Regulation of cell signaling pathways by circular RNAs and microRNAs in different cancers: Spotlight on Wnt/ß-catenin, JAK/STAT, TGF/SMAD, SHH/GLI, NOTCH and Hippo pathways.

Groundbreaking discoveries in molecular oncology have leveraged our understanding altogether to a new level. Mapping of plethora of cell signaling pathways has enabled researchers to drill down deep into the intermeshed regulatory networks which crosstalk to promote carcinogenesis and metastasis. More importantly, discovery of non-coding RNAs has added new layers of complexity to already complicated nature of cell signaling pathways. The discovery of circular RNAs (circRNAs) has opened the door to an ever-widening understanding of cellular processes that are controlled or influenced by circRNAs. In this review, we have summarized most recent advancements in our understanding related to interplay between circular RNAs and microRNAs for the regulation of NOTCH, Wnt/ß-catenin, Hippo, SHH/GLI, JAK/STAT and TGF/SMAD pathways in different cancers.

Alocasia odora-mediated synthesis of silver nanoparticles, their cytotoxicity, and virucidal potential.

Silver nanoparticles (AgNPs) have various applications in the biomedical field and are considered excellent microbicidal agents. Moreover, biological synthesis of AgNPs using medicinal plants further improves the medicinal applicability of these plants. In this study, the aqueous extract of Alocasia odora rhizome (RE) and Alocasia odora stem (SE) were used to synthesize stem aqueous extract-AgNPs (SNP) and rhizome aqueous extract-AgNPs (RNP). Furthermore, RNP and SNP were evaluated for their virucidal potential. The synthesis of SNP and RNP was monitored using a UV spectrophotometer by observing their surface plasmon resonance peak. In addition, scanning electron microscopy (SEM) gave further insight into their morphology and particle size, whereas energy-dispersive X-ray spectroscopy (EDX) confirmed the presence of silver ions. Interestingly, Fourier-transform infrared spectroscopy (FTIR) analysis of AgNPs revealed that phytomolecules acted as capping and stabilizing agents for SNP and RNP. The in vitro cytotoxicity of SNP and RNP was further analyzed using MTT assay on the U87-MG human glioblastoma cancer cell line and SNP found to be the most cytotoxic (43.40 µg/ml) among all. Besides that, SNP has also found to show the maximum cytopathic effects (CPE) against dengue virus type 2 (DENV-2) on Huh-7 cell line. As a result of the observations, it can be concluded that they can become a promising antiviral drug candidate and thus merit further testing. KEY POINTS: • AgNPs were successfully synthesized through Alocasia odora aqueous extract. • AgNPs were more cytotoxic on the U87-MG cell line than the extract alone. • AgNPs have shown significant reduction in the dengue viral infection than the extract alone.

Cancer chemopreventive role of fisetin: Regulation of cell signaling pathways in different cancers.

It is becoming progressively more understandable that pharmaceutical targeting of drug-resistant cancers is challenging because of intra- and inter-tumor heterogeneity. Interestingly, naturally derived bioactive compounds have unique ability to modulate wide-ranging deregulated oncogenic cell signaling pathways. In this review, we have focused on the available evidence related to regulation of PI3K/AKT/mTOR, Wnt/ß-catenin, NF-κB and TRAIL/TRAIL-R by fisetin in different cancers. Fisetin has also been shown to inhibit the metastatic spread of cancer cells in tumor-bearing mice. We have also summarized how fisetin regulated autophagy in different cancers. In addition, this review also covers fisetin-mediated regulation of VEGF/VEGFR, EGFR, necroptosis and Hippo pathway. Fisetin has entered into clinical trials particularly in context of COVID19-associated inflammations. Furthermore, fisetin mediated effects are also being tested in clinical trials with reference to osteoarthritis and senescence. These developments will surely pave the way for full-fledge and well-designed clinical trials of fisetin in different cancers. However, we still have to comprehensively analyze and fully unlock pharmacological potential of fisetin against different oncogenic signaling cascades and non-coding RNAs. Fisetin has remarkable potential as chemopreventive agent and future studies must converge on the identification of additional regulatory roles of fisetin for inhibition and prevention of cancers.

Luteolin mediated targeting of protein network and microRNAs in different cancers: Focus on JAK-STAT, NOTCH, mTOR and TRAIL-mediated signaling pathways.

There has always been a keen interest of basic and clinical researchers to search for cancer therapeutics having minimum off-target effects and maximum anticancer activities. In accordance with this approach, there has been an explosion in the field of natural products research in the past few decades because of extra-ordinary list of natural extracts and their biologically and pharmacologically active constituents having significant medicinal properties. Apparently, luteolin-mediated anticancer effects have been investigated in different cancers but there is superfluousness of superficial data. Generalized scientific evidence encompassing apoptosis, DNA damage and anti-inflammatory effects has been reported extensively. However, how luteolin modulates deregulated oncogenic pathways in different cancers has not been comprehensively uncovered. In this review we have attempted to focus on cutting-edge research which has unveiled remarkable abilities of luteolin to modulate deregulated oncogenic pathways in different cancers. We have partitioned the review into various sections to separately discuss advancements in therapeutic targeting of oncogenic protein networks. We have provided detailed mechanistic insights related to JAK-STAT signaling and summarized how luteolin inhibited STAT proteins to inhibit STAT-driven gene network. We have also individually analyzed Wnt/ß-catenin and NOTCH pathway and how luteolin effectively targeted these pathways. Mapping of the signaling landscape has revealed that NOTCH pathway can be targeted therapeutically. NOTCH pathway was noted to be targeted by luteolin. We have also conceptually analyzed how luteolin restored TRAIL-induced apoptosis in resistant cancers. Luteolin induced an increase in pro-apoptotic proteins and efficiently inhibited anti-apoptotic proteins to induce apoptosis. Luteolin mediated regulation of non-coding RNAs is an exciting and emerging facet. Excitingly, there is sequential and systematic accumulation of clues which have started to shed light on intricate regulation of microRNAs by luteolin in different cancers. Collectively, sophisticated information will enable us to develop a refined understanding of the multi-layered regulation of signaling pathways and non-coding RNAs by luteolin in different cancers.

TRAIL mediated signaling in different cancers: cancer in the "Crosshairs".

Cancer is a therapeutically challenging disease because of its heterogeneous and multifaceted nature. Decades of research have sequentially and systematically enabled us to develop a sharper and better understanding of the heterogeneous nature of cancer. Genetic, genomic and proteomic studies have unraveled wide-ranging signaling cascades which play cornerstone role in disease onset and progression. More importantly, activation of pro-survival signaling and loss of apoptosis also play critical role in cancer progression. TRAIL-mediated signaling pathway has emerged as one of the most comprehensively analyzed cascade because of its exceptional ability to target cancer cells while leaving normal cells intact. TRAIL discovery and landmark achievements related to TRAIL/TRAIL-receptor signaling pathway attracted the attention of researchers. Therefore, scientists started to add missing pieces to an incomplete jig-saw puzzle and allowed contemporary researchers to conceptualize a better molecular snapshot of TRAIL-induced signaling in various cancers. Circumstantial evidence illuminated a functionally unique "push and pull" between anti-apoptotic and pro-apoptotic proteins in different cancers. Overexpression of anti-apoptotic proteins and inactivation of pro-apoptotic proteins shifted the balance towards loss of apoptosis. There has been a breakneck increase in the number of clinical trials related to TRAIL-based therapeutics which validate the true pharmacological potential of TRAIL-based therapeutics as effective anticancer agents. However, apart from advancements in our clinical understanding about the efficacy of TRAIL-based therapeutics, researchers have also faced setbacks in the field of translational medicine. Therefore, in this review, we have attempted to set spotlight on the most recent and landmark discoveries which have leveraged our understanding related to TRAIL-mediated signaling altogether to a new level.

Piceatannol mediated regulation of deregulated signaling pathways in different cancers: Tumbling of the ninepins of molecular oncology.

With the recent technological advancements, a new golden era of natural products drug discovery has dawned. Increasingly it is being realized that structural modularity of many pharmacologically active products derived natural sources allows a building-block approach which can be exploited for analysis of regulation of deregulated oncogenic protein networks in different cancers. Piceatannol has been shown to effectively modulate JAK/STAT, Wnt/ß-catenin, mTOR pathway in different cancers. In addition, certain hints have emerged which shed light on the regulation of microRNAs by piceatannol in some cancers. Regulation of deregulated oncogenic pathways by Piceatannol is gradually capturing attention and might be helpful in the multi-targeting of deregulated oncogenic networks in cancers.

TRAIL mediated signaling as a double-edged sword in pancreatic cancer: Analysis of brighter and darker sides of the pathway.

Genetic, genomic and proteomic studies have refined our concepts related to underlying mechanisms of pancreatic cancer. Increasingly sophisticated knowledge has started to shed light on the fact that pancreatic cancer harbored multiple epigenetic and genetic alterations and revealed complicated and dense tumor microenvironments. Our rapidly evolving knowledge about pancreatic cancer has helped us in identification of myriad of underlying mechanisms which play instrumental role in disease onset, drug resistance and epithelial to mesenchymal transition (EMT). Additionally, loss of apoptosis is the cornerstone of cancer biology and researchers have devoted considerable attention to the versatile regulators involved in loss and restoration of apoptosis. Discovery of TNF/TNFR, FasL/Fas and TRAIL/TRAIL-R opened new horizons for detailed analysis of intracellular mechanisms regulated by these pro-apoptotic molecules. Decades of cutting-edge research helped in translation of TRAIL-based therapeutics into clinically effective therapeutics. In this review, we will focus specifically on groundbreaking achievements which have leveraged our concepts related to TRAIL-mediated signaling to yet another level. We will also discuss how basic and clinical scientists are making efforts to overcome the stumbling blocks associated with efficacy of TRAIL-based therapeutics against TRAIL-resistant pancreatic cancers. We partition this multi-component review into overview of the conceptual breakthroughs in regulation of TRAIL-mediated signaling in pancreatic cancers, push and pull between pro- and anti-apoptotic proteins to regulate TRAIL-mediated apoptosis and how researchers have identified different natural and synthetic molecules to restore apoptosis in TRAIL-resistant pancreatic cancer. We have also summarized how long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) regulated TRAIL-mediated apoptosis in pancreatic cancer. More importantly we will also set spotlight on the darker side of TRAIL/TRAIL-R pathway in pancreatic cancer. Circumstantial evidence highlighted cancer promoting role of TRAIL/TRAIL-R in pancreatic cancer. These diametrically opposed context-dependent roles of TRAIL-pathway are intriguing and need comprehensive research to address outstanding questions.

Investigation of antioxidant and anti-nociceptive potential of isoxazolone, pyrazolone derivatives, and their molecular docking studies.

A series of new isoxazolone (3a-d) and pyrazolone (4a-d) derivatives were synthesized and assessed for their antioxidant and analgesic activity. Among synthesized compounds, 3b and 4b having nitro (NO2 ) group show high analgesic activity at a dose of 6 mg/kg. Analgesic activity was further proceeded to explore the contribution of opioidergic mechanisms in the mediation of analgesic effects. Animals were administered with naloxone, a nonselective opioid inverse agonist, at the dose of 0.5 mg/kg. The results obtained suggested that the analgesic effects of the synthesized compounds were not reversed by naloxone, specifying that the compounds 3b and 4b do not follow the opioidergic pathway in order to relieve pain in animal models. Further, the binding interactions of compounds 3b and 4b were analyzed by docking them against nonopioid receptors COX-1 (3N8X) and COX-2 (3LN1). The results demonstrate the analgesic potential of isoxazolone and pyrazolone derivatives, especially compounds 3b and 4b can be considered promising lead molecules for further investigation and development into potent analgesic drugs. In addition, the antioxidant potential of compounds was also found to be related to better analgesic activity, thus providing an insight into the role of oxidative stress in the mediation of analgesia.

In-silico computational analysis of [6-(2, 3-Dichlorophenyl)-1, 2, 4-Triazine-3, 5-Diamine] metal complexes on voltage gated sodium channel and dihydrofolate reductase enzyme.

Epilepsy is the disease associated with seizures and convulsions. Various antiepileptic drugs have been used widely to treat these disorders. Lamotrigine [6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine] shows certain adverse effects at small doses, to evaluate its efficacy lamotrigine schiff based metal complexes were screened in-silico at voltage gated sodium channel for antiepileptic effect and dihydrofolate reductase enzyme for anticancer activity. Post docking analysis revealed that lamotrigine shows greater antiepileptic effect with its Schiff base complex of tin, with greater binding affinities on voltage gated sodium channel. However, anticancer effect of lamotrigine with its Schiff base silver complex shows highest binding affinity on dihydrofolate reductase enzyme. Study concluded that Schiff base derivative and its metal complexes express significant binding interactions with voltage gated sodium channel and dihydrofolate reductase enzyme.

Development of chitosan based ß-carotene mucoadhesive formulation for skin cancer treatment.

Mucopermeating nanoformulations can enhance mucosal penetration of poorly soluble drugs at their target site. In this work, thiolated chitosan (TCS)-lithocholic acid (LA) nanomicelles loaded with ß-carotene, a safe phytochemical with anticancer properties, were designed to improve the pharmaceutical and pharmacological drug profile. The TCS-LA nanomicelles were characterized by FTIR to confirm the presence of the thiol group that favors skin adhesion, and to corroborate the conjugation of hydrophobic LA with hydrophilic CS to form an amphiphilic polymer derivative. Their crystalline nature and thermal behavior were investigated by XRD and DSC analyses, respectively. According to DLS and TEM, their average size was <300 nm, and their surface charge was +27.0 mV. ß-carotene entrapment and loading efficiencies were 64 % and 58 %, respectively. In vitro mucoadhesion and ex vivo mucopenetration analyses further corroborated the potential of the nanoformulation to deliver the drug in a sustained manner under conditions mimicking cancer micro-environment. Anticancer studies in mice demonstrated that the loaded nanomicelles delayed skin cancer growth, as revealed by both morphological and biochemical parameters. Based on the results obtained herein, it can be concluded that drug-loaded TCS-LA is a novel, stable, effective and safe mucoadhesive formulation of ß-carotene for the potential treatment of skin cancer.

Regulation of ROCK1/2 by long non-coding RNAs and circular RNAs in different cancer types.

Recent breakthroughs in high-throughput technologies have enabled the development of a better understanding of the functionalities of rho-associated protein kinases (ROCKs) under various physiological and pathological conditions. Since their discovery in the late 1990s, ROCKs have attracted the attention of interdisciplinary researchers due to their ability to pleiotropically modulate a myriad of cellular mechanisms. A rapidly growing number of published studies have started to shed light on the mechanisms underlying the regulation of ROCK1 and ROCK2 via long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in different types of cancer. Detailed analyses have suggested that lncRNAs may be characteristically divided into oncogenic and tumor suppressor lncRNAs. Several exciting recent discoveries have also indicated how different lncRNAs and circRNAs modulate ROCK1/2 and mediate multistep cancer onset and progression. The present review chronicles the major advances that have been made in our understanding of the regulatory role of ROCK1/2 in different types of cancer, and how wide-ranging lncRNAs and circRNAs potentiate ROCK-driven signaling by blocking the targeting activities of tumor suppressor microRNAs.

Schiff-Based Metal Complexes of Lamotrigine: Design, Synthesis, Characterization, and Biological Evaluation.

In the current study, a series of Schiff base derivatives of lamotrigine are complexed with zinc, copper, silver, and tin and characterized by spectroscopic techniques and biological assays. Docking analyses revealed six complexes with favorable binding interactions, which were further subjected to in vitro anticancer activity. The complexes 6b and 6c displayed the most potent antiproliferative activity against MCF-7 cell lines with an IC50 value of 11.9 ± 0.27 and 12.0 ± 0.14 µM, respectively, as compared with the standard doxorubicin with an IC50 value of 0.90 ± 0.14 µM. In vivo anticonvulsant activities of the compounds were evaluated by the subcutaneous pentylenetetrazole model and neurotoxic activities by the minimal motor impairment model. The neurotoxicity of targeted compounds was measured using the rotating rod (ROT) method. Computational studies were carried out using the reported crystal structures of multidrug-resistant protein (PDB-ID: 2KAV) and dihydrofolate reductase (PDB-ID: 3GHW), indicating that the compound 6c showed significant interactions at the voltage-gated sodium ion channel in the brain and at dihydrofolate reductase enzyme in the breast. Certain metal complexes of Schiff base ligands (e.g., 6c) were found to possess the most potent anticancer, anticonvulsant, and neurotoxic potential than lamotrigine alone.

Zinc metal carboxylates as potential anti-Alzheimer's candidate: in vitro anticholinesterase, antioxidant and molecular docking studies.

In search of suitable therapy for the management of Alzheimer's disease, this study was designed to evaluate metal complexes against its biochemical targets. Zinc metal carboxylates (AAZ1-AAZ6) were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The antioxidant in combination with anticholinesterase activity can be considered as an important target in the management of Alzheimer's disease. Therefore, these compounds were also screened for ABTS and DPPH free radical scavenging activity. In AChE inhibition assay, we noticed encouraging IC50 values of 33.07 and 59.52 µM for compounds AAZ5 and AAZ3, respectively. However, when we tested BChE activity, we observed an outstanding IC50 of 0.056 µM for compound AAZ6. Amazingly all of our compounds (AAZ1-AAZ6) were proved to be strong antioxidants which actively supplement the anti-Alzheimer's activity. The majority of our compounds exhibited lower IC50 values than the standard ascorbic acid in both DPPH and ABTS assays. We also correlated our results with molecular docking studies. Results elaborated that AAZ1 and AAZ5 exhibit strong interactions with amino acids HIS 362, HIS 398, GLU 306 ARG 289 and SER 237 inside binding pocket of targeted protein. In remarks, we can claim that our synthesized zinc metal carboxylates have strong potency to manage Alzheimer's disease on both anticholinesterase and antioxidant targets. Communicated by Ramaswamy H. Sarma.

Prospective Application of Two New Pyridine-Based Zinc (II) Amide Carboxylate in Management of Alzheimer's Disease: Synthesis, Characterization, Computational and in vitro Approaches.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative illness described predominantly by dementia. Even though Alzheimer's disease has been known for over a century, its origin remains a mystery, and researchers are exploring many therapy options, including the cholinesterase technique. A decreased acetylcholine ACh neurotransmitter level is believed to be among the important factors in the progression of Alzheimer's disease. METHODS: In continuation of synthesizing potential anti-Alzheimer agents and known appreciative pharmacological potential of amide-containing compounds, this study presents the synthesis of two novel amide-based transition metal zinc (II) complexes, AAZ7 and AAZ8, attached with a heterocyclic pyridine ring, which was synthesized and characterized by Fourier transform infrared spectroscopy (FT-IR), elemental analysis, 1H_NMR, and 13C_NMR. FT-IR spectroscopic records showed the development of bidentate ligand as Δν value was decreased in both complexes when compared with the free ligand. Both of the synthesized complexes were analyzed for acetylcholinesterase and butyrylcholinesterase inhibitory potential along with the antioxidizing activity. RESULTS: Importantly, the complex of AAZ8 exhibited more potent activity giving IC50 values of 14 µg/mL and 18µg/mL as AChE and BChE cholinesterase inhibitors, respectively, when compared with standard positive control galantamine. Interestingly, AAZ8 also displayed promising antioxidant potential by showing IC50 values of 35 µg/mL for DPPH and 29 µg/mL for ABTS in comparison with positive control ascorbic acid. CONCLUSION: Herein, we report two new amide carboxylate zinc (II) complexes which were potentially analyzed for various biological applications like acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory potentials, and antioxidant assays. Computational docking studies also simulated results to understand the interactions. Additionally, thermodynamic parameters utilizing molecular dynamic simulation were performed to determine the ligand protein stability and flexibility that supported the results. Studies have shown that these compounds have the potential to be good anti-Alzheimer candidates for future studies due to inhibition of cholinesterase enzymes and display of free radical scavenging potential against DPPH as well as ABTS free radicals.

Rational use of antibiotics in an intensive care unit: a retrospective study of the impact on clinical outcomes and mortality rate.

BACKGROUND: Intensive care units (ICUs) are specialized units where patients with critical conditions are admitted for getting specialized and individualized medical treatment. High mortality rates have been observed in ICUs, but the exact reason and factors affecting the mortality rates have not yet been studied in the local population in Pakistan. AIM: This study was aimed to determine rational use of antibiotic therapy in ICU patients and its impact on clinical outcomes and mortality rate. METHODS: This was a retrospective, longitudinal (cohort) study including 100 patients in the ICU of the largest tertiary care hospital of the capital city of Pakistan. RESULTS: It was observed that empiric antibiotic therapy was initiated in 68% of patients, while culture sensitivity test was conducted for only 19% of patients. Thirty-percent of patients developed nosocomial infections and empiric antibiotic therapy was not initiated for those patients (P<0.05). Irrational antibiotic prescribing was observed in 86% of patients, and among them, 96.5% mortality was observed (P<0.05). The overall mortality rate was 83%; even higher mortality rates were observed in patients on a ventilator, patients with serious drug-drug interactions, and patients prescribed with irrational antibiotics or nephrotoxic drugs. Adverse clinical outcomes leading to death were observed to be significantly associated (P<0.05) with irrational antibiotic prescribing, nonadjustment of doses of nephrotoxic drugs, use of steroids, and major drug-drug interactions. CONCLUSION: It was concluded that empiric antibiotic therapy is beneficial in patients and leads to a reduction in the mortality rate. Factors including irrational antibiotic selection, prescribing contraindicated drug combinations, and use of nephrotoxic drugs were associated with high mortality rate and poor clinical outcomes.