveolar macrophages (J774A.1) as an in vitro model system. AOE showed its potential in reducing the levels of inflammatory mediators including the proinflammatory cytokines and TNF-α. The results obtained in the present investigation established the antioxidant, anticancer, and anti-inflammatory potency of AOE, which may account for subsequent studies in the formulation of herbal-based medicine.
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Liver cancer or hepatocellular carcinoma (HCC) has become a leading cause for cancer burden across the globe, and incidences have tripled since the last two decades. Poor diagnosis of primary liver cancer and limited treatment strategies aggravate the challenges. Researchers globally have shown a steep inclination toward the exploration of plant-based compounds for their nutraceutical and anticancer potential to fit into the role of novel chemotherapeutics. Coleus aromaticus is a well-known culinary herb that earlier has been reported for several medicinal attributes. The current investigation deals with exploring the anticancer potential of ethanolic leaf extract of C. aromaticus (CoL-EtOH) against hepatocellular carcinoma HepG2 cell line. The observations made it evident that CoL-EtOH extract impeded the viability of HepG2 at 400 µg/ml (p < .01). Additionally, the extract also succeeded in escalating ROS production (p < .01) which aided dissipation of mitochondrial membrane potential and disruption of nuclear morphology. CoL-EtOH further activated caspase-8, -9, and -3 which was reaffirmed by increase in apoptosis at 400 µg/ml (p < .01). Moreover, post treatment with CaLEt-OH extract significantly reduced the expression of JAK-1 & STAT-3 genes (p < .01) along with regulated expression of Mcl1, Bcl-2, cyclinD1, p21, and p27 within HepG2 cells. This evidence portrays the promising anticancer potential of CoL-EtOH projecting it as a novel chemotherapeutic agent against HCC. PRACTICAL APPLICATIONS: The herb Coleus aromaticus belonging to Lamiaceae family and Coleus genus is known by various names in different regions of the world and several language-specific vernacular names. The herb has been used in therapeutic and medicinal applications as well as in culinary preparations. Various attributes of the nutritional strength and functional characteristics of the leaves in terms of carotenoids, minerals, phenols, dietary fiber, and antioxidant activity have been reported by several researchers. Carvacrol and thymol are majorly found in the plant, while chlorogenic acid and rosmarinic acid etc. as the phenolic components. The herb has been used in therapeutic and medicinal implications as well as in culinary preparations.
Subject(s)
Carcinoma, Hepatocellular , Coleus , Liver Neoplasms , Antioxidants , Apoptosis , Carcinoma, Hepatocellular/drug therapy , Carotenoids , Caspase 8 , Cell Proliferation , Chlorogenic Acid , Dietary Fiber , Ethanol , Hep G2 Cells , Humans , Janus Kinases/metabolism , Liver Neoplasms/drug therapy , Myeloid Cell Leukemia Sequence 1 Protein , Phenols , Plant Extracts/pharmacology , Reactive Oxygen Species , STAT Transcription Factors/metabolism , ThymolABSTRACT
Cervical cancer (CCa) is the second most frequent carcinoma in females and human papilloma virus (HPV) oncoproteins are regarded as one of the critical etiological agent. Despite recent advances in screening and management of CCa, still it remains the deadliest carcinoma as advanced and metastatic stages are mostly incurable. This urges for the development of newer therapeutic interventions. The current was aimed to investigate the antiproliferative and apoptotic potential of glycyrrhizin (Gly) against HPV16+ CaSki CCa cells. Our findings substantiated that Gly exerted antiproliferative effects on the CaSki cells by obstructing their proliferation rate. Gly substantially enhanced apoptosis in Caski cells in a dose-dependent manner via augmenting the generation of ROS, DNA fragmentation and disruption of the mitochondrial membrane potential. Gly mediated apoptosis in CaSki cells was found to be due to activation of caspase-8 and capsase-9 along with the modulation of pro-and anti-apoptotic gene expression. Moreover, Gly halts the progression of CaSki cells at G0/G1 phase which was found to be due to reduced expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4) along with the enhanced expression of CDK inhibitor p21Cip1. Further, Gly downregulates the expression of HPV oncoproteins (E6 & E7) along with the inhibition of Notch signaling pathway. Taken together, Gly represents as a potential therapeutic modality for CCa which could rapidly be translated for clinical studies.
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Diabetes is a complicated multifactorial disorder in which the patient generally observes polyphagia, polydipsia, and polyuria due to uncontrolled growth in blood sugar levels. For its management, the pharmaceutical industry is working day and night to find a better drug with no or least toxicity. That's why nowadays a more focused branch is to use herbal phytoconstituents for its prevention. Shikonin is a naphthoquinone natural dye that is isolated from the plants of the Boraginaceae family and has proven its role as an anti-cancer, anti-inflammatory, and anti-gonadotrophic agent. In our previous study, we have published its anti-diabetic action by inhibiting the enzyme protein tyrosine phosphatase 1B. In this study, we were more focused on finding out the role of Shikonin and its pharmacophores by inhibiting the action of aldose reductase (AR) enzyme. The study was conducted using pharmacophore modeling, molecular docking, and molecular dynamics simulation studies. The absorption, distribution, metabolism, excretion (ADME), and toxicity profile were also evaluated in this study. Along with all the computational biology parameters we also focused on the in vitro activity and kinetic study of inhibitory activity of Shikonin against aldose reductase.
Subject(s)
Diabetes Mellitus , Naphthoquinones , Aldehyde Reductase/metabolism , Diabetes Mellitus/drug therapy , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Molecular Docking Simulation , Naphthoquinones/pharmacology , Naphthoquinones/therapeutic useABSTRACT
In recent times, nanotechnology has made significant advances in the field of cancer. The majority of chemotherapeutic drugs do not selectively target cancer cells, and they might cause side effects and damage to healthy cells, resulting in a variety of adverse effects. Having a thorough understanding of nanoparticles may improve drug targeting and administration. The nano-engineering of pharmacological and natural compounds can improve the diagnosis and treatment. Polymeric micelles, liposomes, and dendrimers are examples of innovative cancer therapeutic nano-formulations. It has been demonstrated that quantum dots, nano-suspensions, and gold nanoparticles can improve drug delivery. Nanomedicines may be delivered more effectively, focusing on cancerous cells instead of healthy tissues, which minimizes undesirable side effects and drug resistance to chemotherapeutic agents. However, limited water solubility, low stability, poor absorption, and quick metabolism limit their therapeutic effectiveness. Nanotechnology has generated unique formulations to optimise the potential use of phytochemicals in anticancer therapy. Nanocomposites can improve phytochemical solubility and bioavailability, extend their half-life in circulation, and even transport phytochemicals to specific locations. The progress in using phytochemical-based nanoparticles in cancer treatment is summarized in this paper.
Subject(s)
Antineoplastic Agents , Metal Nanoparticles , Nanoparticles , Neoplasms , Humans , Gold/therapeutic use , Neoplasms/drug therapy , Drug Delivery Systems , Nanotechnology/methods , Phytochemicals/therapeutic useABSTRACT
This study reports the therapeutic effectiveness of doxorubicin-conjugated zinc oxide nanoparticles against lung cancer cell line. The zinc oxide nanoparticles (ZnONPs) were first synthesised using a fungus, isolated from air with an extraordinary capability to survive in very high concentrations of zinc salt. Molecular analysis based on 18S rRNA gene sequencing led to its identification as Aspergillus niger with the NCBI accession no. OL636020. The fungus was found to produce ZnONPs via the reduction of zinc ions from zinc sulphate. The ZnONPs were characterised by various biophysical techniques. ZnONPs were further bioconjugated with the anti-cancer drug doxorubicin (DOX), which was further confirmed by different physical techniques. Furthermore, we examined the cytotoxic efficacy of Doxorubicin-bioconjugated-ZnONPs (DOX-ZnONPs) against lung cancer A549 cells in comparison to ZnONPs and DOX alone. The cytotoxicity caused due to ZnONPs, DOX and DOX-ZnONPs in lung cancer A549 cells was assessed by MTT assay. DOX-ZnONPs strongly inhibited the proliferation of A549 with IC50 value of 0.34 µg/mL, which is lower than IC50 of DOX alone (0.56 µg/mL). Moreover, DOX-ZnONPs treated cells also showed increased nuclear condensation, enhanced ROS generation in cytosol and reduced mitochondrial membrane potential. To investigate the induction of apoptosis, caspase-3 activity was measured in all the treated groups. Conclusively, results of our study have established that DOX-ZnONPs have strong therapeutic efficacy to inhibit the growth of lung cancer cells in comparison to DOX alone. Our study also offers substantial evidence for the biogenically synthesised zinc oxide nanoparticle as a promising candidate for a drug delivery system.
Subject(s)
Antineoplastic Agents , Lung Neoplasms , Nanoparticles , Zinc Oxide , A549 Cells , Antineoplastic Agents/pharmacology , Aspergillus niger , Doxorubicin/pharmacology , Humans , Lung Neoplasms/drug therapy , Zinc , Zinc Oxide/pharmacology , Zinc Oxide/therapeutic useABSTRACT
Recent times have seen a strong surge in therapeutically targeting the hedgehog (HH)/GLI signaling pathway in cervical cancer. HH signaling pathway is reported to be a crucial modulator of carcinogenesis in cervical cancer and is also associated with recurrence and development of chemoresistance. Moreover, our previous reports have established that carvacrol (CAR) inhibited the proliferation of prostate cancer cells via inhibiting the Notch signaling pathway and thus, it was rational to explore its antiproliferative effects in cervical cancer cell lines. Herein, the present study aimed to investigate the anticancer and apoptotic potential of CAR on C33A cervical cancer cells and further explore the underlying mechanisms. We found that CAR significantly suppressed the growth of C33A cells, induced cell cycle arrest, and enhanced programmed cell death along with augmentation in the level of ROS, dissipated mitochondrial membrane potential, activation of caspase cascade, and eventually inhibited the HH signaling cascade. In addition, CAR treatment increased the expression of pro-apoptotic proteins (Bax, Bad, Fas-L, TRAIL, FADDR, cytochrome c) and concomitantly reduced the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL) in C33A cells. CAR mediates the activation of caspase-9 and -3 (intrinsic pathway) and caspase-8 (extrinsic pathway) accompanied by the cleavage of PARP in cervical cancer cells. Thus, CAR induced apoptosis by both the intrinsic and extrinsic apoptotic pathways. CAR efficiently inhibited the growth of cervical cancer cells via arresting the cell cycle at G0/G1 phase and modulated the gene expression of related proteins (p21, p27, cyclin D1 and CDK4). Moreover, CAR inhibited the HH/GLI signaling pathway by down regulating the expression of SMO, PTCH and GLI1 proteins in cervical carcinoma cells. With evidence of the above results, our data revealed that CAR treatment suppressed the growth of HPV-C33A cervical cancer cells and further elucidated the mechanistic insights into the functioning of CAR.
ABSTRACT
Growing emphasis on exploring the antiproliferative potential of natural compounds has gathered momentum for the formulation of anticancer drugs. In the present study, the anticancer and apoptotic potential of glycyrrhizin (GLY) was studied on HPV- C33A cervical cancer (CCa) cells. Our results indicated that GLY exerted antiproliferative effects in the C33A cells by inducing significant cytotoxicity. Treatment with GLY substantially increases the apoptosis in a dose-dependent manner via disrupting the mitochondrial membrane potential. GLY induced apoptosis in C33A cells via activation of capsase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway) along with the modulation of pro- and antiapoptotic protein expression. Moreover, GLY also exerted cell cycle arrest in C33A cells at G0/G1 phase which was associated with the decreased expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4) along with the increased expression of CDK inhibitor p21Cip1. Furthermore, GLY treated CCa cells exhibited significant downregulation of Notch signaling pathway which may be associated with increased apoptosis as well as cell cycle arrest in C33A CCa cells. Thus, GLY could be an appendage in the prevention and management of CCa.
Subject(s)
Uterine Cervical Neoplasms , Apoptosis , Cell Cycle , Cell Cycle Checkpoints , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/genetics , Down-Regulation , Female , Glycyrrhizic Acid/pharmacology , Glycyrrhizic Acid/therapeutic use , Humans , Uterine Cervical Neoplasms/drug therapyABSTRACT
Lung carcinoma is the leading cause of cancer-related mortalities worldwide, and present therapeutical interventions are not successful enough to treat this disease in many cases. Recent years have witnessed a surge in exploring natural compounds for their antiproliferative efficacy to expedite the characterization of novel anticancer chemotherapeutics. Swertia chirayita is a valued medicinal herb and possess intrinsic pharmaceutical potential. However, elucidation of its anticancer effects at molecular levels remains unclear and needs to be investigated. We assessed the anticancer and apoptotic efficacy of S. chirayita ethanolic extract (Sw-EtOH) on non-small cell lung cancer (NSCLC) A549 cells during this exploratory study. The results elucidated that S. chirayita extract induced toxic effects within lung cancer cells by ~1 fold during cytotoxicity and LDH release assay at a 400 µg/ml concentration. Sw-EtOH extract elevates the level of ROS, resulting in the disruption of Δψm and release of cytosolic cytochrome c by 3.15 fold. Activation of caspases-3, -8 & -9 also escalated by ~1 fold, which further catalyze the augmentation of PARP cleavage (~3 folds), resulting in a four-fold increase in Sw-EtOH induced apoptosis. The gene expression analysis further demonstrated that Sw-EtOH extracts inhibited JAK1/STAT3 signaling pathway by down-regulating the levels of JAK1 and STAT3 to nearly half a fold. Treatment of Sw-EtOH modulates the expression level of various STAT3 associated proteins, including Bcl-XL, Bcl-2, Mcl-1, Bax, p53, Fas, Fas-L, cyclinD1, c-myc, IL-6, p21 and p27 in NSCLC cells. Thus, our study provided a strong impetus that Sw-EtOH holds the translational potential of being further evaluated as efficient cancer therapeutics and a preventive agent for the management of NSCLC.
ABSTRACT
Diabetes mellitus is a multifactorial disease that affects both developing and developed countries and is a major public health concern. Many synthetic drugs are available in the market, which counteracts the associated pathologies. However, due to the propensity of side effects, there is an unmet need for the investigation of safe and effective drugs. This research aims to find a novel phytoconstituent having diminished action on blood glucose levels with the least side effects. Shikonin is a naturally occurring naphthoquinone dying pigment obtained by the roots of the Boraginaceae family. Besides its use as pigments, it can be used as an antimicrobial, anti-inflammatory, and anti-tumor agent. This research aimed to hypothesize the physicochemical and phytochemical properties of Shikonin's in silico interaction with protein tyrosine phosphate 1B, as well as it's in vitro studies, in order to determine its potential anti-diabetic impact. To do so, molecular docking experiments with target proteins were conducted to assess their anti-diabetic ability. Analyzing associations with corresponding amino acids revealed the significant molecular interactions between Shikonin and diabetes-related target proteins. In silico pharmacokinetics and toxicity profile of Shikonin using ADMET Descriptor, Toxicity Prediction, and Calculate Molecular Properties tools from Biovia Discovery Studio v4.5. Filter by Lipinski and Veber Rule's module from Biovia Discovery Studio v4.5 was applied to assess the drug-likeness of Shikonin. The in vitro studies exposed that Shikonin shows an inhibitory potential against the PTP1B with an IC50 value of 15.51 µM. The kinetics studies revealed that it has a competitive inhibitory effect (Ki = 7.5 M) on the enzyme system, which could be useful in the production of preventive and therapeutic agents. The findings of this research suggested that the Shikonin could be used as an anti-diabetic agent and can be used as a novel source for drug delivery.