Efficacy of Dequalinium Chloride vs Metronidazole for the Treatment of Bacterial Vaginosis: A Randomized Clinical Trial.

Importance: Bacterial vaginosis (BV) is a common cause of vaginal infection. First-line treatments of BV are metronidazole and clindamycin. Due to the increase in antibiotic resistance, effective nonantibiotic treatments for BV are needed. Objective: To examine whether dequalinium chloride, a broad-spectrum antiseptic, is noninferior to oral metronidazole for the treatment of BV. Design, Setting, and Participants: This phase 4, multicenter, triple-blind, double-dummy, parallel, noninferiority randomized clinical trial was conducted from July 29, 2021, to August 25, 2022, with a 1-month follow-up. Participants were premenopausal women 18 years or older with BV from 11 gynecologic practices and 1 hospital in Poland, Slovakia, and the Czech. Intervention: Patients were randomized to treatment with dequalinium chloride vaginal tablets (10 mg once daily for 6 days) or oral metronidazole (500 mg twice daily for 7 days). Double-dummy medication kits contained vaginal and oral tablets with placebo and active medication. Main Outcomes and Measures: The main outcome was the noninferiority margin (of 15 percentage points) in the absolute difference in clinical cure rates between dequalinium chloride and metronidazole 7 to 11 days after start of treatment (visit 1). Noninferiority was met if the lower 95% CI for the difference in clinical cure rate was less than 15 percentage points at visit 1. Results: A total of 147 women (mean [SD] age, 36.7 [9.0] years) were treated with dequalinium chloride (n = 72) or metronidazole (n = 75). The clinical cure rates at visit 1 were 64 of 69 (92.8%) for dequalinium chloride vs 69 of 74 (93.2%) for metronidazole in the intention-to-treat population, whereas in the per-protocol population, cure rates were 54 of 58 (93.1%) for dequalinium chloride vs 48 of 53 (90.6%) for metronidazole. The treatment differences of -0.5 percentage points (95% CI, -10.8 to 9.8 percentage points; P = .002) in the intention-to-treat population and 2.5 percentage points (95% CI, -9.4 to 14.4 percentage points; P = .001) in the per-protocol population confirmed the noninferiority of dequalinium chloride. The tolerability of dequalinium chloride was rated as very good by 30 of 50 patients (60.0%) but only by 21 of 54 (38.9%) for metronidazole. Three patients in the metronidazole group suspended treatment due to an adverse event. Conclusions and Relevance: This randomized clinical trial showed that dequalinium chloride was not inferior to metronidazole for the treatment of BV. Dequalinium chloride had a similarly high cure rate but with better tolerability and fewer adverse events. With a similar efficacy to metronidazole and clindamycin, dequalinium chloride warrants consideration as first-line treatment for BV to help reduce antibiotic consumption. Trial Registration: EudraCT: 2020-002489-15.

Dequalinium Chloride for the Treatment of Vulvovaginal Infections: A Systematic Review and Meta-Analysis.

OBJECTIVE/PURPOSE: Women at reproductive age frequently experience vulvovaginal infections and vaginitis. The most common etiologies are vulvovaginal candidiasis (VVC), bacterial vaginosis (BV), desquamative inflammatory vaginitis/aerobic vaginitis, and trichomoniasis. Various treatment options are available for these infections, such as specific antimicrobial or antiseptic agents. Dequalinium chloride (DQC) is a local antiseptic agent with a broad antimicrobial and antifungal spectrum. Multiple studies suggest that DQC is an efficient treatment for vaginal infections; however, it is not widely recommended as a first-line treatment. This systematic review and meta-analysis aims to evaluate the efficacy of DQC compared with that of standard treatment. METHODS: Our systematic review was conducted according to the PRISMA guidelines. PubMed/MEDLINE, EMBASE, CENTRAL, and clinicaltrials.org were searched to retrieve relevant reports up to October 2022. RESULTS: Four randomized controlled studies and 1 observational study were included in this review. Overall, DQC showed noninferiority to the reference treatments for BV and VVC, and to the evaluated treatment options for desquamative inflammatory vaginitis/aerobic vaginitis. For BV and VVC, this could also be confirmed in a meta-analysis including 3 randomized controlled studies. No serious adverse events were reported in any of these studies. CONCLUSIONS: Dequalinium chloride offers a safe, well-tolerated, and efficient treatment option for vulvovaginal infections of different etiologies. However, further studies are needed to confirm our findings and allow inclusion of DQC as a first-line treatment into guidelines.

COMPARISON OF THE IMPACT OF ANTISEPTIC AGENTS ON GARDNERELLA VAGINALIS AND ATOPOBIUM VAGINAE DETECTED IN THE ORAL CAVITY OF WOMEN WITH BACTERIAL VAGINOSIS.

When women with comorbid bacterial vaginosis visit periodontologist, it is essential to understand the presence of cross-infection processes between the oral cavity and vagina in this particular category of subjects. Conducting detection of Gardnerella vaginalis and Atopobium vaginae, which are provocative microbial factors for bacterial vaginosis, is a mandatory step in the laboratory examination of subjects. When choosing an antiseptic for oral cavity disinfection, the use of 0.25% dequalinium chloride is more advisable. Both subjective and objective examination methods thoroughly demonstrate the higher clinical effectiveness of 0.25% dequalinium chloride: patients report a 20% more frequent improvement in subjective indicators, the index assessment of periodontal status improves by 1.2-1.6 times, and the detection rate of Gardnerella vaginalis and Atopobium vaginae is by 20% lower compared to 0.2% chlorhexidine. The specific composition of oral microbiota in this group of subjects necessitates adjustments to treatment protocols and consideration of the specific impact on Gardnerella vaginalis and Atopobium vaginae.

Tackling antibiotic resistance by inducing transient and robust collateral sensitivity.

Collateral sensitivity (CS) is an evolutionary trade-off traditionally linked to the mutational acquisition of antibiotic resistance (AR). However, AR can be temporally induced, and the possibility that this causes transient, non-inherited CS, has not been addressed. Mutational acquisition of ciprofloxacin resistance leads to robust CS to tobramycin in pre-existing antibiotic-resistant mutants of Pseudomonas aeruginosa. Further, the strength of this phenotype is higher when nfxB mutants, over-producing the efflux pump MexCD-OprJ, are selected. Here, we induce transient nfxB-mediated ciprofloxacin resistance by using the antiseptic dequalinium chloride. Notably, non-inherited induction of AR renders transient tobramycin CS in the analyzed antibiotic-resistant mutants and clinical isolates, including tobramycin-resistant isolates. Further, by combining tobramycin with dequalinium chloride we drive these strains to extinction. Our results support that transient CS could allow the design of new evolutionary strategies to tackle antibiotic-resistant infections, avoiding the acquisition of AR mutations on which inherited CS depends.

The DEVA trial: protocol for a randomised controlled trial of dequalinium chloride versus usual care antibiotics for the treatment of bacterial vaginosis.

BACKGROUND: Bacterial vaginosis (BV) is the most common cause of vaginal discharge in women of reproductive age, and it is estimated that up to a third of women will experience it at some point in their lives. BV produces an offensive vaginal odour and it is associated with serious sequelae. The most frequently prescribed treatment for BV in the UK is 7-day oral metronidazole but recurrences are common following it. Dequalinium chloride (Fluomizin©) is an anti-infective, antiseptic agent administered as a vaginal tablet. Small studies have shown this to be an effective alternative to antibiotics as a BV treatment. This trial aims to investigate whether dequalinium is as effective as current antibiotic treatments for the treatment of BV 1 month after treatment start. METHODS: DEVA is a multi-centre, randomised, open-label, parallel group, non-inferiority trial of dequalinium chloride versus usual care antibiotics for the treatment of BV. Recruitment will take place in 15 GUM clinics in the UK with Leeds Sexual Health also managing remote recruitment via the trial website. Women will be randomised 1:1 to receive dequalinium or usual care antibiotics. The primary outcome is to determine if the proportion of women reporting resolution of BV symptoms 4 weeks after treatment (without the need for additional treatment) is not worse in women treated with dequalinium chloride compared to usual care antibiotics. Questionnaire follow-up will take place 4 and 12 weeks after starting treatment, and remotely recruited patients will also provide a week 4 BV vaginal smear. The sample size is 904. DISCUSSION: This trial will provide high-quality evidence on the use of dequalinium chloride as a BV treatment, which could result in patients reducing the number of antibiotics they take. TRIAL REGISTRATION: ISRCTN ISRCTN91800263. Prospectively registered on 20 January 2020.

Dequalinium chloride is an antagonists of α7 nicotinic acetylcholine receptors.

Dequalinium chloride has been used primarily as antiseptic compounds, but recently has been investigated for its effects on specific targets, including muscarinic acetylcholine receptors. Here we investigated dequalinium chloride as an antagonist to α7 nicotinic acetylcholine receptors. The pharmacological properties of dequalinium were established using cell lines stably co-transfected with the calcium-permeable human α7 nicotinic acetylcholine receptors and its chaperone NACHO, calcium dye fluorescent measurements or a calcium-sensitive protein reporter, and patch clamp recording of ionic currents. Using calcium dye fluorescence plate reader measurements, we find dequalinium chloride is an antagonist of α7 nicotinic acetylcholine receptors with an IC50 of 672 nM in response to activation with 500 µM acetylcholine chloride and positive allosteric modulator PNU-120596. However, using a membrane-tethered GCAMP7s calcium reporter allowed detection of α7-mediated calcium flux in the absence of PNU-120596. Using this approach revealed an IC50 of 157 nM for dequalinium on 300 µM acetylcholine-evoked currents. Using patch clamp recordings with 300 µM acetylcholine chloride and 10 µM PNU-120596, we find lower concentrations are sufficient to block ionic currents, with IC50 of 120 nM for dequalinium chloride and 54 nM for the related UCL 1684 compound. In summary, we find that dequalinium chloride and UCL1684, which are generally used to block SK-type potassium channels, are also highly effective antagonists of α7 nicotinic acetylcholine receptors. This finding, in combination with previous studies of muscarinic acetylcholine receptors, clearly establishes dequalinium compounds within the class of general anti-cholinergic antagonists.

Dequalinium chloride use in adult Spanish women with bacterial vaginosis: an observational study.

Bacterial vaginosis (BV) represents the most frequent vaginal infection in women of childbearing age. The aim of this study was to characterise episodes of BV among adult Spanish women and their management with dequalinium chloride (DQC). Data from 573 DQC-treated BV adult women was obtained on medical records and questionnaires. The study shows that 20.6% had presented vaginal infections previously. Comorbid candidosis was significantly associated to other symptoms, such as pruritus or leucorrhoea. Most patients (64.3%) indicated a moderate-strong impact of the BV episode on their sexual life. After treatment, 84.8% of patients reported no BV symptoms. Patients were given instructions to prevent relapses. Most patients (83.1%) rated DQC as 'satisfactory' or 'very/extremely satisfactory' regarding symptom relief, prevention or treatment of the episode of BV. In conclusion, this study provides a better understanding of BV episodes and the impact of the treatment with DQC in real clinical practice in Spanish patients.IMPACT STATEMENTWhat is already known on this subject? Bacterial vaginosis (BV) is the most commonly reported vaginal infection among women of childbearing age. Despite the availability of antibiotic medications for the treatment of BV, management of this condition remains challenging. In fact, recurrence of BV has been reported for up to 50% of cases. However, antiseptic agents are considered an effective option for BV treatment.What the results of this study add? The study provides a better understanding of the prevalent symptomatology and the impact on quality of life of women with BV. Moreover, it has been observed that antiseptic dequalinium chloride (DQC) efficiently reduces symptoms and improves quality of life of the patients during episodes of BV.What the implications are of these findings for clinical practice and/or further research? In the context of the World Health Organisation recommendations on the rational use of antibiotics, we believe that the use of DQC may be a good alternative to antibiotics as a therapy for BV.

Application Enzymatic Method for Analysis Vaginal Tabletas “Fluomizin” / Aplicación método enzimático para análisis comprimidos vaginales “fluomizin”

Introducción: Desarrollo y validación de un nuevo método cinético-fotométrico enzimático para la determinación cuantitativa de cloruro de decualinio en tabletas vaginales “Fluomizin”, basado en la inhibición de la reacción de hidrólisis enzimática de acetilcolina. Método: El contenido de cloruro de dequalinio en las tabletas “Fluomizin” № 6 se determinó por el grado de inhibición de la reacción enzimática, que se evaluó por la cantidad residual de acetilcolina en la reacción bioquímica. Como indicador, se usó la reacción de oxidación de p-fenetidina con ácido peracético, que se forma durante la reacción auxiliar de perhidrólisis con exceso de peróxido de hidrógeno durante un cierto período de tiempo en la mezcla de reacción. Resultados: Se determinaron las condiciones óptimas para la determinación: pH seleccionado 8,35, concentración de acetilcolina (0,05 mg / ml), colinesterasa (0,4 mg / ml), peróxido de hidrógeno (10%) y p-fenetidina (1%)tiempo de reacción (20 min). Conclusiones: Un método enzimático cinético-fotométrico para determinar el contenido de cloruro de dequalinium en píldoras vaginales “Fluomizin” № 6. La validación del método desarrollado para parámetros tales como linealidad, precisión, precisión y límite de cuantificación. Se determinaron los parámetros cinéticos Km (constante de Michaelis-Menten) y Vmax (velocidad máxima). (AU)

Introduction: Development of a new enzymatic kinetic-photometric method for analysis of Dequalinium chloride, based on the use of enzymatic hydrolysis of acetylcholine, for determine the amount of Dequalinium chloride in the vaginal tablets “Fluomizin” No 6. Method: The amount of Dequalinium chloride (DCh) was determined by the degree of inhibition of the enzymatic reaction, which was evaluated by the residual unreacted substrate - acetylcholine. Determination of the residual amount of acetylcholine in the reaction mixture was performed by a kinetic-photometric method using an indicator oxidation reaction of p-phenetidine with peracetic acid, which is formed during the auxiliary reaction of perhydroly-sis with addition of excess hydrogen peroxide in the reaction mixture over a period of time. Results: Optimal conditions were determined: pH 8.35 was selected, influence of nature of buffer solution, concen-tration of acetylcholine (0.05 mg / ml), cholinesterase (0.4 mg / ml), hydrogen peroxide (10,0%) and p-phenethedine (1 %), the incubation time (10 min). Conclusions: The procedure for determination of Dequalinium chloride content in the vaginal tablets “Fluomizin” No 6 was developed. The kinetic parameters Km (Michaelis–Menten constant) and Vmax (maximal velocity) were determined. (AU)

DQAsomes as the Prototype of Mitochondria-Targeted Pharmaceutical Nanocarriers : An Update.

DQAsomes (dequalinium-based liposome-like vesicles) are the prototype for all mitochondria-targeted vesicular pharmaceutical nanocarrier systems. First described in 1998 in a paper which has been cited as of May 2020 over 150 times, DQAsomes have been successfully explored for the delivery of DNA and low-molecular weight molecules to mitochondria within living mammalian cells. Moreover, they also appear to have triggered the design and development of a large variety of similar mitochondria-targeted nanocarriers . Potential areas of application of DQAsomes and of related mitochondria-targeted pharmaceutical nanocarriers involve mitochondrial gene therapy , antioxidant and updated therapy as well as apoptosis-based anticancer chemotherapy. Here, detailed protocols for the preparation, characterization, and application of DQAsomes are given and most recent developments involving the design and use of DQAsome-related particles are highlighted and discussed.

Medicinal applications and molecular targets of dequalinium chloride.

For more than 60 years dequalinium chloride (DQ) has been used as anti-infective drug, mainly to treat local infections. It is a standard drug to treat bacterial vaginosis and an active ingredient of sore-throat lozenges. As a lipophilic bis-quaternary ammonium molecule, the drug displays membrane effects and selectively targets mitochondria to deplete DNA and to block energy production in cells. But beyond its mitochondriotropic property, DQ can interfere with the correct functioning of diverse proteins. A dozen of DQ protein targets have been identified and their implication in the antibacterial, antiviral, antifungal, antiparasitic and anticancer properties of the drug is discussed here. The anticancer effects of DQ combine a mitochondrial action, a selective inhibition of kinases (PKC-α/ß, Cdc7/Dbf4), and a modulation of Ca2+-activated K+ channels. At the bacterial level, DQ interacts with different multidrug transporters (QacR, AcrB, EmrE) and with the transcriptional regulator RamR. Other proteins implicated in the antiviral (MPER domain of gp41 HIV-1) and antiparasitic (chitinase A from Vibrio harveyi) activities have been identified. DQ also targets α -synuclein oligomers to restrict protofibrils formation implicated in some neurodegenerative disorders. In addition, DQ is a typical bolaamphiphile molecule, well suited to form liposomes and nanoparticules useful for drug entrapment and delivery (DQAsomes and others). Altogether, the review highlights the many pharmacological properties and therapeutic benefits of this old 'multi-talented' drug, which may be exploited further. Its multiple sites of actions in cells should be kept in mind when using DQ in experimental research.

HIV-1 Envelope Spike MPER: From a Vaccine Target to a New Druggable Pocket for Novel and Effective Fusion Inhibitors.

Here we highlight a sound and unique work reported by Chen and co-workers entitled "HIV-1 fusion inhibitors targeting the membrane-proximal external region of Env spikes" (Xiao et al., Nat. Chem. Biol. 2020, 16, 529). In this article, the authors identify, by means of a clever antibody-guided strategy, several small molecules as fusion inhibitors of HIV-1 replication acting at the membrane proximal external region (MPER) of the HIV-1 envelope (Env) spike. MPER, which was previously recognized as a vaccine target, emerges as a novel druggable target for the discovery of HIV-1 fusion inhibitors. The compounds (exemplified by dequalinium and dequalinium-inspired analogues) prevent the conformational changes of Env from the prefusion species to the intermediate states required for membrane fusion. This work not only paves the way to novel, specific and useful anti-HIV-1 inhibitors, but also discloses new therapeutic strategies against other infectious diseases.

Dequalinium-Derived Nanoconstructs: A Promising Vehicle for Mitochondrial Targeting.

The cell's power house, mitochondrion, is a vital organelle for drug targeting in the treatment of many diseases due to its fundamental duties and function related to cell proliferation and death. The mitochondrial membrane comprises bilayer artifact and poses extremely negative potential, creating hurdles for therapeutic molecules in reaching mitochondria. To accomplish mitochondrial targeting, the scientific community has explored diverse pharmaceutical formulations like liposomes, polymeric nanoparticles (NPs), and inorganic NPs. However, the game changing technology was a modification of these carriers by mitochondriotropic moiety, dequalinium chloride (DQA) or delivering the chemotherapeutics by DQAsomes. The DQA represents a distinctive mitochondriotropic delocalized cation that displays their selectivity towards accumulation in mitochondria of carcinoma cells. Attributed to this characteristics, DQAsomes have been formulated using DQA and explored for successful mitochondrial targeting of bioactives. In this review, it is discussed the effectiveness of DQA nanocarriers which efficiently and selectively transmit the cytotoxic drug to the tumor cell. The DQA based nanoformulations have evidently displayed augmented pharmacological and therapeutic outcomes than their counterparts both in vitro and in vivo. Thus, DQAsomes symbolizes an ideal carrier with excellent potential as mitochondrial targeting agent.

The potential value of dequalinium chloride in the treatment of cancer: Focus on malignant glioma.

Dequalinium chloride has been known as one kind of antibiotic that displays a broad antimicrobial spectrum and has been clinically proven to be very safe. In recent years, studies have shown that dequalinium chloride can inhibit the growth of malignant tumours, and reports were mainly used for solid tumours. Glioblastoma is the most common malignant neuroepithelial tumour of the central nervous system in adults, and the prognosis of glioblastoma is poor as it has a high resistance to apoptosis. This review summarizes the current understanding of dequalinium chloride-induced cancer cell apoptosis and its potential role in glioblastoma resistance and progression. Particularly, we focus on dequalinium chloride as it exerts a wide range of anti-cancer activity through its ability to target and accumulate in the mitochondria, and it effectively inhibits the growth of glioblastoma cells in vitro and vivo. Dequalinium chloride is an inhibitor of XIAP and can also act as a mitochondrial targeting agent, which gives it an interesting perspective regarding recent advances in the treatment of malignant glioma.

Vaginal tablets of dequalinium chloride 10 mg versus clotrimazole 100 mg for vaginal candidiasis: a double-blind, randomized study.

PURPOSE: To compare the clinical response, microscopic examination and fungal culture between dequalinium chloride (DQC) and clotrimazole (CT) for treating vaginal candidiasis (VC). METHODS: The double-blind, randomized study was conducted from September 2014 to September 2016 at Siriraj Hospital, Thailand. Eligible participants were Thai women diagnosed with VC by microscopic examination. The exclusion criteria included immunocompromised conditions, consumption of antifungal drugs, and having recurrent VC. Each participant was randomized with a 1:1 allocation to receive six vaginal tablets of 100 mg CT or 10 mg DQC. Two visits included 10 ± 2 days (C1) and 38 ± 4 days (C2). Outcome measures were improvement of VC symptoms, microscopic examination, culture, satisfaction and tolerability. RESULTS: Of 155 eligible participants, 150 were randomized and allocated into CT (N = 76) and DQC (N = 74). The average age was 31.1 ± 7.2 years. Comparable improvement of clinical response was demonstrated (OR at C1 0.79, 95% CI 0.56-1.10, p = 0.197; and OR at C2 0.99, 95% CI 0.69-1.43, p = 0.985). Of CT and DQC groups, the microscopic examination was positive at 11/75 (14.9%) vs 18/72 (25.3%) at C1 and 18/74 (24.3%) vs 28/66 (42.4%) at C2. And the culture was positive at 25/75 (33.8%) vs 46/72 (65.7%) at C1 and at 26/74 (36.6%) vs 46/66 (69.7%) at C2. Most participants had high satisfaction and tolerability and none reported any side effects. CONCLUSION: DQC and CT show comparable clinical response but CT results in greater improvement of microscopic examination and fungal culture. CLINICAL TRIAL REGISTRATION: The Clinical Trial Registry number was NCT02242695. (September 17, 2014).

Inhibition of porcine reproductive and respiratory syndrome virus by PKC inhibitor dequalinium chloride in vitro.

As a severe disease characterized by reproductive failure and respiratory distress, porcine reproductive and respiratory syndrome (PRRS) is one of the most leading threats to the swine industry worldwide. Highly evolving porcine reproductive and respiratory syndrome virus (PRRSV) strains with distinct genetic diversity make the current vaccination strategy much less cost-effective and thus urge alternative protective host directed therapeutic approaches. RACK1-PKC-NF-κB signalling axis was suggested as a potential therapeutic target for PRRS control, therefore we tested the inhibitory effect of PKC inhibitor dequalinium chloride (DECA) on the PRRSV infection in vitro. RT-qPCR, western blot, Co-IP and cytopathic effect (CPE) observations revealed that DECA suppressed PRRSV infection and protected Marc-145 cells and porcine alveolar macrophages (PAMs) from severe cytopathic effects, by repressing the PKCα expression, the interaction between RACK1 and PKCα, and subsequently the NF-κB activation. In conclusion, the data presented in this study shed more light on deeper understanding of the molecular pathogenesis upon PRRSV infection and more importantly suggested DECA as a potential promising drug candidate for PRRS control.

Repositioning Dequalinium as Potent Muscarinic Allosteric Ligand by Combining Virtual Screening Campaigns and Experimental Binding Assays.

Structure-based virtual screening is a truly productive repurposing approach provided that reliable target structures are available. Recent progresses in the structural resolution of the G-Protein Coupled Receptors (GPCRs) render these targets amenable for structure-based repurposing studies. Hence, the present study describes structure-based virtual screening campaigns with a view to repurposing known drugs as potential allosteric (and/or orthosteric) ligands for the hM2 muscarinic subtype which was indeed resolved in complex with an allosteric modulator thus allowing a precise identification of this binding cavity. First, a docking protocol was developed and optimized based on binding space concept and enrichment factor optimization algorithm (EFO) consensus approach by using a purposely collected database including known allosteric modulators. The so-developed consensus models were then utilized to virtually screen the DrugBank database. Based on the computational results, six promising molecules were selected and experimentally tested and four of them revealed interesting affinity data; in particular, dequalinium showed a very impressive allosteric modulation for hM2. Based on these results, a second campaign was focused on bis-cationic derivatives and allowed the identification of other two relevant hM2 ligands. Overall, the study enhances the understanding of the factors governing the hM2 allosteric modulation emphasizing the key role of ligand flexibility as well as of arrangement and delocalization of the positively charged moieties.

Dequalinium chloride inhibits the growth of human glioma cells in vitro and vivo: a study on molecular mechanism and potential targeted agents.

BACKGROUND: Our current understanding of the role of dequalinium chloride (DECA) in the progression of glioma remains very limited. This study was aimed to investigate the effect of DECA on human glioma cell lines in vitro and vivo. METHODS: The underlying molecular mechanism was analyzed for developing potential targeted agents. MTT assay, genomic DNA electrophoresis, DAPI staining, TUNEL staining, and wound scratch assay were performed to evaluate the effect of DECA on human glioma cell lines. Bioinformatics methods were used to screen the possible signaling pathway proteins, and the expression of these proteins and the corresponding mRNA was measured. RESULTS: DECA significantly inhibited the growth and proliferation of human glioma cells. Screening of apoptosis-related proteins showed the mRNA expression level of 6 genes was significantly changed after DECA administration. CONCLUSION: This study shows that DECA effectively inhibits the growth of glioma cells in vitro and vivo. DECA may promote glioma cell apoptosis by affecting the expression of NFKB2, HRAS, NF1, CBL, RAF1, and BCL-2 genes.

Rapid mechanochemical synthesis of metal-organic frameworks using exogenous organic base.

Metal-organic frameworks (MOFs) bearing coordinatively unsaturated metal centers, exemplified by the MOF-74 family of frameworks, are promising for applications ranging from gas separations and storage to Lewis acid catalysis. However, the scalable synthesis of MOF-74 analogues remains a significant challenge. Recently, mechanochemistry has emerged as a sustainable strategy for the preparation of MOFs in the solid state with minimal solvent waste. Mechanochemical methods typically rely on metal salts bearing basic anions to deprotonate the conjugate acid of the organic linker and a small amount of organic solvent or water to facilitate liquid assisted grinding. Here, we demonstrate that the liquid exogenous organic base Hünig's base (N,N-diisopropylethylamine) can fulfill both roles, enabling the mechanochemical synthesis of M2(dobdc) analogues (M = Mg, Mn, Co, Ni, Cu, Zn; dobdc4- = 2,5-dioxidobenzene-1,4-dicarboxylate) using metal nitrate salts in only 5 minutes at room temperature. Importantly, we demonstrate that this straightforward method can be generalized to prepare the isomeric framework Mg2(m-dobdc) (m-dobdc4- = 2,4-dioxidobenzene-1,5-dicarboxylate) and the expanded framework Mg2(dobpdc) (dobpdc4- = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate) under solvent-free conditions for the first time. The MOFs prepared using this method possess high crystallinities and surface areas, with the Mg2(m-dobdc) prepared herein representing the first reported permanently porous variant of this framework. This new sustainable mechanochemical synthesis of MOF-74 analogues should enable their preparation on a large scale for industrial applications.

Preparation and antitumor evaluation of hinokiflavone hybrid micelles with mitochondria targeted for lung adenocarcinoma treatment.

Hinokiflavone (HF) is a natural biflavonoid extracted from medicinal plants such as Selaginella tamariscina and Platycladus orientalis. HF plays a crucial role in the treatment of several cancers. However, its poor solubility, instability, and low bioavailability have limited its use. In this study, soluplus/d-α-tocopherol acid polyethylene glycol 1000 succinate (TPGS)/dequalinium (DQA) was applied to improve the solubilization efficiency and stability of HF. HF hybrid micelles were prepared via thin-film hydration method. The physicochemical properties of micelles, including particle size, zeta potential, encapsulation efficiency, drug loading, CMC value, and stability were investigated. The in vitro cytotoxicity assay showed that the cytotoxicity of the HF hybrid micelles was higher than that of free HF. In addition, the HF hybrid micelles improved anticancer efficacy and induced mitochondria-mediated apoptosis, which is associated with the high levels of ROS inducing decreased mitochondrial membrane potential, promoting apoptosis of tumor cells. Furthermore, in vivo tumor suppression, smaller tumor volume and increased expression of pro-apoptotic proteins were found in nude mice treated with HF hybrid micelles, suggesting that HF hybrid micelles had stronger tumor suppressive activity compared with free HF. In summary, HF hybrid micelles developed in this study enhanced antitumor effect, which may be a potential drug delivery system for the treatment of lung adenocarcinoma.

HIV-1 fusion inhibitors targeting the membrane-proximal external region of Env spikes.

Combination antiretroviral therapy has transformed HIV-1 infection, once a fatal illness, into a manageable chronic condition. Drug resistance, severe side effects and treatment noncompliance bring challenges to combination antiretroviral therapy implementation in clinical settings and indicate the need for additional molecular targets. Here, we have identified several small-molecule fusion inhibitors, guided by a neutralizing antibody, against an extensively studied vaccine target-the membrane proximal external region (MPER) of the HIV-1 envelope spike. These compounds specifically inhibit the HIV-1 envelope-mediated membrane fusion by blocking CD4-induced conformational changes. An NMR structure of one compound complexed with a trimeric MPER construct reveals that the compound partially inserts into a hydrophobic pocket formed exclusively by the MPER residues, thereby stabilizing its prefusion conformation. These results suggest that the MPER is a potential therapeutic target for developing fusion inhibitors and that strategies employing an antibody-guided search for novel therapeutics may be applied to other human diseases.