Targeted anti-cancer therapy: Co-delivery of VEGF siRNA and Phenethyl isothiocyanate (PEITC) via cRGD-modified lipid nanoparticles for enhanced anti-angiogenic efficacy

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvβ3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.

Metabologenomics and network pharmacology to understand the molecular mechanism of cancer research

In this editorial I comment on the article“Network pharmacological and molecular docking study of the effect of Liu-Wei-Bu-Qi capsule on lung cancer”published in the recent issue of the World Journal of Clinical Cases 2023 November 6;11(31):7593-7609.Almost all living forms are able to manufacture particular chemicals-metabolites that enable them to differentiate themselves from one another and to overcome the unique obstacles they encounter in their natural habitats.Numerous methods for chemical warfare,communication,nutrition acquisition,and stress prevention are made possible by these specialized metabolites.Metabolomics is a popular technique for collecting direct mea-surements of metabolic activity from many biological systems.However,con-fusing metabolite identification is a typical issue,and biochemical interpretation is frequently constrained by imprecise and erroneous genome-based estimates of enzyme activity.Metabolite annotation and gene integration uses a biochemical reaction network to obtain a metabolite-gene association so called metabologe-nomics.This network uses an approach that emphasizes metabolite-gene consensus via biochemical processes.Combining metabolomics and genomics data is beneficial.Furthermore,computer networking proposes that using meta-bolomics data may improve annotations in sequenced species and provide testable hypotheses for specific biochemical processes.CONCLUSION The genome and metabolites of biological organisms are not fully characterized with current technologies.However,increasing high-throughput metabolomics and genomics data provide promising generation of paired data sets to understand the molecular mechanism of biochemical processes as well as determining targets for pharmaceutical drug design.Contemporary network infrastructures to integrate omics analysis can provide molecular mechanism of biochemical pathways.Furthermore,clinical data may be integrated to gene expression–metabolite expression by system genetics approach.Calculating pair-wise correlations and weighted correlation network analysis provide the basis of this integration[11-13].The occurrence of strong correlations between classified metabolites and co-expression transcripts implies either various roles of metabolites or linkages between metabolic pathways and the immune system.

Fhyroid hormone controls the gene expression of HSV-1 .AT and ICPO in neuronal cells

Various factors/pathways including hormonal regulation have been suggested to control herpes simplex virus type 1 （HSV-1） latency and reactivation. Our computer analysis identified a DNA repeat containing thyroid hormoneresponsive elements （TRE） in the regulatory region of HSV-1 latency-associated transcript （LAT）. Thyroid hormone （triiodothyronine, T3） functions via its receptor TR （thyroid hormone receptor）, a transcription factor. Present study investigated the roles of TR and T3 in HSV-1 gene expression using cultured neuoroblastoma cell lines. We demonstrated that liganded TR activated LAT transcription, but repressed infected cell protein no. 0 （ICP0） transcription in the presence of LAT TRE. Chromatin immunoprecipitation （CHIP） assays showed that TRs were recruited to LAT TREs independently of T3 and hyperacetylated H4 was associated with the LAT promoter that was transcriptionally active. In addition, ChIP results showed that the chromatin insulator protein CCCTC-binding factor was enriched at the LAT TREs in the presence of TR and T3. In addition, the BRG1 chromatin remodeling complex is found to participate in the T3/TR-mediated LAT activation since overexpression of BRG1 enhanced the LAT transcription and the dominant-negative mutant K785R abolished the activation. This is the first report revealing that TR elicits epigenetic regulation on HSV-1 ICP0 expression in neuronal cells and could have a role in the complex processes of HSV-1 latency/reactivation.

Advance in bioequivalence assessment of topica dermatological products

Bioequivalence(BE) assessment of topical dermatological products is a long standing challenge. The development of generic topical dermatological products has often been hampered due to the limited number of acceptable approaches, which are capable of determining the BE between generic products and reference list products. The aim of this manuscript is to review different BE assessment approaches of topical dermatological products. Besides, the advances in BE evaluation and biowaivers are also provided. Currently, except in the case of dermatological corticosteroids, the golden rule to establish the BE of most topical dermatological products still heavily relied on clinical endpoint trials,which are often unreliable, time-consuming and expensive. The regulatory agencies and pharmaceutical industries are forging ahead to the development of new surrogate BE assessment approaches for other topical dermatological products. These promising approaches include dermatopharmacokinetic study(DPK), dermal microdialysis(DMD), in vitro studies, pharmacokinetic study(PK), near-infrared spectrometry(NIR), and confocal Raman spectroscopy(CRS). In addition, the expansion of biowaivers for topical dermatological products has been explored by pharmaceutical scientists. In conclusion, to accelerate the development and approval of topical dermatological products, emphasis should be put on the following areas, i.e., optimizing and standardizing the existing BE assessment methods, exploring novel alternatives of BE assessment approaches, and expanding biowaivers for topical dermatological products.

Molecular weight determination of a newly synthesized guanidinylated disulfide-containing poly(amido amine) by gel permeation chromatography

A cationic gene delivery vector, guanidinylated disulfide-containing poly(amido amine)(CARCBA), was synthesized by Michael addition reaction between N,N′-cystaminebisacrylamide(CBA) and guanidine hydrochloride(CAR). Gel permeation chromatography(GPC) was used to evaluate the molecular weight of synthesized CAR-CBA. Polyethyleneimine(PEI) with molecular weight of 25 kDa was adopted as a reference, and polyethylene glycols(PEG) with different molecular weights were used to establish a standard curve for determining the molecular weight of CAR-CBA. The effects of two critical factors, namely columns and eluents,on the molecular weight measurement of CAR-CBA were investigated to optimize the GPC quantitative method. The results showed that Ultrahydrogel columns(120, 250) and HAc–NaAc(0.5 M, pH 4.5) buffer solution were the optimal column and GPC eluent, respectively.The molecular weight of the synthesized CAR-CBA was analyzed by the optimized GPC method and determined to be 24.66 kDa.

Phenolic compounds affect production of pyocyanin, swarming motility and biofilm formation of Pseudomonas aeruginosa

Objective: To investigate the effects of plant-derived phenolic compounds(i.e. caffeic acid, cinnamic acid, ferulic acid and vanillic acid) on the production of quorum sensing regulated virulence factors such as pyocyanin, biofilm formation and swarming motility of Pseudomonas aeruginosa(P. aeruginosa) isolates.Methods: Fourteen clinical P. aeruginosa isolates obtained from urine samples and P. aeruginosa PA01 strain were included in the study. The antibacterial effects of phenolic compounds were screened by well diffusion assay. Pyocyanin and biofilm activity were measured from culture supernatants and the absorbance values were measured using a spectrophotometer. Swarming plates supplemented with phenolic acids were point inoculated with P. aeruginosa strains and the ability to swarm was determined by measuring the distance of swarming from the central inoculation site.Results: Tested phenolic compounds reduced the production of pyocyanin and biofilm formation without affecting growth compared to untreated cultures. Moreover, these compounds blocked about 50% of biofilm production and swarming motility in P. aeruginosa isolates.Conclusions: We may suggest that if swarming and consecutive biofilm formation could be inhibited by the natural products as shown in our study, the bacteria could not attach to the surfaces and produce chronic infections. Antimicrobials and natural products could be combined and the dosage of antimicrobials could be reduced to overcome antimicrobial resistance and drug side effects.

Determination of Elements by Atomic Absorption Spectrometry in Medicinal Plants Employed to Alleviate Common Cold Symptoms

Eleven important medicinal plants generally used by the people of Turkey for the treatment of common cold have been studied for their mineral contents.Eleven minor and major elements(essential,non-essential and toxic)were identified in the Asplenium adiantum-nigrum L.,Althaea officinalis L.,Verbascum phlomoides L.,Euphorbia chamaesyce L.,Zizyphus jujube Miller,Peganum harmala L.,Arum dioscoridis Sm.,Sambucus nigra L.,Piper longum L.,Tussilago farfara L.and Elettaria cardamomum Maton by employing flame atomic absorption and emission spectrometry and electro-thermal atomic absorption spectrometry.Microwave digestion procedure for total concentration was applied under optimized conditions for dissolution of medicinal plants.Plant based biological certified reference materials(CRMs)served as standards for quantification.These elements are found to be present in varying concentrations in the studied plants.The baseline data presented in this work can be used in understanding the role of essential,non-essential and toxic elements in nutritive,preventive and therapeutic properties of medicinal plants.

Intracellular distribution and internalization pathways of guanidinylated bioresponsive poly(amido amine)s in gene delivery

Guanidinylated bioresponsive poly(amido amine)s polymers, CAR-CBA and CHL-CBA, weresynthesized by Michael-type addition reaction between guanidine hydrochloride(CAR) orchlorhexidine(CHL) and N,N-cystaminebisacrylamide(CBA). Previous studies have shownthat both polymers had high transfection efficiencies as gene delivery carriers. In this study,we investigated the nucleolus localization abilities and cellular internalization pathways ofthese two polymers in gene delivery. Each polymer condensed plasmid DNA(p DNA) andformed nanoparticle complexes, and then their transfection studies were performed inMCF-7 cells. Both complexes were found enriched in nucleolus after cellular transfection,and their transfection efficiencies were significantly improved when transfection was per-formed on MCF-7 cells arrested at M phase. The transfection efficiency of CAR-CBA-pDNAwas inhibited by chlorpromazine, and cell endosomes were disrupted after being exposedto CAR-CBA-pDNA. In regards to CHL-CBA-pDNA, its transfection efficiency was not affected by three types of endocytosis inhibitors used in the study, and CHL-CBA-pDNA showed no effect on endosomes. Cellular lactate dehydrogenase release and membrane morphology were changed after cells were transfected by the two complexes. The results indicated that both CAR-CBA and CHL-CBA polymers demonstrated good nucleolus localization abilities. It was beneficial for transfection when cells were arrested at M phase. CAR-CBA-pDNA cellular internalization was involved with clathrin-mediated endocytosis pathway, and escaping from endosomal entrapment, while the cellular uptake of CHL-CBA-pDNA occurs via clathrin-and caveolae-independent mechanism.

A simple method to improve the dissolution of repaglinide and exploration of its mechanism

In the present study,a simple and rapid method was developed to improve the in vitro dissolution of repaglinide,an oral antidiabetic drug,which was based on addition of meglumine in 50%(v/v)ethanol to dissolve repaglinide,and the drug dissolved in meglumine/50%ethanol was used directly with a binder to prepare tablets.The mechanism of solubilization of repaglinide by meglumine was studied by using infrared spectrum(IR),ultraviolet(UV)measurement through dual wavelength,differential scanning calorimetry(DSC)and X-ray powder diffraction methods.Dissolution tests of repaglinide tablets were performed in the media with different pH values and the repaglinide concentrations were analyzed by High Performance Liquid Chromatography(HPLC)method.The solubility data showed that with the meglumine concentration increasing,the solubility of repaglinide was increased.Meanwhile,tablets with the molar ratio of repaglinide and meglumine 1:2(n/n)resulted in a significant increase in dissolution compared to the repaglinide tablets without using meglumine,and nearly equal to the commercial preparations of Novo-Norm^(®),which concluded that meglumine had a great role in promoting the dissolution of repaglinide.The results of IR and UV dual wavelength methods suggested the formation of repaglinideemeglumine(REPeMEG)molecular complex.DSC results showed that the melting peak of repaglinide disappeared in the REPeMEG coprecipitate,which indicated that repaglinide was stable when existing at amorphous or molecular state.The experiment of X-ray powder diffraction showed that with the solubilization of meglumine,the crystal diffraction peak of repaglinide disappeared,which further inferred that repaglinide was formed complexes with meglumine.It was demonstrated that the method of improving repaglinide with meglumine was reliable and could be suitable for repaglinide tablets production in industry.This study also provides a feasible way to enhance the dissolution of drugs with low solubility,which will be leading to improved bioavailability of these drugs.

Exosome-based small RNA delivery:Progress and prospects

RNA interfering(RNAi), mediated by small interfering RNAs and microRNAs, is currently one of the most promising tools of gene therapy. Small RNAs are capable of inducing specific post-transcriptional gene silencing, providing a potentially effective platform for the treatment of a wide array of diseases. However, similar to other nucleic acid-based drugs,the major hurdle of RNAi therapy is lack of efficient and non-immunogenic delivery vehicles. Currently, viruses, synthetic polymers, and lipid-based carriers are among the most widely studied vehicles for small RNA delivery. However, many drawbacks are reported to be associated with these delivery vehicles. There is a pressing need to replace them with more efficient and better-tolerated approaches. Exosomes secreted from the endocytic compartment of live cells, are a subtype of endogenous extracellular vesicles that transfer genetic and biochemical information among different cells, thus playing an important role in cellcell communication. Recently, accumulating attention has been focused on harnessing exosomes as nanaocarriers for small RNAs delivery. Due to their natural role in shuttling endogenous nucleic acid in our body, exosomes may exhibit higher delivery efficiency, lower immunogenicity, and better compatibility than existing foreign RNA carriers. Importantly,exosomes own intrinsic homing capacity that can guide small RNAs across natural membranous barriers. Moreover, such a capacity can be further improved by adding appropriate targeting moieties. In this manuscript, we briefly review the progress and challenges of RNAi therapy, and discuss the potential of exosomes' applications in small RNA delivery with focus on the most recent advances in exosome-based small RNA delivery for disease therapy.

ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 10(ABCC1O) are not primary resistance factors for cabazitaxel

Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.

Early Growth Response gene 1 (Egr-1) regulates HSV-1 ICP4 and ICP22 gene expression

The molecular mechanisms mediating herpes simplex virus type 1 （HSV- 1） gene silencing during latent infection are not clear. Five copies of early growth response gene 1 （Egr-1） binding elements were identified in the intron of HSVol ICP22 （infected cell protein No. 22） gene, leading to the hypothesis that Egro 1 binds to the viral genome and regulates the viral gene expression. Transient co-transfection assays indicated that Egr-1 negatively regulated the transcription of both full-length and intron-removed ICP22 promoters. The same assays also revealed that Egr-1 repressed ICP4 （infected cell protein No. 4） promoter activity in a dose-dependent manner but showed less inhibition when the intron was removed. Histone deacetylation was not involved in this regulation since histone deacetylase inhibitor trichostatin A did not exhibit any effect on Egr-l-mediated repression. Chromatin immunoprecipitation assays showed that Egr-1 reduced the binding of Spl to the promoters and that the co-repressor Nab2 （NGFI-A/EGRl-binding protein） was recruited to the proximity of ICP4 in the presence of Egr-1. These results suggested that the multi functional transcription factor Egr-1 can repress HSV-1 immediate-early gene expression through the recruitment ofco-repressor Nab2 and reduction of Sp 1 occupancy, and thus may play a critical role in HSV-1 gene silencing during latency.

Liquisolid technique and its applications in pharmaceutics

Most of the newly developed drug candidates are lipophilic and poorly water-soluble. Enhancing the dissolution and bioavailability of these drugs is a major challenge for the pharmaceutical industry. Liquisolid technique, which is based on the conversion of the drug in liquid state into an apparently dry, non-adherent, free flowing and compressible powder,is a novel and advanced approach to tackle the issue. The objective of this article is to present an overview of liquisolid technique and summarize the progress of its applications in pharmaceutics. Low cost, simple processing and great potentials in industrial production are main advantages of this approach. In addition to the enhancement of dissolution rate of poorly water-soluble drugs, this technique is also a fairly new technique to effectively retard drug release. Furthermore, liquisolid technique has been investigated as a tool to minimize the effect of pH variation on drug release and as a promising alternative to conventional coating for the improvement of drug photostability in solid dosage forms. Overall, liquisolid technique is a newly developed and promising tool for enhancing drug dissolution and sustaining drug release, and its potential applications in pharmaceutics are still being broadened.

Phytocompounds and lipid-based drug delivery system for neurodegenerative diseases

Across the annals of time,organic molecules sourced from nature have found innumerable uses within the realms of healthcare,pharmaceuticals,and the study of living organisms.This abundant source of natural compounds has exhibited immense promise in the cure of diverse ailments,mainly neurodegenerative diseases owing to their minimum toxic and adverse effects.However,different challenges exist with phytocompounds from plants such as poor permeation,poor solubility(water/lipid),unsteadiness under extremely acidic pH conditions,and lack of targeting specificity.Furthermore,as a result of the existence of blood-brain barrier membrane and inconvenient pharmacokinetics characteristics of phytocompounds,their passage into the brain is constrained.In order to address this issue and augment the transportation of medications into the brain at a therapeutically effective level,it is imperative to formulate an innovative and pragmatic strategy.Many papers have shown that nanoformulations containing phytocompounds(resveratrol,quercetin,ferulic acid,curcumin,berberine,etc.)effectively improved many neurodegenerative diseases such as Parkinson’s,Alzheimer’s and Huntington’s diseases.This study provides an overview of phytocompounds that are used in nanosized lipid drug delivery systems.These systems are categorized according to lipid types and preparation techniques used in the formulation.Some studies regarding these systems and phytocompounds are also summarized.

Single low-dose lipopolysaccharide preconditioning:neuroprotective against axonal injury and modulates glial cells

Aim:Over 7 million traumatic brain injuries (TBI) are reported each year in the United States.However,treatments and neuroprotection following TBI are limited because secondary injury cascades are poorly understood.Lipopolysaccharide (LPS) administration before controlled cortical impact can contribute to neuroprotection.However,the underlying mechanisms and whether LPS preconditioning confers neuroprotection against closed-head injuries remains unclear.Methods:The authors hypothesized that preconditioning with a low dose of LPS (0.2 mg/kg) would regulate glial reactivity and protect against diffuse axonal injury induced by weight drop.LPS was administered 7 days prior to TBI.LPS administration reduced locomotion,which recovered completely by time of injury.Results:LPS preconditioning significantly reduced the post-injury gliosis response near the corpus callosum,possibly by downregulating the oncostatin M receptor.These novel findings demonstrate a protective role of LPS preconditioning against diffuse axonal injury.LPS preconditioning successfully prevented neurodegeneration near the corpus callosum,as measured by fluorojade B.Conclusion:Further work is required to elucidate whether LPS preconditioning confers long-term protection against behavioral deficits and to elucidate the biochemical mechanisms responsible for LPS-induced neuroprotective effects.

Tailored nanocarriers and bioconjugates for combating glioblastoma and other brain tumors

Worldwide,the incidence of primary brain tumors is on the rise.Unfortunately,noninvasive drug therapy is hampered by poor access of most drugs to the brain due to the insurmountable blood-brain barrier(BBB).Nanotechnology holds great promise for noninvasive therapy of severe brain diseases.Furthermore,recent bioconjugation strategies have enabled the invasion of the BBB via tailored-designed bioconjugates either with targeting moieties or alterations in the physicochemical and/or the pharmacokinetic parameters of central nervous system(CNS)active pharmaceutical ingredients.Multifunctional systems and new entities are being developed to target brain cells and tumor cells to resist the progression of brain tumors.Direct conjugation of an FDA-approved drug with a targeting moiety,diagnostic moiety,or pharmacokinetic-modifying moiety represents another current approach in combating brain tumors and metastases.Finally,genetic engineering,stem cells,and vaccinations are innovative nontraditional approaches described in different patents for the management of brain tumors and metastases.This review summarizes the recent technologies and patent applications in the past five years for the noninvasive treatment of glioblastoma and other brain tumors.Till now,there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases.Intensive research efforts are ongoing to bring novel CNS delivery systems to potential clinical application.