Targeting PI3K and CDKs as effective therapeutic option for PPGLs in vitro and in vivo

Background: Inflammation is a complex response of the host defense system to different internal and external stimuli. It is believed that persistent inflammation may lead to chronic inflammatory diseases such as, inflammatory bowel disease, neurological and cardiovascular diseases. Oxidative stress is the main factor responsible for the augmentation of inflammation via various molecular pathways. Therefore, alleviating oxidative stress is effective a therapeutic option against chronic inflammatory diseases. Methods: This review article extends the knowledge of the regulatory mechanisms of flavonoids targeting inflammatory pathways in chronic diseases, which would be the best approach for the development of suitable therapeutic agents against chronic diseases. Results: Since the inflammatory response is initiated by numerous signaling molecules like NF-κB, MAPK, and Arachidonic acid pathways, their encountering function can be evaluated with the activation of Nrf2 pathway, a promising approach to inhibit/prevent chronic inflammatory diseases by flavonoids. Over the last few decades, flavonoids drew much attention as a potent alternative therapeutic agent. Recent clinical evidence has shown significant impacts of flavonoids on chronic diseases in different in-vivo and in-vitro models. Conclusion: Flavonoid compounds can interact with chronic inflammatory diseases at the cellular level and modulate the response of protein pathways. A promising approach is needed to overlook suitable alternative compounds providing more therapeutic efficacy and exerting fewer side effects than commercially available antiinflammatory drugs.

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Cardioprotective Effects of Puerarin-V on Isoproterenol-Induced Myocardial Infarction Mice Is Associated with Regulation of PPAR-Υ/NF-κB Pathway

Molecules ◽

10.3390/molecules23123322 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3322 ◽

Cited By ~ 9

Author(s):

Xuguang Li ◽

Tianyi Yuan ◽

Di Chen ◽

Yucai Chen ◽

Shuchan Sun ◽

...

Keyword(s):

Myocardial Infarction ◽

Inflammatory Responses ◽

Therapeutic Option ◽

Crystal Form ◽

Human Coronary Artery ◽

Beneficial Effects ◽

Ppar Γ ◽

Cardioprotective Effects

Puerarin is a well-known traditional Chinese medicine which has been used for the treatment of cardiovascular diseases. Recently, a new advantageous crystal form of puerarin, puerarin-V, has been developed. However, the cardioprotective effects of puerarin-V on myocardial infarction (MI) heart failure are still unclear. In this research, we aim to evaluate the cardioprotective effects of puerarin-V on the isoproterenol (ISO)-induced MI mice and elucidate the underlying mechanisms. To induce MI in C57BL/6 mice, ISO was administered at 40 mg/kg subcutaneously every 12 h for three times in total. The mice were randomly divided into nine groups: (1) control; (2) ISO; (3) ISO + puerarin injection; (4–9) ISO + puerarin-V at different doses and timings. After treatment, cardiac function was evaluated by electrocardiogram (ECG), biochemical and histochemical analysis. In vitro inflammatory responses and apoptosis were evaluated in human coronary artery endothelial cells (HCAECs) challenged by lipopolysaccharide (LPS). LPS-induced PPAR-Υ/NF-κB and subsequently activation of cytokines were assessed by the western blot and real-time polymerase chain reaction (PCR). Administration of puerarin-V significantly inhibits the typical ST segment depression compared with that in MI mice. Further, puerarin-V treatment significantly improves ventricular wall infarction, decreases the incidence of mortality, and inhibits the levels of myocardial injury markers. Moreover, puerarin-V treatment reduces the inflammatory milieu in the heart of MI mice, thereby blocking the upregulation of proinflammatory cytokines (TNF-α, IL-1β and IL-6). The beneficial effects of puerarin-V might be associated with the normalization in gene expression of PPAR-Υ and PPAR-Υ/NF-κB /ΙκB-α/ΙΚΚα/β phosphorylation. In the in vitro experiment, treatment with puerarin-V (0.3, 1 and 3 μM) significantly reduces cell death and suppresses the inflammation cytokines expression. Likewise, puerarin-V exhibits similar mechanisms. The cardioprotective effects of puerarin-V treatment on MI mice in the pre + post-ISO group seem to be more prominent compared to those in the post-ISO group. Puerarin-V exerts cardioprotective effects against ISO-induced MI in mice, which may be related to the activation of PPAR-γ and the inhibition of NF-κB signaling in vivo and in vitro. Taken together, our research provides a new therapeutic option for the treatment of MI in clinic.

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N-Cadherin Upregulation Promotes the Neurogenic Differentiation of Menstrual Blood-Derived Endometrial Stem Cells

Stem Cells International ◽

10.1155/2018/3250379 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Yanli Liu ◽

Fen Yang ◽

Shengying Liang ◽

Qing Liu ◽

Sulei Fu ◽

...

Keyword(s):

Stem Cells ◽

Peripheral Nerve ◽

Therapeutic Option ◽

In Vivo Studies ◽

Menstrual Blood ◽

Neurogenic Differentiation ◽

Endometrial Stem Cells ◽

Medical Disorders

Peripheral nerve injuries are typically caused by either trauma or medical disorders, and recently, stem cell-based therapies have provided a promising treatment approach. Menstrual blood-derived endometrial stem cells (MenSCs) are considered an ideal therapeutic option for peripheral nerve repair due to a noninvasive collection procedure and their high proliferation rate and immunological tolerance. Here, we successfully isolated MenSCs and examined their biological characteristics including their morphology, multipotency, and immunophenotype. Subsequent in vitro studies demonstrated that MenSCs express high levels of neurotrophic factors, such as NT3, NT4, BDNF, and NGF, and are capable of transdifferentiating into glial-like cells under conventional induction conditions. Moreover, upregulation of N-cadherin (N-cad) mRNA and protein expression was observed after neurogenic differentiation. In vivo studies clearly showed that N-cad knockdown via in utero electroporation perturbed the migration and maturation of mouse neural precursor cells (NPCs). Finally, a further transfection assay also confirmed that N-cad upregulation in MenSCs results in the expression of S100. Collectively, our results confirmed the paracrine effect of MenSCs on neuroprotection as well as their potential for transdifferentiation into glial-like cells and demonstrated that N-cad upregulation promotes the neurogenic differentiation of MenSCs, thereby providing support for transgenic MenSC-based therapy for peripheral nerve injury.

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TERT Promoter Revertant Mutation Inhibits Melanoma Growth through Intrinsic Apoptosis

Biology ◽

10.3390/biology11010141 ◽

2022 ◽

Vol 11 (1) ◽

pp. 141

Author(s):

Yanbing Wang ◽

Yiwu Chen ◽

Chang Li ◽

Zhiwei Xiao ◽

Hongming Yuan ◽

...

Keyword(s):

Therapeutic Option ◽

B Cell Lymphoma ◽

Inhibitory Effect ◽

Migration And Invasion ◽

Catalytic Core ◽

Tert Promoter ◽

Human Telomerase ◽

Mutant Cells

Human telomerase is a specialized DNA polymerase whose catalytic core includes both TERT and human telomerase RNA (hTR). Telomerase in humans, which is silent in most somatic cells, is activated to maintain the telomere length (TEL) in various types of cancer cells, including melanoma. In the vast majority of tumor cells, the TERT promoter is mutated to promote proliferation and inhibit apoptosis. Here, we exploited NG-ABEmax to revert TERT -146 T to -146 C in melanoma, and successfully obtained TERT promoter revertant mutant cells. These TERT revertant mutant cells exhibited significant growth inhibition both in vitro and in vivo. Moreover, A375−146C/C cells exhibited telomere shortening and the downregulation of TERT at both the transcription and protein levels, and migration and invasion were inhibited. In addition, TERT promoter revertant mutation abrogated the inhibitory effect of mutant TERT on apoptosis via B-cell lymphoma 2 (Blc-2), ultimately leading to cell death. Collectively, the results of our work demonstrate that reverting mutations in the TERT promoter is a potential therapeutic option for melanoma.

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The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.749242 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ming Ji ◽

Zhihui Zhang ◽

Songwen Lin ◽

Chunyang Wang ◽

Jing Jin ◽

...

Keyword(s):

Signaling Pathway ◽

Hedgehog Signaling ◽

Kinase Inhibitor ◽

Therapeutic Option ◽

Hedgehog Signaling Pathway ◽

Orthotopic Mouse Model ◽

Cycle Arrest ◽

The Central Nervous System

Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. Temozolomide (TMZ)–based adjuvant treatment has improved overall survival, but clinical outcomes remain poor; TMZ resistance is one of the main reasons for this. Here, we report a new phosphatidylinositide 3-kinase inhibitor, XH30; this study aimed to assess the antitumor activity of this compound against TMZ-resistant GBM. XH30 inhibited cell proliferation in TMZ-resistant GBM cells (U251/TMZ and T98G) and induced cell cycle arrest in the G1 phase. In an orthotopic mouse model, XH30 suppressed TMZ-resistant tumor growth. XH30 was also shown to enhance TMZ cytotoxicity both in vitro and in vivo. Mechanistically, the synergistic effect of XH30 may be attributed to its repression of the key transcription factor GLI1 via the noncanonical hedgehog signaling pathway. XH30 reversed sonic hedgehog–triggered GLI1 activation and decreased GLI1 activation by insulin-like growth factor 1 via the noncanonical hedgehog signaling pathway. These results indicate that XH30 may represent a novel therapeutic option for TMZ-resistant GBM.

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A Bibliometric Review of Artificial Extracellular Matrices Based on Tissue Engineering Technology Literature: 1990 through 2019

Materials ◽

10.3390/ma13132891 ◽

2020 ◽

Vol 13 (13) ◽

pp. 2891

Author(s):

Pilar Simmons ◽

Taylor McElroy ◽

Antiño R. Allen

Keyword(s):

Tissue Engineering ◽

Therapeutic Option ◽

Extracellular Matrices ◽

Engineering Technology ◽

Network Analyses ◽

Bibliometric Review ◽

Artificial Extracellular Matrix ◽

Tissue Engineering Technology

Artificial extracellular matrices (aECMs) are an extension of biomaterials that were developed as in-vitro model environments for tissue cells that mimic the native in vivo target tissues’ structure. This bibliometric analysis evaluated the research productivity regarding aECM based on tissue engineering technology. The Web of Science citation index was examined for articles published from 1990 through 2019 using three distinct aECM-related topic sets. Data were also visualized using network analyses (VOSviewer). Terms related to in-vitro, scaffolds, collagen, hydrogels, and differentiation were reoccurring in the aECM-related literature over time. Publications with terms related to a clinical direction (wound healing, stem cells, artificial skin, in-vivo, and bone regeneration) have steadily increased, as have the number of countries and institutions involved in the artificial extracellular matrix. As progress with 3D scaffolds continues to advance, it will become the most promising technology to provide a therapeutic option to repair or replace damaged tissue.

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Combining Ceftriaxone with Doxycycline and Daptomycin Reduces Mortality, Neuroinflammation, Brain Damage, and Hearing Loss in Infant Rat Pneumococcal Meningitis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00220-19 ◽

2019 ◽

Vol 63 (7) ◽

Cited By ~ 6

Author(s):

Lukas Muri ◽

Michael Perny ◽

Jonas Zemp ◽

Denis Grandgirard ◽

Stephen L. Leib

Keyword(s):

Adjuvant Therapy ◽

Antibiotic Therapy ◽

Brain Damage ◽

Pneumococcal Meningitis ◽

Therapeutic Option ◽

Case Fatality ◽

Content Type ◽

Anti Inflammatory

ABSTRACTDespite appropriate antibiotic therapy, pneumococcal meningitis (PM) is associated with a case fatality rate of up to 30% in high-income countries. Survivors often suffer from severe lifelong disabilities. An excessive inflammatory reaction drives the pathophysiology, leading to brain damage and neurologic sequelae. We aimed to improve the outcome of experimental PM by simultaneously targeting different pathophysiological mechanisms with combined adjunctive therapies previously shown to be neuroprotective.In vitro, the anti-inflammatory effects of doxycycline and daptomycin were evaluated on primary rat astroglial cells stimulated withStreptococcus pneumoniae. Eleven-day-old infant Wistar rats were infected intracisternally withS. pneumoniaeand randomized for treatment with ceftriaxone or combination adjuvant therapy consisting of ceftriaxone, daptomycin, and doxycycline. During acute PM, combined-adjuvant therapy with ceftriaxone, daptomycin, and doxycycline increased the survival rate from 64.1% to 85.8% (P < 0.01) and alleviated weight loss compared to ceftriaxone monotherapy (P < 0.01). Levels of inflammatory cytokines were significantly reduced by combined-adjuvant therapyin vitro(P < 0.0001) and in cerebrospinal fluidin vivo(P < 0.05). In infected animals treated with combined adjunctive therapy, cortical damage was significantly reduced (P < 0.05), and animals showed a trend toward better hearing capacity 3 weeks after the infection (P = 0.089), an effect which was significant in mildly infected animals (48 decibels [dB] versus 67.22 dB;P < 0.05). These mildly infected animals showed significantly reduced cochlear fibrous occlusion (P < 0.01). By combining nonbacteriolytic daptomycin and anti-inflammatory doxycycline with ceftriaxone, the previously reported beneficial effects of the drugs were cumulated and identified the triple-antibiotic therapy as a promising therapeutic option for pediatric PM.

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Hypersensitivity Reactions to Monoclonal Antibodies in Children

Medicina ◽

10.3390/medicina56050232 ◽

2020 ◽

Vol 56 (5) ◽

pp. 232

Author(s):

Francesca Mori ◽

Francesca Saretta ◽

Annamaria Bianchi ◽

Giuseppe Crisafulli ◽

Silvia Caimmi ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Therapeutic Option ◽

Provocation Test ◽

Type I ◽

Hypersensitivity Reactions ◽

Biologic Drugs ◽

Type Iv ◽

Drug Provocation Test

Biologic drugs are widely used in pediatric medicine. Monoclonal antibodies (mAbs) in particular are a therapeutic option for rheumatic, autoinflammatory and oncologic diseases. Adverse drug reactions and hypersensitivity reactions (HSR) to mAbs may occur in children. Clinical presentation of HSRs to mAbs can be classified according to phenotypes in infusion-related reactions, cytokine release syndrome, both alpha type reactions and type I (IgE/non-IgE), type III, and type IV reactions, all beta-type reactions. The aim of this review is to focus on HSRs associated with the most frequent mAbs in childhood, with particular attention to beta-type reactions. When a reaction to mAbs is suspected a diagnostic work-up including in-vivo and in-vitro testing should be performed. A drug provocation test is recommended only when no alternative drugs are available. In selected patients with immediate IgE-mediated drug allergy a desensitization protocol is indicated. Despite the heavy use of mAbs in childhood, studies evaluating the reliability of diagnostic test are lacking. Although desensitization may be effective in reducing the risk of reactions in children, standardized pediatric protocols are still not available.

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Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Cancers ◽

10.3390/cancers12030672 ◽

2020 ◽

Vol 12 (3) ◽

pp. 672 ◽

Cited By ~ 5

Author(s):

Roberta Affatato ◽

Laura Carrassa ◽

Rosaria Chilà ◽

Monica Lupi ◽

Valentina Restelli ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

High Throughput Screening ◽

Therapeutic Option ◽

Xenograft Model ◽

Antimitotic Drugs ◽

M Phase ◽

Sirna Library

Mucinous epithelial ovarian cancer (mEOC) is a rare subset of epithelial ovarian cancer. When diagnosed at a late stage, its prognosis is very poor, as it is quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using a siRNA library directed against human protein kinases in a mEOC cell line, and polo-like kinase1 (PLK1) was identified as the kinase whose downregulation interfered with cell proliferation. Both PLK1 siRNA and two specific PLK1 inhibitors (onvansertib and volasertib) were able to inhibit cell growth, induce apoptosis and block cells in the G2/M phase of the cell cycle. We evaluated, in vitro, the combinations of PLK1 inhibitors and different chemotherapeutic drugs currently used in the treatment of mEOC, and we observed a synergistic effect of PLK1 inhibitors and antimitotic drugs. When translated into an in vivo xenograft model, the combination of onvansertib and paclitaxel resulted in stronger tumor regressions and in a longer mice survival than the single treatments. These effects were associated with a higher induction of mitotic block and induction of apoptosis, similarly to what was observed in vitro. These data suggest that the combination onvansertib/paclitaxel could represent a new active therapeutic option in mEOC.

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siRNA Versus Antisense Locked Nucleic Acids: Stay Single!.

Blood ◽

10.1182/blood.v106.11.614.614 ◽

2005 ◽

Vol 106 (11) ◽

pp. 614-614

Author(s):

Phil Kearney ◽

Majken Westergaard ◽

Henrik F. Hansen ◽

Ellen M. Staarup ◽

Troels Koch ◽

...

Keyword(s):

Nucleic Acid ◽

Therapeutic Option ◽

Phase 1 ◽

Locked Nucleic Acid ◽

Target Validation ◽

Host Animal ◽

Clinical Phase ◽

Potent Inhibition

Abstract Much discussion has centred around the utility and benefits of siRNA in both target validation and as a therapeutic option. This has been driven by significant publications including that of Soutcheck et al (Nature432, 173–177 2004), which demonstrated liver targeting as well as in vivo efficacy when siRNA against ApoB was tethered to a cholesterol moiety. Santaris Pharma has developed a third generation nucleic acid chemistry referred to as locked nucleic acid (LNA) which delivers unmatched affinity and stabiliy benefits, largely overcoming the drawbacks associated with traditional antisense molecules. We therefore sought to compare this chemistry with targets which siRNA has been successfully used in in vivo/in vitro settings. The same motif used in the Soutcheck study was targeted with a LNA molecule, and the free siRNA activity was compared to the cholesterol linked and free LNA molecules in their ability ot down regulate ApoB expression. LNA (SPC3197) inhibited ApoB expression by 90% while at an equimolar concentration siRNA was ineffective in the liver and jejunum. Cholesterol linked siRNA was only effective in the jejunum (c50% reduction in mRNA) Fig1. Only the LNA mediated inhibition of ApoB expression was paralleled by a drop in serum cholesterol in the host animal. In a second model siRNA molecules targeting Hif-1a mRNA (Yu et al Lab Invest84, 553–561 2004) were compared to our lead LNA molecule targeting Hif-1a, SPC2968. Interestingly in in vitro analyses these 2 molecules were equally effective. However in a murine model the increased half life of the LNA molecules translated to a potent inhibition of Hif-1a as measured by QPCR. This effect was noted in jejunum and liver, and persisted for at least 4 days. Hif-1a inhibition mediated by siRNA was not seen in any tissue analysed (Fig 2). Finally a 3rd molecule targeting Bcl-2 has entered clinical Phase 1 trials, and data will be presented documenting its improved affinity and stabitily in relation to competitor molecules such as Genasense. Figure Figure

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