Significant Therapeutic Activity Research Articles

Trifluoro-Icaritin Ameliorates Neuroinflammation Against Complete Freund's Adjuvant-Induced Microglial Activation by Improving CB2 Receptor-Mediated IL-10/β-endorphin Signaling in the Spinal Cord of Rats.

The underlying pathogenesis of chronic inflammatory pain is greatly complex, but the relevant therapies are still unavailable. Development of effective candidates for chronic inflammatory pain is highly urgent. We previously identified that trifluoro-icaritin (ICTF) exhibited a significant therapeutic activity against complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, however, the precise mechanisms remain elusive. Here, the paw withdrawal threshold (PWT), paw withdrawal latency (PWL), and CatWalk gait analysis were used to determine the pain-related behaviors. The expression and co-localization of pain-related signaling molecules were detected by Western blot and immunofluorescence staining. Our results demonstrated that ICTF (3.0mg/kg, i.p.) effectively attenuated mechanical allodynia, thermal hyperalgesia and improved motor dysfunction induced by CFA, and the molecular docking displayed that CB2 receptor may be the therapeutic target of ICTF. Furthermore, ICTF not only up-regulated the levels of CB2 receptor, IL-10, β-endorphin and CD206, but also reduced the expression of P2Y12 receptor, NLRP3, ASC, Caspase-1, IL-1β, CD11b, and iNOS in the spinal cord of CFA rats. Additionally, the immunofluorescence staining from the spinal cord showed that ICTF significantly increased the co-expression between the microglial marker Iba-1 and CB2 receptor, IL-10, β-endorphin, respectively, but markedly decreased the co-localization between Iba-1 and P2Y12 receptor. Conversely, intrathecal administration of CB2 receptor antagonist AM630 dramatically reversed the inhibitory effects of ICTF on CFA-induced chronic inflammatory pain, leading to a promotion of pain hypersensitivity, abnormal gait parameters, microglial activation, and up-regulation of P2Y12 receptor and NLRP3 inflammasome, as well as the inhibition of CB2 receptor and IL-10/β-endorphin cascade. Taken together, these findings highlighted that ICTF alleviated CFA-induced neuroinflammation by enhancing CB2 receptor-mediated IL-10/β-endorphin signaling and suppressing microglial activation in the spinal cord, and uncovered that CB2 receptor may be exploited as a novel and promising target for ICTF treatment of chronic inflammatory pain.

Surface-modified nanoparticles based on ibuprofen prodrug and exploring its anti-inflammatory and anti-cancer potential

Cancer aggressiveness and metastases represent a major cause of death worldwide. Cyclooxygenase-2 (COX-2), and its metabolites significantly influence the tumor development, and metastatic processes. The design and synthesis of prodrugs intended for nonsteroidal anti-inflammatory drugs (NSAIDs) have garnered considerable attention from medicinal chemists, particularly in the last decade. A pH-sensitive drug delivery carrier based on TEG-derivatized ibuprofen Ibu-TEG was synthesized to serve as a dual-delivery system for anti-inflammatory and anticancer agents. The successful synthesis was confirmed through various spectroscopic techniques. This amphiphilic and biodegradable prodrug was self-assembled into micellar nanoparticles (Ibu-TEG-NPs). Their surface was subsequently modified with biocompatible molecules, chitosan (Ibu-TEG-NPs-CHI), and poly-dopamine (Ibu-TEG-NPs-PDA), to enhance the drug efficacy and thermal stability. As-prepared NPs were characterized through FT-IR, DLS, TGA, AFM, and SEM. These surface-modified NPs were significantly active against ROS and NO generation, and showed a lower IC50 value than ibuprofen. Moreover, Ibu-TEG-NPs, Ibu-TEG-NPs-CHI, and Ibu-TEG-NPs-PDA revealed significant therapeutic activity against lung–NCI–H460, and hepato-HepG2 cancer cell lines, demonstrating low IC50 values.

A Comprehensive Review on the Anti-inflammatory Activity of Chalconesderived Moieties

Background: In recent decades, all-embracing research accounting for thousands of natural bioactive compounds have been detailed on behalf of their origin, pharmacological activity, active phytoconstituents, and therapeutic applications. Chalcones, secondary metabolites have shown therapeutic potential against various forms of inflammation, pain, and cancer in multiple research papers targeting their pathway inhibition and their significant therapeutic activity. Area Covered: Diverse aspects of chalcones have been focused on with their biological source, pathway inhibition, and pharmacological activity. Objectives: This study aims to focus on the chalcones being the origin of ethnopharmacological, possess extensive pharmacological activities, including anti-neoplastic, antimicrobial, anti-inflammatory, antioxidant, anti-acne, anti-aging, hepatoprotective, neuroprotective, psychoactive, anti-parasitic, and many others. Method: Chalcones display anti-inflammatory activity via COX-2, NO synthase, and TNF-α inhibition. Furthermore, comprehensive studies will be discussed with a viewpoint of the chalcones’s role in the alleviation of inflammation. According to recent advancements, chalcones clinically have been used in the treatment of inflammation, anti-aging, oxidative stress reduction, autophagy, and apoptosis. Conclusion: This article focuses on the molecular progression of inflammation and the chalcone role in combating inflammation by targeting inflammatory mediators and pathways.

Spectroscopic and electrochemical investigation of ternary Cu (II) complex interaction with calf thymus DNA

Aiming to design unique metallic drugs with significant therapeutic activity, in this work, mixed ligand Cu (II) complex involving 2,2′‐bipyridine and phenylalanine [Cu (bpy) (phenala.)Cl].2H2O has been fabricated and characterized using IR spectroscopy. The interaction of Cu (II) complex with CT‐DNA molecules was examined through UV–vis absorption titration plots, thermal denaturation experiments, viscosity measurements, and electrochemical studies. Cyclic voltammetry, electrochemical impedance spectroscopy, and chronoamperometry measurements have been exploited to elucidate their binding style. The negative potential shift in ΔE and E1/2 values as well as the increased current density of Cu (II)/Cu(I) redox couple suggested the promoted rate of electron transfer process in presence of CT‐DNA molecules in the examined solution. Some kinetic parameters were also estimated such as the diffusion coefficient, the exchange current density, and Tafel slope values. Based on the results of these binding experiments, a groove and/or electrostatic interaction mode was expected. The antimicrobial activity of the studied Cu (II) complex was screened against a series of bacteria and fungi. An outstanding performance was shown when treating different Gram‐positive and Gram‐negative bacteria types. Moreover, an enhanced cytotoxicity behavior toward some human tumor cell lines, including MCF7, HEPG2, and HFB4, was detected with respective IC50 values of 43.02, 51.21, and >200 μM when incubated with Cu (II) complex for 72 h. These results suggest the application of [Cu (bpy) (phenala.)Cl].2H2O complex as a chemotherapeutic agent with a promising output in the drug discovery field.

Solubility enhancement of extract of Lagenaria siceraria by development of Phospholipon® 90 H modulated phospholipid complex employing Box-Behnken design

In the past decade, plant sterols gained more attention due to their significant therapeutic activity, but their poor solubility and low bioavailability limited their use. Here, we developed and optimized phospholipon® 90H modulated phospholipid (PmP) complex of ethanolic extract of Lagenaria siceraria (EELs) by solvent evaporation using Box-Behnken Design. The optimized PmP complex was then evaluated physico-chemically and functionally by particle size and zeta potential, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR) and apparent solubility studies. Phospholipon® 90 H (1-Oleoyl-2-palmitoyl-phosphatidylcholine) consists of 85% stearic acid and about 15% palmitic acid., with N,N,N-trimethylethanolammonium cation (choline) as a polar head attached to phosphate group acting as an anion, which forms a weaker intermolecular hydrogen bonding with the third hydroxyl group of isolated sterols. This interaction causes the sterols to get incorporated into the phospholipid at the molecular level. Thereby it leads to the formation of PmP-complex, which enhanced chemical stability with improved solubility. The apparent solubility study demonstrated more than 26-fold increase in aqueous solubility of EELs after forming PmP-complex. This complex with enhanced solubility may be formulated into various pharmaceutical dosage forms, and further pharmacological studies may solve the biopharmaceutical aspects related to therapeutic efficacy.

Antiviral lectin Q-Griffithsin suppresses fungal infection in murine models of vaginal candidiasis.

Resistance to antifungal agents in vulvovaginal candidiasis has resulted in increasing morbidity among women globally. It is therefore crucial that new antimycotic agents are developed to counter this rising challenge. Q-Griffithsin (Q-GRFT) is a red algal lectin, manufactured in Nicotiana benthamiana. Griffithsin has well characterized broad spectrum antiviral activity and has demonstrated potent in vitro activity against multiple strains of Candida, including C. albicans. We have been working to incorporate Q-GRFT into topical microbicide products to prevent HIV-1 and HSV-2 transmission. The goal of this study was to evaluate the efficacy of a prototype Q-GRFT dosage form in prophylactic and therapeutic murine models of vaginal candidiasis, through microbiologic, histopathologic, and immune studies. In a preventive model, in comparison with infected controls, Q-GRFT treatment resulted in a lower fungal burden but did not alter the number of vaginal neutrophils and monocytes. In a therapeutic model, Q-GRFT enhanced fungal clearance when compared with infected untreated controls. Finally, histopathology demonstrated lower vaginal colonization with C. albicans following Q-GRFT treatment. Our results demonstrate that Q-GRFT has significant preventive and therapeutic activity in vaginal candidiasis offering additional benefit as a topical microbicide for prevention of HIV-1 and HSV-2 transmission.

Formulation and Comparison of Cobalt and Molybdenum Glucomannan Metallocomplexes

Metallopharmaceutics is regarded as the subject in which drugs are complex with metals like platinum, zinc iron, etc. It is becoming the field of interest in medical sciences including oncology and diabetes. In this study, molybdenum and cobalt are used to prepare the metal complexes using glucomannan as the ligand. Pre-formulation studies performed for the drug proved to be of optimal results, which included angle of repose and swelling index. Stability studies were conducted for a time period of three months. The post-formulation studies including UV analysis and dissolution studies using egg membrane were performed. The drug had a distinct but weak peak at 267 nm. Formulation batch F5 had the best dissolution rate in terms of sustainability. Release kinetic studies showed that F5 (Glucomannan 500 mg + cobalt 1000 mg) had a linearity of 0.997 in the Higuchi diffusion plot. This infers that the plant-based extracts which possess low but significant therapeutic activity can be improved by using metals.

Antibacterial Activity of Aureonuclemycin Produced by Streptomyces aureus Strain SPRI-371.

Actinomycetes play a vital role as one of the most important natural resources for both pharmaceutical and agricultural applications. The actinomycete strain SPRI-371, isolated from soil collected in Jiangsu province, China, was classified as Streptomyces aureus based on its morphological, physiological, biochemical and molecular biological characteristics. Its bacterial activity metabolites were identified as aureonuclemycin (ANM), belonging to adenosine derivatives with the molecular formula C16H19N5O9 for ANM A and C10H13N5O3 for ANM B. Simultaneously, the industrial fermentation process of a mutated S. aureus strain SPRI-371 was optimized in a 20 m3 fermentation tank, featuring a rotation speed of 170 rpm, a pressure of 0.05 MPa, an inoculum age of 36–40 h and a dissolved oxygen level maintained at 1–30% within 40–80 h and at >60% in the later period, resulting in an ANM yield of >3700 mg/L. In the industrial separation of fermentation broth, the sulfuric acid solution was selected to adjust pH and 4# resin was used for adsorption. Then, it was resolved with 20% ethanol solution and concentrated in a vacuum (60–65 °C), with excellent results. Antibacterial experiments showed that ANM was less active or inactive against Xanthomonas oryzae pv. oryzae, Xanthomonas citri subsp. citri and Xanthomonas oryzae pv. oryzicola and most bacteria, yeast and fungi in vitro. However, in vivo experiments showed that ANM exhibited extremely significant protective and therapeutic activity against diseases caused by X. oryzae pv. oryzae and X. oryzae pv. oryzicola in rice and X. citri in oranges and lemons. In field trials, ANM A 150 gai/ha + ANM B 75 gai/ha exhibited excellent therapeutic activity against rice bacterial leaf blight, citrus canker and rice bacterial leaf streak. Furthermore, as the dosage and production cost of ANM are lower than those of commercial drugs, it has good application prospects.

Oral Fast Disintegrating Films of Phytochemicals: A Novel Drug Delivery System

Oral fast disintegrating films (OFDFs) have been developed as a viable alternative to conventional oral solid dosage forms such as tablets, capsules, and syrups for patients who struggle consuming them. OFDFs are thin strips that disintegrate or dissolve rapidly when placed in the oral cavity, allowing quick onset of action. These films are prepared by incorporating active pharmaceutical ingredients with film-forming polymers and other ingredients. OFDFs are also developed by incorporating active constituents present in phytochemicals such as flavonoids and polyphenols. In recent years, researchers have developed OFDFs by incorporating active phytoconstituents and/or herbal extracts to produce significant therapeutic activity. Phytochemical-based OFDFs show pharmacological activities such as anti-inflammatory, antiviral, immunomodulatory, antimigraine, antiarrhythmic, antioxidant and antibacterial. These films can also be used in the management of dementia, cerebral insufficiency and Alzheimer’s disease. The present review focuses on the formulation and development of phytochemical-loaded OFDFs and recent research carried out on the same in tabular form.
 Keywords: Oral fast disintegrating film, phytochemicals, active phytoconstituents, herbal extracts, natural active compounds, oral mucosa, mouth dissolving film

Neoantigen Immunotherapeutic-Gel Combined with TIM-3 Blockade Effectively Restrains Orthotopic Hepatocellular Carcinoma Progression.

Herein, we integrate the Hepa1-6 liver cancer-specific neoantigen, toll-like receptor 9 agonist and stimulator of interferon genes agonist by silk-hydrogel package, and combine with TIM-3 blockade to elicit robust antitumor immunity for effectively suppressing orthotopic hepatocellular carcinoma (HCC) progression. Unlike intradermal injection of simple mixed components with short-term immune protection, the neoantigen immunotherapeutic-gels evoke long-term immune protection to achieve significant prophylactic and therapeutic activity against HCC through only one-shot administration without any side effects. Notably, the synergized immunotherapy by further combining NGC-gels with TIM-3 antibody significantly reduces regulatory T-cells and increases the IFN-γ and IL-12p70 levels in tumor tissues for promoting the infiltration of IFN-γ+CD8+T-cells and 41BB+CD8+T-cells to achieve complete remission (4/7) and prevent pulmonary metastasis in orthotopic HCC, and establish long-term memory against tumor rechallenge with remarkably longer survival time (180 days). Overall, this study provides an attractive and promising synergistic strategy for HCC immunotherapy with possible clinical translation prospects.

EgGLUT1 Is Crucial for the Viability of Echinococcus granulosus sensu stricto Metacestode: A New Therapeutic Target?

Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by infection with the larvae of Echinococcus granulosus sensu lato (s.l.) cluster. It is urgent to identify novel drug targets and develop new drug candidates against CE. Glucose transporter 1 (GLUT1) is mainly responsible for the transmembrane transport of glucose to maintain its constant cellular availability and is a recent research hotspot as a drug target in various diseases. However, the role of GLUT1 in E. granulosus s.l. (EgGLUT1) was unknown. In this study, we cloned a conserved GLUT1 homology gene (named EgGLUT1-ss) from E. granulosus sensu stricto (s.s.) and found EgGLUT1-ss was crucial for glucose uptake and viability by the protoscoleces of E. granulosus s.s. WZB117, a GLUT1 inhibitor, inhibited glucose uptake by E. granulosus s.s. and the viability of the metacestode in vitro. In addition, WZB117 showed significant therapeutic activity in E. granulosus s.s.-infected mice: a 10 mg/kg dose of WZB117 significantly reduced the number and weight of parasite cysts (P < 0.05) as efficiently as the reference drug, albendazole. Our results demonstrate that EgGLUT1-ss is crucial for glucose uptake by the protoscoleces of E. granulosus s.s., and its inhibitor WZB117 has a therapeutic effect on CE.

Antinociceptive activity of standardized extract of Bacopa monnieri in different pain models of zebrafish

Ethnopharmacological relevanceBacopa monnieri L. (Scrophulariaceae) is commonly known as Brahmi and traditionally used as a neuroprotective herbal medicine. Recently, Bacopa monnieri exhibited significant therapeutic activity against animal model of neuropathic pain. However, the therapeutic potential of methanolic extract of Bacopa monnieri in experimental animal model is yet to establish. Aim of the studyThe present study was designed to evaluate the anti-nociceptive potential of standardized methanolic extract of Bacopa monnieri in experimental adult zebrafish (Danio rerio) model of pain. Materials and methodsThe methanolic extract of Bacopa monnieri (BME) was standardized to bacoside-A using chromatographic method. Subsequently, BME (0.75, 1.25 and 5.0 mg/ml) was evaluated for anti-nociceptive activity using adult zebrafish model. ResultsStandardized BME showed antioxidant effect through radical quenching activity in in vitro study. BME at 1.25 mg/ml significantly decreased the nociceptive effect induced by different noxious agents like acetic acid where as BME at 2.5 mg/ml exhibited significant antinociceptive activity against glutamate, formalin, capsaicin, cinnamaldehyde when compared to control and sham group animals. ConclusionBME exerted antinociceptive activity in adult zebrafish. It could be presumed that BME may involve glutamatergic receptor, ASIC and TRP channel activity in its anti-nociceptive effect. BME could be considered as a potential therapeutic option in the management of pain.

Successful Chimeric Antigen Receptor (CAR) T-Cell Treatment in Aggressive Lymphoma Despite Coronavirus Disease 2019 (CoVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication - Case Report

In patients with compromised immune function, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (CoVID-19) impose particular challenges. Especially in hematological malignancies, including lymphoma, the demands by this novel virus disease are further enhanced during sophisticated treatments, such as chimeric antigen receptor (CAR) T-cell therapy. Here, we present the first case of a patient with refractory diffuse-large B-cell lymphoma, who underwent CAR T-cell treatment in the context of SARS-CoV-2. Irrespective of prolonged and active SARS-CoV-2 infection, T cells were successfully isolated by apheresis and processed to anti-CD19 CAR T cells (axicabtagene-ciloleucel). In light of the aggressive lymphoma course, lymphodepleting chemotherapy and CAR-T cells were administered in early recovery after oxygen-dependent CoVID-19 pneumonia. Except for moderate cytokine release, this cellular immunotherapy was well tolerated. Notably, there is no deterioration of the SARS-CoV-2 infection; however, complete lymphoma response and full clinical recovery were observed. In conclusion, CAR T-cell treatment in aggressive lymphoma in the setting of SARS-CoV-2 infection is feasible and may offer significant therapeutic activity in refractory disease.

Hedgehog Pathway Mutations Drive Oncogenic Transformation in High-Risk T-Cell Acute Lymphoblastic Leukemia

Despite recent advances in improving outcome for patients with T-cell acute lymphoblastic leukemia (T-ALL), those who relapse or who have resistant disease are in urgent need of new therapeutic approaches. Recently, mutations in the Hedgehog pathway have been described in T-ALL, but the role of Hedgehog signaling in normal and malignant T-cell development is controversial, and whether these mutations are prognostic or drive oncogenic transformation is unknown, hindering the rationale for therapeutic intervention.Through targeted next generation sequencing on a cohort of 109 diagnostic lymphoblast specimens from children with newly diagnosed T-ALL enrolled on contemporary clinical trials (DFCI 05-001 and COG AALL0434), we identified mutations in the Hedgehog pathway in 16% of patients (n = 17/109); PTCH1, the major negative regulator of the pathway, was the most frequently mutated Hedgehog pathway gene with 8% of patients harboring heterozygous missense mutations (n = 9/109). Remission bone marrow samples were evaluable by Sanger sequencing for 5 of the 9 PTCH1 mutations, and revealed that 3 of these mutations were absent at remission, indicating a somatic origin, whereas, 2 of these mutations were detected at remission, suggestive of either an underlying cancer predisposition syndrome, or somatic mutations associated with clonal hematopoiesis. Hedgehog pathway mutations predicted resistance to induction chemotherapy, as defined by ≥ 5% residual lymphoblasts in the bone marrow by morphology or flow cytometry (P= 0.009).To investigate the role of Hedgehog signaling in T-ALL, we focused on PTCH1 because this was the most commonly mutated Hedgehog gene identified. Transduction of wild-type PTCH1 into a PTCH1 -mutant T-ALL cell line downregulated Hedgehog pathway activity, impaired viability (P < 0.001), and induced apoptosis (P= 0.005). The effect on both viability and apoptosis was reversed by downstream Hedgehog pathway activation using a small molecule Smoothened agonist (P < 0.001 and P= 0.007, respectively), indicating on-target toxicity. Most of the PTCH1 mutations identified in human T-ALL were significantly less toxic than wild-type PTCH1 when transduced into PTCH1 -mutant T-ALL cells, indicating these encode functionally defective alleles.To test whether PTCH1 mutations accelerate the onset of T-ALL in vivo, we turned to a CRISPR/Cas9 system for tissue-specific gene disruption in transgenic zebrafish. We first identified guide RNAs that effectively mutagenized zebrafish ptch1, or the locus syntenic to the human AAVS1 safe-harbor locus as a negative control. Guide RNAs were cloned into a vector that drives ubiquitous expression of the guide RNA, together with lineage-restricted expression of a Cas9-T2A-GFP self-cleaving protein under the control of the zebrafish rag2 promoter. Using this model, we found that inducing ptch1 mutations in thymocytesaccelerated the onset of notch1- induced T-ALL, with a median time to T-ALL onset of 12.3 weeks in the ptch1 -mutant group versus median not reached for the aavs1 -control group (P= 0.0004). These ptch1 -mutant leukemias were transplantable into irradiated wild-type recipients, and subsequent treatment of these animals with the Hedgehog pathway inhibitor cyclopamine had significant therapeutic activity (P= 0.002).In conclusion, our findings indicate that Hedgehog-activating mutations are associated with resistance to induction chemotherapy and drive oncogenic transformation in high-risk T-ALL. Together, these findings provide a molecular rationale for targeted therapy with Hedgehog pathway inhibitors for patients with PTCH1 -mutant high-risk T-ALL. DisclosuresNeuberg:Synta Pharmaceuticals: Other: Stock shares. Hunger:Jazz Pharmaceuticals: Honoraria; Novartis: Consultancy; Amgen: Consultancy, Equity Ownership; Erytech Pharmaceuticals: Consultancy.

Thymoquinone Loaded Topical Nanoemulgel for Wound Healing: Formulation Design and In-Vivo Evaluation.

Thymoquinone is a natural bioactive with significant therapeutic activity against multiple ailments including wound healing. The poor aqueous solubility and low skin permeability limit its therapeutic efficacy. The present investigation aimed to improve the biopharmaceutical attributes of thymoquinone to enhance its topical efficacy in wound healing. A nanoemulsion-based hydrogel system was designed and characterized as a nanotechnology-mediated drug delivery approach to improve the therapeutic efficacy of thymoquinone, utilizing a high-energy emulsification technique. The black seed oil, as a natural home of thymoquinone, was utilized to improve the drug loading capacity of the developed nanoemulsion system and reduced the oil droplet size to <100 nm through ultrasonication. The influence of formulation composition, and the ultrasonication process conditions, were investigated on the mean globule size and polydispersity index of the generated nanoemulsion. Irrespective of surfactant/co-surfactant ratio and % concentration of surfactant/co-surfactant mixture, the ultrasonication time had a significant (p < 0.05) influence on the mean droplet size and polydispersity index of the generated nanoemulsion. The developed nanoemulgel system of thymoquinone demonstrated the pseudoplastic behavior with thixotropic properties, and this behavior is desirable for topical application. The nanoemulgel system of thymoquinone exhibited significant enhancement (p < 0.05) in skin penetrability and deposition characteristics after topical administration compared to the conventional hydrogel system. The developed nanoemulgel system of thymoquinone exhibited quicker and early healing in wounded Wistar rats compared to the conventional hydrogel of thymoquinone, while showing comparable healing efficacy with respect to marketed silver sulfadiazine (1%) cream. Furthermore, histopathology analysis of animals treated with a developed formulation system demonstrated the formation of the thick epidermal layer, papillary dermis along with the presence of extensive and organized collagen fibers in newly healed tissues. The outcome of this investigation signifies that topical delivery of thymoquinone through nanoemulgel system is a promising candidate which accelerates the process of wound healing in preclinical study.

New Potential Antitumor Pyrimidine Derivatives: Synthesis and Cytotoxicity Evaluation

A new series of pyrimidine derivatives are reported here as antitumor agents such as pyrimidine carboxamide linked to thiophene, pyrazole, and thiazole moieties have been synthesized from the readily available (2-cyano-N-(5-cyano-2-phenyl-6-arylpyrimidin-4-yl)acetamide (6a,b). All the new compounds were screened for their antitumor activity in vitro against a panel of three human tumor cell lines namely, hepatocellular carcinoma (liver) HepG2, colon cancer HCT-116, and mammary gland breast MCF-7. Compounds 9b, 10b, 11b, and 19b displayed a significant therapeutic activity. All the synthesized new compounds were established their structures by means of spectroscopic analysis.

Chitosan-coated poly(є-caprolactone) nanocapsules for mucoadhesive applications of perillyl alcohol

ABSTRACT Perillyl alcohol (POH) is an essential oil found in several plants and presents significant therapeutic and chemo-preventive activity against some tumors. However, it exhibits low aqueous solubility and thereby reduced oral absorption and bioavailability. Nanoencapsulation of POH can be an important tool to overcome such limitations. In this work, chitosan was used for coating poly (ε-caprolactone) nanocapsules for mucoadhesive applications of POH. The nanocapsules were obtained by the nanoprecipitation method and presented a mean diameter of about 330 nm, spherical morphology, polydispersity index of 0.14, zeta potential of +32 mV, and POH encapsulation efficiency of 56%. POH was prolonged released from nanocapsules. In mucoadhesion studies, nanocapsules showed higher adsorption to mucin compared to free POH, possibly due to electrostatic interactions between chitosan and mucin. In the cytotoxicity assay, POH-loaded nanocapsules presented higher IC50 than free POH; however, they were more selective for HT-29 tumor cells than for normal Vero cells. The results demonstrate the potential application of chitosan-coated nanocapsules for the oral administration of POH intended for cancer therapy.

Development and characterization of a novel flavopiridol formulation for treatment of acute myeloid leukemia

For more than 30 years, treatment of acute myeloid leukemia (AML) has remained largely unchanged and reliant on chemotherapeutic drug combinations, specifically cytarabine and daunorubicin (the 7 + 3 regimen). One broad spectrum drug, flavopiridol (also known as Alvocidib) has shown significant activity against AML through the inhibition of cyclin-dependent kinases. Flavopiridol is a semisynthetic flavonoid and our research team recently described methods to formulate another flavonoid, quercetin, through the ability of flavonoids to bind divalent metals. This method relies on use of copper-containing liposomes to enhance the apparent solubility of flavopiridol and to create formulations suitable for intravenous (i.v.) use. Similar to quercetin, flavopiridol is defined as an aqueous-insoluble compound (< 1 mg/mL in water) and this research sought to evaluate whether the copper-binding capabilities of flavopiridol could be used to prepare an injectable formulation that would exhibit enhanced exposure and improved efficacy. Flavopiridol powder was added directly to preformed copper-containing liposomes (DSPC:Chol or DSPC:DSPE-PEG2000) and the resulting formulations were characterized. Pharmacokinetic and efficacy studies were then conducted. The liposomal flavopiridol formulations were well-tolerated in mice following i.v. administration at a dose of 5 mg/kg with no apparent acute or chronic toxicities. In vivo pharmacokinetics of the optimized DSPC/DSPE-PEG2000 liposomal flavopiridol formulation demonstrated a 30-fold increase in AUC (0.804 μg-hr/mL versus 26.92 μg-hr/mL) compared to the free flavopiridol formulation. The resultant liposomal formulation also demonstrated significant therapeutic activity in MV4–11 and MOLM-13 subcutaneous AML models. Additional studies will be required to define whether formulation changes can be made to enhance flavopiridol retention in the selected composition. The results suggest that further increases in flavopiridol retention will result in improved therapeutic activity.

Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway

HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.

Use of Medicinal Plants for Respiratory Diseases in Bahawalpur, Pakistan.

The most common ethnomedicinal plants being effective in respiratory disorders were studied for the first time in Bahawalpur District. The herbal medication represents a low-cost treatment for the local community. There is a need for documenting the traditional uses of plants for further investigation of bioactive compounds. Using a qualitative approach, the ethnobotanical data was collected from the district of Bahawalpur, Pakistan, from February 2018 to February 2020 through semistructured interviews with the local people and traditional healers. The quantitative analysis included use value, informant consensus factor, family importance value, and relative frequency citation. A total of 20 indigenous plants belonging to 17 families were documented from 185 informants. These plants were claimed to be used for the treatment of 10 respiratory ailments. The plant habit, part of the plant used, and mode of preparation were standardized for authentication. The herbs are the most used life form (55%), while trees and shrubs are also used. Leaves dominate with high use value (47.62%) followed by fruit, stem, flower, and other parts of plants. For the preparation of traditional remedies, decoction (76.19%) and extract (71.43%) are common preparation methods. However, other methods of paste infusion, powder juice, and ash are used to a lower extent. The plants with higher use value are Glycyrrhiza glabra, Acacia arabica, and Mentha piperita; these have significant potential therapeutic activity for respiratory disease. The ethnomedicinal importance of plants against respiratory diseases used by the local population (traditional healers) is the commercial availability of the herbal product. It is a first-time study in this area to fill the gap between traditional practices and synthetic medicine to screen out the phytochemical and pharmacological properties of plants that have a highly futuristic use value to develop antibiotic drug with least side effects by using sustainable methods.