Development Of Drug Resistance Research Articles

ANGPTL3 overcomes sorafenib resistance via suppression of SNAI1 and CPT1A in liver cancer.

Liver cancer, encompassing hepatocellular carcinoma (HCC) and hepatoblastoma, the latter of which primarily occurs in early childhood, is the most common malignant tumor arising from liver and is responsible for a significant number of cancer-related deaths worldwide. Targeted drugs have been used for anti-liver cancer treatment in the advanced stage, while their efficacy is greatly compromised by development of drug resistance. Drug resistance is a complicated process regulated by intrinsic and extrinsic signals and has been associated with poorer prognosis in cancer patients. In the current study, online available dataset analysis uncovered that angiopoietin-like protein 3 (ANGPTL3) manifested lower expression in sorafenib-resistant liver cancer cell lines. Additionally, ANGPTL3 was downregulated in HCC tissues, with its expression positively correlated with good prognosis. Functionally, ectopic expression of ANGPTL3 re-sensitized sorafenib-resistant cells, enhancing the sorafenib-induced reduction in cell viability and migration by suppressing zinc finger protein SNAI1 (SNAI1) expression and the protein stability of carnitine O-palmitoyltransferase 1, liver isoform (CPT1A). Clinical correlation analysis revealed that ANGPTL3 was negatively associated with SNAI1 expression. In conclusion, we identify a novel association between ANGPTL3, SNAI1 and CPT1A on sorafenib therapeutic response. Targeting ANGPTL3/SNAI1/CPT1A axis may serve as a therapeutic approach to improve prognosis of liver cancer patients with sorafenib resistance.

Cancer drug resistance as learning of signaling networks.

Drug resistance is a major cause of tumor mortality. Signaling networks became useful tools for driving pharmacological interventions against cancer drug resistance. Signaling datasets now cover the entire human cell. Recently, network adaptation became understood as a learning process. We review rapidly increasing evidence showing that the development of cancer drug resistance can be described as learning of signaling networks. During drug adaptation, the network forgets drug-affected pathways by desensitization and relearns by strengthening alternative pathways. Thus, resistant cancer cells develop a drug resistance memory. We show that all key players of cellular learning (i.e., IDPs, protein translocation, microRNAs/lncRNAs, scaffolding proteins and epigenetic/chromatin memory) have important roles in the development of cancer drug resistance. Moreover, all of them are central components of the epithelial-mesenchymal transition leading to metastases and resistance. Phenotypic plasticity was recently listed as a hallmark of cancer. We review how network plasticity induces rare, pre-existent drug-resistant cells in the absence of drug treatment. Key network methods assessing the development of drug resistance and network pharmacological interventions against drug resistance are summarized. Finally, we highlight the class of cellular memory drugs affecting cellular learning and forgetting, and we summarize current challenges to prevent or break drug resistance using network models.

Analysis of the efficacy of Langhans giant cells in controlling cutaneous Mycobacterium marinum infections.

Cutaneous Mycobacterium marinum (M. marinum) infection can lead to the formation of infectious granulomas containing Langhans giant cells (LGCs). Due to concerns about prolonged antibiotic use and the development of drug resistance, its treatment poses challenges. As active participants in granulomas, the therapeutic effect of LGCs has not been studied in animal models. We aim to investigate the antibacterial efficacy and immune response after transplanting LGCs into a mouse model of cutaneous M. marinum infection. LGCs effectively reduced the bacterial load and limited the growth of granulomas in the mouse footpads. Also, LGC treatment increased the production of inflammatory cytokines such as IL-1β and IL-10 and antimicrobial peptides S100A8/A9. Overall, our results show that LGCs reduced the bacterial load in the mouse footpads and limited the growth of granulomas while simultaneously accelerating the immune response and maintaining immune homeostasis. These findings further confirm the beneficial role of LGCs in controlling mycobacterial infections in mice and provide promising new alternatives for future treatments.

Evaluation of multi-drug resistance, virulence factors, and antimicrobial resistance genes of non-typhoidal Salmonella isolated from ruminants as a potential human health threat in Razavi Khorasan, northeastern Iran.

Non-typhoidal Salmonella (NTS) is a significant foodborne pathogen that poses a threat to human health by causing infections and potentially acquiring antibiotic resistance. We evaluated thirty-five Salmonella serovars previously isolated from cattle, sheep, goats, and their retail meat in Razavi Khorasan Province, Iran. The isolates were confirmed with Salmonella polyvalent antiserum. Furthermore, PCR was used to identify the Salmonella Enteritidis, Salmonella Typhimurium, and the host-adapted serovars Salmonella Dublin and Salmonella Abortusovis. Additionally, the antimicrobial susceptibility of the serovars was evaluated using the disk diffusion method. Subsequently, the occurrence of antimicrobial resistance genes and virulence factors was evaluated using the PCR technique. Molecular typing revealed that 20% of the isolates were S. Typhimurium, 11.4% were S. Dublin, 8.6% were S. Enteritidis, 5.7% were S. Abortusovis, and 54.3% (19 isolates) were classified as non-typed serovars. Salmonella isolates showed high susceptibility to ciprofloxacin (91.4%), colistin (88.6%), gentamicin (88.6%), and cefotaxime (85.7%) while exhibiting high resistance to others such as ampicillin (88.6%), streptomycin (74.3%), and tetracycline (51.4%). The most prevalent resistance genes in non-typhoidal Salmonella (NTS) are blaTEM (91.4%), sul1 (65.7%), and aadA (54.3%). Additionally, twenty-five isolates (71.4%) showed multi-drug resistance profiles. The most frequent virulence genes are stn (100%), iroN (100%), and pefA (42.9%). The current study has revealed that Salmonella serovars isolated from sheep and goats, like those from cattle, exhibit multi-drug resistance and harbor antimicrobial resistance genes. Additionally, they possess diverse virulence factors that can threaten human health by spreading diseases and developing drug resistance, leading to antibiotic treatment failure.

Synthesis of tetra-substituted thiophene derivatives as potential Hits combating antibiotic resistant bacteria ESKAPE.

The escalating prevalence of antibiotic-resistant bacteria has led to a serious global public health problem; therefore, there is an urgent need for the development of structurally innovative antibacterial agents. In our study, different series of tetra-substituted thiophene derivatives were designed and synthesized by multi-component reactions (MCRs) in moderate to excellent yields. Some of the designed final compounds were synthesized by both microwave assisted method and traditional synthesis. Thirteen compounds were evaluated against antibiotic resistance bacteria ESKAPE, among which compounds 11, 13 and 17 showed the most potent inhibitory activities against multidrug-resistant Enterococcus faecalis with MIC (minimum inhibitory concentration) values as low as 15.62, 7.61 and 15.62µg/mL, respectively. Two potent candidates 11 and 13 not only showed rapid bactericidal properties and impeded E. faecalis biofilm formation to effectually relieve the development of drug resistance, but also performed low toxicity toward human normal cells. Moreover, time dependent killing assay was performed that showed the reduction of the concentration of bacteria by 5.0 Log (CFU/mL) within 6h, stronger than reference drug, ampicillin at the same concentration. Additionally, mechanistic investigation demonstrated that both compounds 11 and 13 could exert inhibitory activity against DHPS with IC50 value of 1.73 and 4.67µM, respectively and against DNA gyrase enzyme with IC50 value of 0.07 and 0.04µM, respectively. Moreover, the cytotoxic activity of the most active compound was crucial to be determined that showed IC50 value of 75.42µM. Molecular docking indicated that the binding of both compounds 11 and 13 to DHPS and DNA gyrase enzymes could hinder their function. These results can provide novel structures of antibacterial drugs chemically different from currently known antibiotics and broaden prospects for the development of effective antibiotics against antibiotic-resistant bacteria.

Camptothecin Triggers Apoptosis in Human and Mouse Drug-resistant Glioblastoma Cells via ROS-mediated Activation of the p53-p21-CD1/CDK2-E2F1-Bcl-xL Signaling Axis.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor. Temozolomide (TMZ) is the first-line treatment for GBM. However, most patients with GBM develop drug resistance. Our previous study showed the effects of camptothecin (CPT) and CRLX101, a nanoparticle of CPT, in suppressing GBM growth by targeting drug-sensitive glioblastoma cells. This study evaluated the effects of CPT on drug-resistant glioblastoma cells and explored the underlying molecular mechanisms. Expression of type I topoisomerase (Topo-1) gene in GBM was analyzed using the UALCAN database. Human U87MG-R and mouse GL261-R TMZ-resistant glioblastoma cells were developed. After CPT treatment, apoptotic events were successively determined. The role of the p53-p21-cyclin D1 (CD1)/cyclin-dependent kinase 6 (CDK6)-E2F1-Bcl-xL signaling axis was subsequently investigated. The expression of Topo-1 gene was up-regulated in human GBM compared to normal human brains. Treatment of human U87MG-R cells with CPT decreased cell viability. Sequentially, exposure to CPT led to activation of caspase-3, fragmentation of chromosomal DNA, and cell apoptosis. Furthermore, intracellular reactive oxygen species (iROS) were augmented following CPT treatment. Suppression of iROS production concurrently alleviated CPT-triggered apoptotic insults. CPT enhanced the levels of p53, phosphorylated p53, and p21. In contrast, levels of CDK6, CD1, E2F1, and Bcl-xL were decreased by CPT. Attenuating p53 transactivation activity using pifithrin-α also mitigated the CPT-induced apoptosis. The effects of CPT on killing drug-resistant glioblastoma cells were further confirmed in mouse GL261-R cells. CPT could effectively induce apoptosis in drug-resistant glioblastoma cells via iROS-mediated activation of the p53-p21-CD1/CDK6-E2F1-Bcl-xL axis.

Electrochemical Detection of Miltefosine in Urine Using Amino Functionalised Multi-walled Carbon Nanotubes and [Fe(CN)6]−3/−4 as a Redox Couple

Abstract Miltefosine is an alkyllylosophospholipid analogue used to treat visceral leishmaniasis. Recently, reports have been made of suspected counterfeit miltefosine on the Indian market. With the risk counterfeit drugs pose to drug resistance development, quality control of antileishmanial drugs has become important. Hence, in this study, amino-functionalized multi-walled carbon nanotubes (MWCNT-NH2) were synthesised and characterised using Fourier transform infrared spectroscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. Also, electrochemical impedance spectroscopy and cyclic voltammetry were used to study the electrochemical properties of the synthesised MWCNT-NH2. A complex was formed between MWCNT-NH2 and miltefosine (Mil-MWCNT-NH2). Five microliters of Mil-MWCNT-NH2 was drop-cast on glassy carbon electrode, and differential pulse voltammetry studies were carried out to assess the performance of the sensor. Using [Fe(CN)6]-3/-4 as a redox couple, a calibration study was carried out at different concentrations (0–250 µM) to establish the concentration range of the sensor. A linear response was established. With a detection limit of 1 µM, the fabricated sensor is a viable tool for detecting antileishmanial drug miltefosine in urine samples and possible application in quality control of miltefosine against counterfeiting. Graphical Abstract

CircTTC13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the miR-513a-5p/SLC7A11 axis

The high mortality rate from hepatocellular carcinoma (HCC) is due primarily to challenges in early diagnosis and the development of drug resistance in advanced stages. Many first-line chemotherapeutic drugs induce ferroptosis, a form of programmed cell death dependent on ferrous iron-mediated oxidative stress, suggesting that drug resistance and ensuing tumor progression may in part stem from reduced ferroptosis. Since circular RNAs (circRNAs) have been shown to influence tumor development, we examined whether specific circRNAs may regulate drug-induced ferroptosis in HCC. Through circRNA sequencing, we identified a novel hsa_circ_0000195 (circTTC13) that is overexpressed in HCC tissues. This overexpression is linked to higher tumor grade, more advanced tumor stage, decreased ferroptosis, and poorer overall survival. Overexpression of CircTTC13 in HCC cell lines and explant tumors was associated with increased proliferation rates, enhanced metastatic capacity, and resistance to sorafenib, while also inhibiting ferroptosis. Conversely, circTTC13 silencing reduced malignant characteristics and promoted ferroptosis. In silico analysis, luciferase assays, and fluorescence in situ hybridization collectively demonstrated that circTTC13 directly targets and reduces miR-513a-5p expression, which in turn leads to the upregulation of the negative ferroptosis regulator SLC7A11. Moreover, the inhibition of SLC7A11 mirrored the effect of circTTC13 knockdown, whereas ferroptosis inhibition mimicked the effect of circTTC13 overexpression. Both circTTC13 and SLC7A11 were highly expressed in drug-resistant HCC cells, and circTTC13 silencing induced ferroptosis and reversed sorafenib resistance in explant tumors. These findings identify circTTC13 as a critical driver of HCC progression and resistance to drug-induced ferroptosis via upregulation of SLC7A11. The cicTTC13/miR-513a-5p/SLC7A11 axis represents a potential therapeutic target for HCC.

Dysfunctional mitochondrial bioenergetics sustains drug resistance in cancer cells.

Resistance to drugs is one of the major issues affecting the response to pharmacological treatments for tumors. Different mechanisms have been proposed to explain the development of cancer drug resistance (CDR), and several approaches to overcome it have been suggested. However, the biological basis of CDR remains unclear. Here, we investigated whether mitochondrial damage and consequent mitochondrial dysfunction are major causes of drug resistance in different tumors. To this end, we used cell lines from three tumors: hepatocellular carcinoma, breast cancer, and colon cancer. We then applied a protocol that recapitulates chemotherapy regimens in patients, rendering each cell line resistant to the drug commonly used in their respective treatments. The combination of cellular respiration analysis, gene expression analysis of cytochrome c oxidase isoforms, and mass spectrometry assessment of cardiolipin reveals that mitochondrial dysfunction is the underlying cause of the resistant phenotype. Importantly, we disclosed for the first time the rapid inhibition of oxidative phosphorylation (OXPHOS) by L-lactate, the major product of fermentation. Finally, we demonstrated that inhibition of lactic acid fermentation and activation of OXPHOS can increase drug sensitivity in all tested drug-resistant cancer cells. Taken together, our results suggest that inhibiting fermentation and enhancing mitochondrial function in cancer cells may be a concrete option to control the worrisome phenomenon of CDR.

Novel inhibitors of the (VIBVN) NAT protein identified through pharmacophore modeling

Arylamine N-acetyltransferases (NATs, E.C. 2.3.1.5) constitute a family of phase II drug metabolizing enzymes. These enzymes catalyze the transfer of acetyl groups from acetyl-CoA to a variety of substrates including arylamines, arylhydrazines, and N-hydroxyarylamines. By facilitating these reactions, NATs play a pivotal role in the detoxification and metabolic processing of a wide range of drugs and carcinogens. NAT in marine V. vulnificus plays a role in the metabolism of drugs, leading to the development of drug resistance in marine V. vulnificus. However, inhibitors targeted marine V. vulnificus NAT [(VIBVN)NAT] remain unclear. Therefore, our research aimed to identify potential hit compounds that target (VIBVN)NAT. We integrated multiple computational approaches to screen for effective inhibitors. From this process, we identified two hit compounds, AK-968-11563024 and AG-205-36710025, with IC50 values of 18.86 µM and 33.27 µM, respectively. Molecular dynamics simulations further elucidated the binding mechanism between (VIBVN)NAT and AK-968-11563024. Our study revealed that AK-968-11563024 forms stable interactions with PHE124, HIS167, and TRP230, which may contribute to its biological activity. Our findings provide a valuable foundation for the future development of drugs targeted therapeutics against (VIBVN)NAT.

Drug combination assays using Caenorhabditis elegans as a model system.

The C. elegans drug combination assay evaluates the effects of drug combinations in the nematode Caenorhabditis elegans, serving as a valuable tool to assess the efficacy of pharmaceutical agents and natural compounds. Using C. elegans as a model organism, this method allows for the efficient screening of the combined effects of different drugs and evaluation of synergistic effects in drug combinations, which reduces the risk of developing drug resistance. Combination therapy, involving commercial drugs, new agents, or natural products, broadens treatment effectiveness by targeting multiple pathways, effectively managing complex diseases with minimized side effects. The method focuses on discovering effective drug combinations, such as anthelmintic drugs, streamlining early-stage drug discovery to save time and resources. Additionally, its versatility allows for application across most areas of pharmacology and toxicology, extending its usefulness beyond anthelmintic treatments. In the experiments, synchronized worms are exposed to different drug concentrations to evaluate behavioral changes, mostly alterations in worm locomotion. Concentration-response curves for changes in behavior are generated and EC50 or IC50 values determined for the individual drugs. To determine whether the effects of a drug combination are synergistic, additive, or antagonistic, at least three different concentration ratios must be tested. These combinations are then analyzed using specialized drug combination analysis software. This methodology ensures consistent and precise outcomes and evaluates drug impacts on worm behavior parameters crucial for effective pharmacological activity. In conclusion, the C. elegans drug combination assay provides critical insights for developing successful market formulations applicable across a wide range of pharmacological treatments. Its ability to efficiently screen for synergistic, additive, or antagonistic effects makes it a valuable tool for identifying effective therapeutic strategies, potentially reducing drug resistance and improving treatment outcomes in various medical and toxicological fields.

Global dissemination of Klebsiella pneumoniae in surface waters: Genomic insights into drug resistance, virulence, and clinical relevance.

The aquatic environment is a major pathway for the spread of antibiotic resistance (AR) among microorganisms. Among these, Klebsiella pneumoniae reveals high genome plasticity, adaptability, and the ability to colonize humans, animals, and the natural environment, awarding it a significant role in the spread of AR. This work presents an in-depth analysis of the whole sequences of 149 K. pneumoniae genomes isolated from surface waters available in databases. The sequences were obtained from 20 countries in five continents. The analyses showed a high genomic diversity of isolates, classifying them into 94 unique sequence types. The isolates carried numerous virulence and drug resistance determinants in their genomes, including genes for carbapenem and colistin resistance. The critical resistance genes were located on plasmids, indicating their high mobility and ease of access in water environments. Sublineage 258 members, in particular ST11, have been identified as important carriers of both important drug resistance determinants and key virulence factors, thus posing a substantial threat to human health. Our analysis revealed the direct transmission of drug-resistant and virulent clinical strains to the natural environment, highlighting the role of K. pneumoniae in the dissemination of drug resistance within the "One Health" framework. Surface waters represent an environment conducive to the spread and evolution of drug resistance, and K. pneumoniae plays a significant role in this process by providing clinically-significant antibiotic resistance genes to environmental recipients.

Hypotheses of development and strategies for overcoming drug resistance in epilepsy. Part I: Hypotheses of development

Currently, the problem of effective therapy for drug-resistant epilepsy remains vastly relevant. The severity of drug-resistant epilepsy, remarkable negative social sequelae and sudden death in epilepsy pose a heavy burden on healthcare system. Although many innovative antiepileptic drugs have been developed in recent decades, surgical approach remains the only effective way to treat drug-resistant epilepsy which is coupled to significant health risks and does not guarantee freedom from seizures. The stumbling block in managing this pathology is the lack of knowledge on pathogenetic mechanisms, leaving a significant proportion of patients without quality medical care. There are different viewpoints on developing drug resistance in epilepsy, which are characterized by multilayered and overlapping molecular disease bases. The review presents the analysis of the existing hypotheses regarding the mechanisms underlying drug resistance development in epilepsy.

In Vivo and In Vitro Studies Assessing the Antiviral Efficacy of Double Combinations Against Coxsackievirus B Infection.

Coxsackievirus B (CVB) infections, ranging from mild to severe diseases, lack specific antiviral treatments, underscoring the need for novel therapeutic strategies. Drug therapy is an important tool for controlling enterovirus infections, but clinically effective drugs do not currently exist, mainly due to the development of drug resistance. Combination therapy with two or more drugs has the potential to successfully inhibit viral infection more effectively than either drug alone as well as delay the development of resistance. This study explores the consecutive alternating administration (CAA) scheme in mice with CVB1 infection, utilizing double antiviral combinations consisting of pleconaril and MDL-860, with guanidine hydrochloride and oxoglaucine. The CAA combinations of pleconaril achieved a survival rate, in infected mice, of up to 59%, while the combinations of MDL-860 showed no significant effects. CAA reduced mortality, prolonged mean survival time (up to 5 days), and mitigated drug resistance compared to monotherapy or simultaneous administration. Monotherapeutic courses and daily administration of double combinations had no effect. Phenotypic characterization using the IC50 marker of virus isolates from brain tissue of infected and treated mice was of particular importance for the evaluation of the CAA treatment scheme. The results show increased susceptibility of the virus isolates to the partner compounds in double CAA combinations. In contrast, virus isolates from the monotherapeutic groups manifested a diminished susceptibility to their respective compound, which signals the development of drug resistance. All data obtained prove the potential of the CAA scheme for the development of effective chemotherapy of enterovirus infections.

The Evolution of Antimicrobial Resistance in Acinetobacter baumannii and New Strategies to Fight It.

Acinetobacter baumannii is considered one of the prioritized ESKAPE microorganisms for the research and development of novel treatments by the World Health Organization, especially because of its remarkable persistence and drug resistance. In this review, we describe how this can be acquired by the enzymatic degradation of antibiotics, target site modification, altered membrane permeability, multidrug efflux pumps, and their ability to form biofilms. Also, the evolution of drug resistance in A. baumannii, which is mainly driven by mobile genetic elements, is reported, with particular reference to plasmid-associated resistance, resistance islands, and insertion sequences. Finally, an overview of existing, new, and alternative therapies is provided.

Synthetic Vesicle-Based Drug Delivery Systems for Oral Disease Therapy: Current Applications and Future Directions.

Oral diseases such as dental caries, periodontitis, and oral cancer are prevalent and present significant challenges to global public health. Although these diseases are typically treated through procedures like dental preparation and resin filling, scaling and root planning, or surgical excision, these interventions are often not entirely effective, and postoperative drug therapy is usually required. Traditional drug treatments, however, are limited by factors such as poor drug penetration, significant side effects, and the development of drug resistance. As a result, there is a growing need for novel drug delivery systems that can enhance therapeutic efficacy, reduce side effects, and improve treatment outcomes. In recent years, drug-loaded vesicles, such as liposomes, polymersomes, and extracellular vesicles (EVs), have emerged as promising drug delivery platforms due to their high drug encapsulation efficiency, controlled release properties, and excellent biocompatibility. This review provides an in-depth examination of the characteristics, advantages, and limitations of liposomes, polymersomes, and extracellular vesicles in the context of oral disease treatment. It further explores the reasons for their advantages and limitations and discusses the specific applications, development prospects, and strategies for optimizing these vesicle-based systems for improved clinical outcomes.

Bioactive Products Targeting C-Met As Potential Antitumour Drugs.

With increasing duration of treatment, many tumours gradually develop drug resistance. Therefore, novel antitumour drugs need to be developed to treat patients with tumours. Targeting c-met inhibitors may be an effective treatment strategy. Scientific databases such as ScienceDirect, PubMed, the Wiley Online Library, and Social Sciences Citation Index were used to collect information. All the relevant literature was reviewed, and the available literature was screened. The upstream and downstream pathways of c-Met and their relevance to antitumour effects were searched based on the articles' title, abstract, and full text. The c-Met-targeting drugs with antitumour effects are summarized below. A "citation within a citation" or snowballing approach was used in this screening process to identify additional papers that may have been missed in the initial literature screening process. High-quality studies published in peer-reviewed journals were summarized and prioritized for citation in the review. In recent years, research on small-molecule targeted drugs has developed rapidly. Many results have also been achieved in the synthesis and isolation of c-Met inhibitors from natural compounds and traditional Chinese medicines. This article summarizes the developments in anti-c-Met drugs, which are synthesized and isolated from natural compounds and traditional Chinese medicine (TCM). This study provides primary resources for the development of c-Met inhibitors.

Structural Modifications and Prospects of Histone Deacetylase (HDAC) Inhibitors in Cancer.

Histone deacetylases (HDACs) play a crucial role in the regulation of cancer progression and have emerged as key targets for antitumor therapy. Histone Deacetylase Inhibitors (HDACis) effectively suppress tumor cell proliferation, induce apoptosis, and cause cell cycle arrest, demonstrating broad-spectrum antitumor activity. This article primarily focuses on enhancing the selectivity of HDACis through structural modification using natural compounds. It provides detailed insights into the structure modification of histone deacetylase 8 (HDAC8) and histone deacetylase 10 (HDAC10), as well as dual-- target inhibitors and their pharmacological effects. Furthermore, conventional HDAC inhibitors are susceptible to off-target effects and the development of drug resistance. Our research focuses on augmenting the targeting specificity of HDAC inhibitors through their combination with proteolysis targeting chimera (PROTAC). Lastly, the latest advancements in clinical research on HDAC inhibitors were summarized, revealing that these inhibitors possess limitations in their clinical applications due to intrinsic or acquired resistance. Consequently, this article primarily focuses on summarizing the current status and prospects of structural modifications for HDAC inhibitors, with the aim of inspiring researchers to develop novel HDAC inhibitors exhibiting enhanced activity for improved application in clinical research.

Bis-3-chloropiperidines: a novel motif for anthelmintic drug design.

Parasites account for huge economic losses by infecting agriculturally important plants and animals. Furthermore, morbidity and death caused by parasites affect a large part of the world population, especially in economically weak regions. Anthelmintic drugs to tackle this challenge remain scarce and their efficiency becomes increasingly endangered by the advent of drug resistance development. In the present study, we assessed the anthelmintic potential of bis-3-chloropiperidines, a family of compounds which have already demonstrated antiproliferative activity against various cell lines. We synthesized and tested the activity of 21 bis-3-chloropiperidine derivatives against two strains of the free-living nematode Caenorhabditis elegans (N2 and DC19) and the parasitic flatworm Schistosoma mansoni. Overall, bifunctional chloropiperidines featuring an aromatic linker performed best against the tested indicator organisms and could be considered for future optimization efforts. Ultimately, out of the 21 analyzed bis-3-chloropiperidines, four derivatives (2, 5, 9 and 11) reduced vitality parameters against S. mansoni and five the motility of C. elegans (2, 4, 5, 13, 21) while exhibiting no or low cytotoxicity.

Safety and efficacy of long-acting cabotegravir/rilpivirine versus standard oral antiretroviral therapy: a systematic review and meta-analysis.

In 2023, there were 39.9 million people living with HIV (PLWH) worldwide and 630 000 deaths related to HIV. New strategies are needed, and long-acting antiretrovirals (LAAs) are now widely considered to have great potential to help end the HIV epidemic. This systematic review and meta-analysis compare the safety and efficacy of LAA versus standard oral treatment (SOT) for HIV. PubMed and Embase databases, supplemented by ClinicalTrials.gov and grey literature, were searched. Randomized controlled trials (RCTs) reporting efficacy and/or safety of LAA versus SOT for PLWH until June 2024 were included. Efficacy (HIV RNA < 50 copies/mL) and HIV RNA ≥ 50 copies/mL, adverse events (AEs), treatment discontinuation, CD4 count, metabolic parameters and drug resistance were assessed. Prespecified subgroup analyses were conducted. The risk of bias was assessed with Cochrane RoB 2.0. Certainty of evidence was assessed using GRADE. Six RCTs were eligible for inclusion, involving 2829 participants. LAA was non-inferior to SOT in suppressing HIV RNA < 50 copies/mL [Risk Difference (RD), -0.00; 95% CI, -0.03-0.02; P = 0.83; I2 = 51%; high quality of evidence (QoE)]. LAA was associated with higher drug resistance (percentage pooled estimate, 57%; 95% CI, 33%-78% versus 9%; 95% CI, 2%-30%; moderate QoE) and risk of grade 1-4 AEs than SOT [Risk Ratio (RR), 1.22; 95% CI, 1.12-1.33; P < 0.001; I2 = 62%; moderate QoE]. LAA has non-inferior efficacy compared to SOT. However, participants receiving LAA were at a higher risk of developing drug resistance, cross-resistance and AEs.