Corrigendum: Sesquiterpene lactones attenuate paclitaxel resistance via inhibiting MALAT1/STAT3/ FUT4 axis and P-Glycoprotein transporters in lung cancer cells.

[This corrects the article DOI: 10.3389/fphar.2022.795613.].

Evaluating the biological (antidiabetic) potential of TEM, FTIR, XRD, and UV-spectra observed berberis lyceum conjugated silver nanoparticles.

Diabetes is a life-threatening disease that affects different parts of the body including the liver, kidney, and pancreas. The core root of diabetes is mainly linked to oxidative stress produced by reactive oxygen species (ROS). Berberis lyceum Royle (BLR) is the source of natural products. It comprises numerous bioactive compounds having antioxidant activities. In the current investigation, silver nanoparticles from BLR root extract were synthesized, characterized, and assessed for antidiabetic potential. UV spectrophotometry, Transmission electron microscopy (TEM), Fourier transform infra-red spectroscopy (FTIR), and x-ray diffraction (XRD) were applied for the characterization of NPs. It was evident from the morphological studies that the synthesized NPs were spherical and the average size was 11.02 nm. Results revealed that BLR-AgNPs showed higher radical scavenging activity as compared to BLR extract. Moreover, BLR-AgNPs displayed superior in vivo and in vitro antidiabetic activity in comparison to BLR extract. Glucose level (116.5 ± 5.1 mg/dL), liver function test (ALAT: 54.038 ± 6.2 IU/L; ASAT: 104.42 ± 13.9 IU/L; ALP: 192.6 ± 2.4 IU/L; bilirubin: 1.434 ± 0.14 mg/dL; total protein: 5.14 ± 0.24 mg/dL), renal function test (urea: 39.6 ± 0.63 mg/dL; uric acid: 21.4 ± 0.94 mg/dL; creatinine: 0.798 ± 0.03 mg/dL; albumin: 4.14 ± 0.2 mg/dL), lipid profile level (cholesterol: 101.62 ± 3 mg/dL; triglyceride: 110.42 ± 7 mg/dL; HDL-C: 29.7 ± 3 mg/dL; LDL-C: 47.056 ± 1 mg/dL; VLDL-C: 22.0 ± 1.3 mg/dL) and hematology (WBCs: 3.82 ± 0.24 103 /µL; RBCs: 4.78 ± 0.42 106 /µL; Hb: 12.6 ± 1.0 g/dL; Hematocrit: 39.4 ± 3.7%; MCV: 65.8 ± 3 fL; platelets: 312 ± 22.4; neutrophils: 34.8 ± 1.87; eosinophils: 3.08 ± 0.43; monocytes: 3.08 ± 0.28; lymphocytes: 75.6 ± 3.77) confirmed the significant antidiabetic potential of BLR-AgNPs. Histopathological examination authenticated that BLR-AgNPs caused a significant revival in the morphology of the liver, kidney, and pancreas. Hence, findings of the study suggested the BLR-AgNPs as a potent antidiabetic agent and could be an appropriate nanomedicine to prevent diabetes in future. RESEARCH HIGHLIGHTS: Berberis lyceum extract as a reducing, capping, and stabilization agent for the BLR-AgNPs synthesis Evaluation of α-amylase inhibition, antioxidant, and α-glucosidase inhibition potential Thorough characterization using Fourier transform infrared spectroscopy, Transmission electron microscopy, x-ray diffraction, and UV-VIS spectrophotometer, which is 1st of its kind In-vivo antidiabetic activity evaluation through multiple biomarkers.

Quercetin attenuates angiotensin II-induced proliferation of vascular smooth muscle cells and p53 pathway activation in vitro and in vivo.

Quercetin is an essential flavonoid mostly found in herbal plants, fruits, and vegetables, which exhibits anti-hypertension properties. However, its pharmacological impact on angiotensin II (Ang II) induced the increase of blood pressure along with in-depth mechanism needs further exploration. The present study pointed out the anti-hypertensive role of quercetin and its comprehensive fundamental mechanisms. Our data showed that quercetin treatment substantially reduced the increase in blood pressure, pulse wave velocity, and aortic thickness of abdominal aorta in Ang II-infused C57BL/6 mice. RNA sequencing revealed that quercetin treatment reversed 464 differentially expressed transcripts in the abdominal aorta of Ang II-infused mice. Moreover, overlapping KEGG-enriched signaling pathways identified multiple common pathways between the comparison of Ang II versus control and Ang II + quercetin versus Ang II. Likewise, these pathways included cell cycle as well as p53 pathways. Transcriptome was further validated by immunohistochemistry, indicating that quercetin treatment significantly decreased the Ang II-induced expression of proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase-4 (CDK4), and cyclin D1, while increased protein expression of p53, and p21 in abdominal aortic tissues of mice. In vitro, quercetin treatment meaningfully decreased the cell viability, arrested cell cycle at G0/G1 phase, and up-regulated the p53 and p21 proteins expression, as well as down-regulated the protein expression of cell cycle-related markers, for example, CDK4, cyclin D1 in Ang II stimulated vascular smooth muscle cells (VSMCs). This study addresses pharmacologic and mechanistic perspectives of quercetin against Ang-II-induced vascular injury and the increase of blood pressure.

Quercetin inhibits angiotensin II-induced vascular smooth muscle cell proliferation and activation of JAK2/STAT3 pathway: A target based networking pharmacology approach.

The rapid growth of vascular smooth muscle cells (VSMCs) represents crucial pathological changes during the development of hypertensive vascular remodeling. Although quercetin exhibits significantly therapeutic effects on antihypertension, the systematic role of quercetin and its exact mode of action in relation to the VSMCs growth and its hypertension-related networking pharmacology is not well-documented. Therefore, the effect of quercetin was investigated using networking pharmacology followed by in vitro strategies to explore its efficacy against angiotensin II (Ang II)-induced cell proliferation. Putative genes of hypertension and quercetin were collected using database mining, and their correlation was investigated. Subsequently, a network of protein-protein interactions was constructed and gene ontology (GO) analysis was performed to identify the role of important genes (including CCND1) and key signaling pathways [including cell proliferation and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway]. We therefore further investigated the effects of quercetin in Ang II-stimulated VSMCs. This current research revealed that quercetin significantly reduced the cell confluency, cell number, and cell viability, as well as expression of proliferating cell nuclear antigen (PCNA) in Ang II-stimulated VSMCs. Mechanistic study by western blotting confirmed that quercetin treatment attenuated the activation of JAK2 and STAT3 by reducing its phosphorylation in Ang II stimulated VSMCs. Collectively, the current study revealed the inhibitory effects of quercetin on proliferation of Ang II stimulated VSMCs, by inhibiting the activation of JAK2/STAT3 signaling might be one of underlying mechanisms.

Research on Structural Performance of Hybrid Ferro Fiber Reinforced Concrete Slabs.

Reinforced concrete structures, particularly in cold areas, experience early deterioration due to steel corrosion. Fiber-Reinforced Concrete (FRC) is an emerging construction material and cost-effective substitute for conventional concrete to enhance the durability and resistance against crack development. This article examines the structural performance of hybrid ferro fiber reinforced concrete slabs (mix ratio of mortar 1:2) comprising silica fume, layers of spot-welded mesh and different ratios of polypropylene fibers. The ferrocement slabs are compared with a conventional Reinforced Cement Concrete (RCC) slab (mix ratio of 1:2:4). The experimental work comprised a total of 13 one-way slabs, one control specimen and three groups of ferrocement slabs divided based on different percentages of Poly Propylene Fibers (PPF) corresponding to 0.10%, 0.30% and 0.50% dosage in each group. Furthermore, in each group, the percentage of steel ratio in ferrocement slabs varied between 25% and 100% of the steel area in the reinforced concrete control slab specimen. For evaluating the structural performance, the observation of deflection, stress-strain behavior, cracking load and energy absorption are critical parameters assessed using LVDTs and strain gauges. At the same time, the slabs were tested in flexure mode with third point loading. The experimental results showed that the first cracking load and ultimate deflection for fibrous specimens with 0.5% fiber and 10% silica fume increased by 15.25% and 13.2% compared with the reference RCC control slab. Therefore, by increasing the percentage of PPF and steel wire mesh reinforcement in the ferrocement slab, the post-cracking behavior in terms of deflection properties and energy absorption capacity was substantially enhanced compared to the RCC control slab.

Sesquiterpene Lactones Attenuate Paclitaxel Resistance Via Inhibiting MALAT1/STAT3/ FUT4 Axis and P-Glycoprotein Transporters in Lung Cancer Cells.

Paclitaxel resistance is a challenging factor in chemotherapy resulting in poor prognosis and cancer recurrence. Signal transducer and activator of transcription factor 3 (STAT3), a key transcription factor, performs a critical role in cancer development, cell survival and chemoresistance, while its inactivation overwhelms drug resistance in numerous cancer types including lung cancer. Additionally, the fucosyltransferase 4 (FUT4) is a crucial enzyme in post-translational modification of cell-surface proteins involved in various pathological conditions such as tumor multidrug resistance (MDR). The P-glycoprotein (P-GP) is the well-known ABC transporter member that imparts drug resistance in different cancer types, most notably paclitaxel resistance in lung cancer cells. LncRNA-MALAT1 exerts a functional role in the cancer development as well as the drug resistance and is linked with STAT3 activation and activity of FUT4. Moreover, STAT3-mediated induction of P-GP is well-documented. Natural compounds of Sesquiterpene Lactone (SL) family are well-known for their anticancer properties with particular emphasis over STAT3 inhibitory capabilities. In this study, we explored the positive correlation of MALAT1 with STAT3 and FUT4 activity in paclitaxel resistant A549 (A549/T) lung cancer cells. Additionally, we investigated the anticancer activity of two well-known members of SLs, alantolactone (ALT) and Brevilin A (Brv-A), in A549/T lung cancer cells. ALT and Brv-A induced apoptosis in A549/T cells. Furthermore, these two natural SLs suppressed MALAT1 expression, STAT3 activation, and FUT4 and P-GP expression which are the hallmarks for paclitaxel resistance in A549 lung cancer cells. The inhibition of MALAT1 enhanced the competence of these SLs members significantly, which accounted for the growth inhibition as well as anti-migratory and anti-invasive effects of ALT and Brv-A. These findings suggest SLs to be the promising agents for overcoming paclitaxel resistance in A549 lung cancer cells.

Role of MicroRNAs and their corresponding ACE2/Apelin signaling pathways in hypertension.

Hypertension is controlled via the alteration of microRNAs (miRNAs), their therapeutic targets angiotensin II type I receptor (AT1R) and cross talk of signaling pathways. The stimulation of the Ang II/AT1R pathway by deregulation of miRNAs, has also been linked to cardiac remodeling as well as the pathophysiology of high blood pressure. As miRNAs have been associated to ACE2/Apelin and Mitogen-activated protein kinases (MAPK) signaling, it has revealed an utmost protective impact over hypertension and cardiovascular system. The ACE2-coupled intermodulation between RAAS, Apelin system, MAPK signaling pathways, and miRNAs reveal the practicalities of high blood pressure. The research of miRNAs may ultimately lead to the expansion of an innovative treatment strategy for hypertension, which indicates the need to explore them further at the molecular level. Therefore, here we have focused on the mechanistic importance of miRNAs in hypertension, ACE2/Apelin signaling as well as their biological functions, with a focus on interplay and crosstalk between ACE2/Apelin signaling, miRNAs, and hypertension, and the progress in miRNA-based diagnostic techniques with the goal of facilitating the development of new hypertension-controlling therapeutics.

Latcripin-7A from Lentinula edodes C91-3 induces apoptosis, autophagy, and cell cycle arrest at G1 phase in human gastric cancer cells via inhibiting PI3K/Akt/mTOR signaling.

Gastric cancer (G.C) is one of the most lethal cancer types worldwide. Current treatment requires surgery along with chemotherapy, which causes obstacles for speedy recovery. The discovery of novel drugs is needed for better treatment of G.C with minimum side effects. Latcripin-7A (LP-7A) is a newly discovered peptide extracted from Lentinula edodes. It is recently studied for its anti-cancer activity. In this study, LP-7A was modeled using a phyre2 server. Anti-proliferation effects of LP-7A on G.C cells were examined via CCK-8, colony formation, and morphology assay. Apoptosis of LP-7A treated G.C cells was evaluated via Hoechst Stain, western blot and flow cytometry. Autophagy was assessed via acridine orange staining and western blot. The cell cycle was assessed via flow cytometry assay and western blot. Pathway was studied via western blot and STRING database. Anti-migratory effects of LP-7A treated G.C cells were analyzed via wound healing, western blot, and migration and invasion assay. LP-7A effectively inhibited the growth of G.C cells by inhibiting the PI3K/Akt/mTOR pathway. G.C cells treated with LP-7A arrested the cell cycle at the G1 phase, contributing to the inhibition of migration and invasion. Furthermore, LP-7A induced apoptosis and autophagy in gastric cancer cells. These results indicated that LP-7A is a promising anti-cancer agent. It affected the proliferation and growth of G.C cells (SGC-7901 and BGC-823) by inducing apoptosis, autophagy, and inhibiting cell cycle at the G1 phase in G.C cells.

IL-1ß Promotes Vasculogenic Mimicry of Breast Cancer Cells Through p38/MAPK and PI3K/Akt Signaling Pathways.

Vasculogenic mimicry (VM), a micro vessel-like structure formed by the cancer cells, plays a pivotal role in cancer malignancy and progression. Interleukin-1 beta (IL-1ß) is an active pro-inflammatory cytokine and elevated in many tumor types, including breast cancer. However, the effect of IL-1ß on the VM of breast cancer has not been clearly elucidated. In this study, breast cancer cells (MCF-7 and MDA-MB-231) were used to study the effect of IL-1ß on the changes that can promote VM. The evidence for VM stimulated by IL-1ß was acquired by analyzing the expression of VM-associated biomarkers (VE-cadherin, VEGFR-1, MMP-9, MMP-2, c-Fos, and c-Jun) via western blot, immunofluorescent staining, and Immunohistochemistry (IHC). Additionally, morphological evidence was collected via Matrigel-based cord formation assay under normoxic/hypoxic conditions and microvessel examination through Hematoxylin and Eosin staining (H&E). Furthermore, the STRING and Gene Ontology database was also used to analyze the VM-associated interacting molecules stimulated by IL-ß. The results showed that the expression of VM biomarkers was increased in both MCF-7 and MDA-MB-231 cells after IL-1ß treatment. The increase in VM response was observed in IL-1ß treated cells under both normoxia and hypoxia. IL-1ß also increased the activation of transcription factor AP-1 complex (c-Fos/c-Jun). The bioinformatics data indicated that p38/MAPK and PI3K/Akt signaling pathways were involved in the IL-1ß stimulation. It was further confirmed by the downregulated expression of VM biomarkers and reduced formation of the intersections upon the addition of the signaling pathway inhibitors. The study suggests that IL-1ß stimulates the VM and its associated events in breast cancer cells via p38/MAPK and PI3K/Akt signaling pathways. Aiming the VM-associated molecular targets promoted by IL-1ß may offer a novel anti-angiogenic therapeutic strategy to control the aggressiveness of breast cancer cells.

Inhibition of JNK-Mediated Autophagy Promotes Proscillaridin A- Induced Apoptosis via ROS Generation, Intracellular Ca+2 Oscillation and Inhibiting STAT3 Signaling in Breast Cancer Cells.

Breast cancer is the most heterogenous cancer type among women across the world. Despite concerted efforts, breast cancer management is still unsatisfactory. Interplay between apoptosis and autophagy is an imperative factor in categorizing therapeutics for cancer treatment. Proscillaridin A (PSD-A), a well-known cardiac glycoside used for cardiac arrest and arrythmias, has been unveiled in many cancer types but the underlying mechanism for apoptosis and autophagy in breast cancer is not fully understood. In our study, PSD-A restricted cell growth, inhibited STAT3 activation and induced apoptosis and autophagy in breast cancer cells via ROS generation and Ca+2 oscillation. Pretreatment of NAC and BAPTA-AM restored PSD-A induced cellular events in breast cancer cells. PSD-A induced apoptosis via DNA fragmentation, caspase-cascade activation, PARP cleavage, mitochondrial dysfunction, Bax/Bcl-2 proteins modulation and ER chaperone GRP78 inhibition along with decreased phosphorylation of ERK1/2. Inhibition of STAT3 activation was found to be associated with decreased phosphorylation of SRC. Moreover, PSD-A induced events of autophagy i.e. conversion of LC3-I to LC3-II, and Atg3 expression via JNK activation and decreased mTOR and AKT phosphorylation. In this study, pretreatment of SP600125, a JNK inhibitor, reduced autophagy and enhanced STAT3 inhibition and apoptosis. Additionally, SB203580, a commercial p38 inhibitor, stimulated STAT3 activation and improved autophagic events rate in breast cancer cells, displaying the role of the MAPK signaling pathway in interplay between apoptosis and autophagy. Our data suggest that the rate of apoptotic cell death is improved by blocking JNK-induced autophagy in PSD-A treated MCF-7 and MDA-MB-231 breast cancer cells.

Latcripin-7A, derivative of Lentinula edodes C91-3, reduces migration and induces apoptosis, autophagy, and cell cycle arrest at G1 phase in breast cancer cells.

Due to the high mortality rate and an increase in breast cancer incidence, it has been challenging for researchers to come across an effective chemotherapeutic strategy with minimum side effects. Therefore, the need for the development of effective chemotherapeutic drugs is still on the verge. Consequently, we approached a new mechanism to address this issue. The naturally available peptide named latcripin-7A (LP-7A), extracted from a mushroom called Lentinula edodes, provided us promising results in terms of growth arrest, apoptosis, and autophagy in breast cancer cells (MCF-7 and MDA-MB-231). Expressions of protein markers for apoptosis, autophagy, and cell cycle were confirmed via Western blot analysis. Migration and invasion assays were performed to analyze the anti-migratory and anti-invasive properties of LP-7A, while cell cycle analysis was performed via flow cytometry to evaluate its affect over cell growth. Supportive assays were performed like acridine orange, Hoechst 33258 stain, DNA fragmentation, and mitochondrial membrane potential (MMP) to further confirm the anticancer effect of LP-7A on breast cancer cell lines. It is concluded that LP-7A effectively reduces migration and promotes apoptosis as well as autophagy in MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell growth arrest at G0/G1 phase and decreasing mitochondrial membrane potential without adverse effects on MCF-10A normal breast cells. KEY POINTS: • In this study, we have investigated the anti-cancer activity of novel latcripin-7A (LP-7A), a protein extracted as a result of de novo characterization of Lentinula edodes C91-3. • We conclude in our research work that LP-7A can initiate diverse cell death-related events, i.e., apoptosis and autophagy in both triple-positive and triple-negative breast cancer cell lines by interacting with different nodes of cellular signaling that can further be investigated in vivo to gain a better understanding.

Brevilin A induces ROS-dependent apoptosis and suppresses STAT3 activation by direct binding in human lung cancer cells.

Sesquiterpene lactones have been shown to be promising leads for anticancer drug development. Brevilin A (BLN-A), a sesquiterpene lactone compound of Centipeda minima has been shown to exhibit anticancer effects against various cancer cells. However, the anticancer mechanism and cellular targets of BLN-A remain elusive. Here in this study, BLN-A inhibits proliferation and induces cell morphological changes in A549 and NCI-H1650 non-small cell lung cancer cells in a dose-dependent manner. Moreover, BLN-A increased ROS generation and bax/bcl-2 ratio while decreased intracellular glutathione (GSH), and mitochondrial membrane potential which resulted in induction of apoptosis as evident by annexin-V/FITC staining, caspase-3 activation and PARP cleavage. Supplementation of cells with NAC (ROS Scavenger) effectively protected the cells from BLN-A-induced apoptosis. Finally, BLN-A inhibited constitutive as well as IL-6- and EGF-induced STAT3 activation at Tyr705. Using molecular docking and SPR analyses, we found that BLN-A directly binds with STAT3 and thereby inhibits its activation. Knocking down of STAT3 by stable transfection with shRNA suppressed growth and augmented cytotoxicity of BLN-A, indicating the key role of STAT3 in BLN-A-mediated apoptosis. Cumulative findings suggest that BLN-A is a promising lead structure for developing it into a potent STAT3 inhibitor and therapeutic agent against NSCLC as well.

Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells.

PURPOSE: Breast cancer is the most common malignancy among women across the globe. Despite concerted efforts to improve the prevailing treatment modalities, the overall prognosis of breast cancer remains unsatisfactory. Recently, antiproliferative activity of Brevilin A (Brv-A), a sesquiterpene lactone compound of Centipeda minima, has been unveiled in various cancer types. Here, we have explored anticancer activity of Brv-A in MCF-7 breast carcinoma cells by targeting various pathways. MATERIALS AND METHODS: Cell proliferation rate was determined by CCK-8 and clonogenic assay. Cellular morphological changes were observed under phase contrast microscope while calcein-AM and PI was used for live/dead assay. Cell cycle assay was performed by flow cytometry. Apoptotic cell percentage was determined by Hoechst 33258 staining and flow cytometric analysis. ROS generation and mitochondrial membrane potential were measured using commercially available kits while protein expression was measured by Western blotting. RESULTS: In our study, Brv-A exerted antiproliferative effect through mitotic arrest at G2/M phase of cell cycle and induced apoptosis in MCF-7 cells in a dose-dependent manner. Induction of apoptosis by Brv-A was found to be associated with ROS generation by targeting NOX2 and NOX3, mitochondrial dysfunction (MMP dissipation and Bcl-2 family proteins modulation), DNA fragmentation, JNK and p38 MAPK activation, endoplasmic reticulum (ER) stress by increasing Bip/GRP78, ATF4 and CHOP protein expressions and inhibition of STAT3 activation via decreased phosphorylation of JAK2 and SRC. Pretreatment of NAC, a ROS scavenger, partially reversed the aforesaid cellular events indicating ROS generation as the primary event to modulate cellular targets for induction of apoptosis. Besides, Brv-A has also been documented for inhibition of cell migration via decrease in COX-2 and MMP-2 expression. CONCLUSION: Taken together, Brv-A induces G2/M phase arrest, ROS-dependent apoptosis, ER stress, mitochondrial dysfunction and inhibits STAT3 activation in MCF-7 cells signifying it to be one of the potential anticancer therapeutics in future.

Taurine Promotes Neuritic Growth of Dorsal Root Ganglion Cells Exposed to High Glucose in Vitro.

Diabetic neuropathy (DN) is the most common chronic complication of DM and its major pathological changes show axonal dysfunction, atrophy and loss. However, there are few reports that taurine promotes neurite growth of dorsal root ganglion (DRG) cells. In current study, DRG neurons were exposed to high glucose (HG) with or without taurine. The neurite outgrowth of DRG neurons was observed by fluorescent immunohistochemistry method. Expression of Gap-43, Akt, phosphorylated Akt, mTOR and phosphorylated mTOR was determined by Western blot assay. Our results showed that HG significantly decreased the neurite outgrowth and expression of Gap-43 in DRG neurons. Moreover, phosphorylated levels of Akt and mTOR were downregulated in DRG neurons exposed to HG. On the contrary, taurine supplementation significantly reversed the decreased neurite outgrowth and Gap-43 expression, and the downregulated phosphorylated levels of Akt and mTOR. However, the protective effects of taurine were blocked in the presence of PI3K antagonists LY294002 or Akt antagonists Perifosine. These results indicate that taurine promotes neurite outgrowth of DRG neurons exposed to HG via activating Akt/mTOR signal pathway.