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Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women.

BACKGROUND: Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection. METHODS: We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have se

Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1.

Animal models are essential to study novel antiretroviral drugs, resistance-associated mutations (RAMs), and treatment strategies. Bictegravir (BIC) is a novel potent integrase strand transfer inhibitor (INSTI) that has shown promising results against HIV-1 infection in vitro and in vivo and against clinical isolates with resistance against INSTIs. BIC has a higher genetic barrier to the development of resistance than two clinically approved INSTIs, termed raltegravir and elvitegravir. Another clinically approved INSTI, dolutegravir (DTG) also possesses a high genetic barrier to resistance, wh

A Novel Cryptococcal Meningitis Therapy: The Combination of Amphotericin B and Posaconazole Promotes the Distribution of Amphotericin B in the Brain Tissue.

The deficient brain tissue distribution of amphotericin B (AMPB) seriously restricts its treatment for the clinical efficacy of cryptococcus neoformans meningitis (CNM). We strive to develop a tactic to increase its concentration in brain tissue. We aimed to investigate whether the combination of AMPB and posaconazole (POS) could be more effective in the treatment of CNM and to elucidate its potential mechanisms. HPLC analysis was used to analyze the concentration of AMPB in mouse serum, brain tissue, and BCECs cells. Schrodinger molecular docking, in vitro plasma balance dialysis, and ultrafi

HIV-1 Tat Protein Enhances Expression and Function of Breast Cancer Resistance Protein.

ATP binding cassette (ABC) transporters can transfer a variety of antiviral agents from the cytoplasm to body fluid, which results in a reduced intracellular concentration of the drugs. Proteins of HIV-1, e.g., Tat and gp120, altered some types of ABC transporter expression in brain microvascular endothelial cells and astrocytes. However, the effect of Tat on ABC transporters in T lymphocytes is unclear. In this study the status of breast cancer resistance protein (BCRP) in Tat expressing cell lines was examined with real-time PCR and flow cytometry. It was found that HIV-1 Tat protein upregul

Predictive Efficacy of Dual Therapies Combining Integrase Strand Transfer Inhibitors with Second-Generation Non-Nucleoside Reverse Transcriptase Inhibitors Following HIV-1 Treatment Failure in Cameroon: Implications for the Use of a Long-Acting Therapeutic Strategy in Low- and Middle-Income Countries.

Dual therapies (DT) combining integrase strand transfer inhibitors (INSTIs) with second-generation non-nucleoside reverse transcriptase inhibitors (2nd-Gen-NNRTIs) offer new possibilities for HIV treatment to improve adherence. However, drug resistance associated mutations (RAMs) to prior antiretrovirals may jeopardize the efficacy of DT. We herein describe the predicted efficacy of DT combining INSTIs + 2nd-Gen-NNRTI following treatment failure among Cameroonian patients. We genotyped the HIV-1 pol gene using Sanger sequencing and assessed acquired RAMs to NNRTIs and INSTIs in patients failin

Genome-Wide CRISPR Screens Identify ABCG2-Mediated Drug Resistance to the Threonine Tyrosine Kinase (TTK) Inhibitor CFI-402257 in Breast Cancer.

CRISPR screens are a powerful functional genomics approach for identifying genes that confer sensitivity and resistance to anti-cancer therapies. CFI-402257 (luvixasertib, 2257) is a small molecule inhibitor of threonine tyrosine kinase (TTK), a promising therapeutic target in genomically unstable cancers due to its critical role in establishing the spindle assembly checkpoint (SAC) during mitosis. To inform its ongoing development and evaluation in clinical trials, we sought to use CRISPR activation (i.e., gain of function) screens to identify cellular mechanisms of resistance to 2257 in mode

Structural basis of small-molecule inhibition of human multidrug transporter ABCG2.

ABCG2 is an ATP-binding cassette (ABC) transporter that protects tissues against xenobiotics, affects the pharmacokinetics of drugs and contributes to multidrug resistance. Although many inhibitors and modulators of ABCG2 have been developed, understanding their structure-activity relationship requires high-resolution structural insight. Here, we present cryo-EM structures of human ABCG2 bound to synthetic derivatives of the fumitremorgin C-related inhibitor Ko143 or the multidrug resistance modulator tariquidar. Both compounds are bound to the central, inward-facing cavity of ABCG2, blocking

Safety and efficacy of epelsiban in the treatment of men with premature ejaculation: a randomized, double-blind, placebo-controlled, fixed-dose study.

AIM: To assess the efficacy and safety of the selective oxytocin receptor antagonist epelsiban in the treatment of premature ejaculation (PE). METHODS: Double-blind, randomized, parallel-group, placebo-controlled, stopwatch-monitored, phase 2, multicenter study (GSK557296; NCT01021553) conducted in men (N=77) 18-55 years of age, with PE defined as per International Society for Sexual Medicine consensus definition. Patients provided informed consent prior to a 4-week un-medicated run-in to determine baseline intravaginal ejaculatory latency times (IELT) recorded in an electronic diary. Patient

[Secondary effects of treatment with maraviroc and other CCR5 antagonists. Potential impact of the CCR5 blocker].

Maraviroc is the first inhibitor of CCR5 co-receptors to be marketed as an antiretroviral. The pre-clinical studies and phase III trials have shown that it has a very favourable safety profile. No characteristic adverse effect of maraviroc has been identified. Unlike with aplaviroc, where its clinical development was stopped due to serious hepatoxicity, no increase in liver toxicity has been demonstrated in patients treated with maraviroc even if they are co-infected by hepatotropic virus. Nor was there any evidence of an increase in the incidence of neoplasms or serious infections in patients

Topoisomerase II and histone deacetylase inhibitors delay the G2/M transition by triggering the p38 MAPK checkpoint pathway.

When early prophase PtK(1) or Indian muntjac cells are exposed to topoisomerase II (topo II) inhibitors that induce little if any DNA damage, they are delayed from entering mitosis. We show that this delay is overridden by inhibiting the p38, but not the ATM, kinase. Treating early prophase cells with hyperosmotic medium or a histone deacetylase inhibitor similarly delays entry into mitosis, and this delay can also be prevented by inhibiting p38. Together, these results reveal that agents or stresses that induce global changes in chromatin topology during G2 delay entry into mitosis, independe

c-MET tyrosine kinase inhibitors reverse multidrug resistance in breast cancer cells by targeting ABCG2 transporter.

BACKGROUND: Overcoming multidrug resistance (MDR), which is often caused by the overexpression of ATP binding cassette (ABC) transporters in cancer cells remains a major challenge for cancer treatment. Receptor tyrosine kinase inhibitors have demonstrated potential in reversing MDR. This study aimed to investigate the effects of c-MET RTKIs on the reversal of MDR induced by ABCG2 in breast cancer cells. METHODS: MTT assay was employed to assess antiproliferative activity of c-MET inhibitors, including cabozantinib, crizotinib, and PHA665752. The accumulation of the fluorescent probe mitoxantr

Characterization and Validation of Canine P-Glycoprotein-Deficient MDCK II Cell Lines for Efflux Substrate Screening.

PURPOSE: We characterized three canine P-gp (cP-gp) deficient MDCKII cell lines. Their relevance for identifying efflux transporter substrates and predicting limitation of brain penetration were evaluated. In addition, we discuss how compound selection can be done in drug discovery by using these cell systems. METHOD: hMDR1, hBCRP-transfected, and non-transfected MDCKII ZFN cells (all with knock-down of endogenous cP-gp) were used for measuring permeability and efflux ratios for substrates. The compounds were also tested in MDR1_Caco-2 and BCRP_Caco-2, each with a double knock-out of BCRP/MRP

The role of efflux transporters on the transport of highly toxic aconitine, mesaconitine, hypaconitine, and their hydrolysates, as determined in cultured Caco-2 and transfected MDCKII cells.

Aconitum alkaloids including aconitine (AC), mesaconitine (MA), hypaconitine (HA), are highly toxic. Their hydrolysates, such as benzoylaconine (BAC), benzoylmesaconine (BMA), benzoylhypaconine (BHA), aconine, and mesaconine, are considerably less toxic. Efflux transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein isoform 2 (MRP2), act as a first line of defence and play key roles in toxicity prevention. The aim of the present study was to determine the role of efflux transporters in the transport of Aconitum alkaloi

Coordinated requirements of human topo II and cohesin for metaphase centromere alignment under Mad2-dependent spindle checkpoint surveillance.

Cohesin maintains sister chromatid cohesion until its Rad21/Scc1/Mcd1 is cleaved by separase during anaphase. DNA topoisomerase II (topo II) maintains the proper topology of chromatid DNAs and is essential for chromosome segregation. Here we report direct observations of mitotic progression in individual HeLa cells after functional disruptions of hRad21, NIPBL, a loading factor for hRad21, and topo II alpha,beta by RNAi and a topo II inhibitor, ICRF-193. Mitosis is delayed in a Mad2-dependent manner after disruption of either or both cohesin and topo II. In hRad21 depletion, interphase pericen

Chk1 is dispensable for G2 arrest in response to sustained DNA damage when the ATM/p53/p21 pathway is functional.

In the presence of sustained DNA damage occurring in S-phase or G2, normal cells arrest before mitosis and eventually become senescent. The checkpoint kinases Chk1/Chk2 and the CDK inhibitor p21 are known to have important complementary roles in this process, in G2 arrest and cell cycle exit, respectively. However, additional checkpoint roles have been reported for these regulators and it is not clear to what extent their functions are redundant. Here we compared the respective roles of Chk1, Chk2 and p21 in DNA damage-induced G2 arrest in normal human fibroblasts, normal epithelial cells and

Promising Activities of Marine Natural Products against Hematopoietic Malignancies.

According to the WHO classification of tumors, more than 150 typologies of hematopoietic and lymphoid tumors exist, and most of them remain incurable diseases that require innovative approaches to improve therapeutic outcome and avoid side effects. Marine organisms represent a reservoir of novel bioactive metabolites, but they are still less studied compared to their terrestrial counterparts. This review is focused on marine natural products with anticancer activity against hematological tumors, highlighting recent advances and possible perspectives. Until now, there are five commercially avai

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… Plinabulin is a synthetic analog of the diketopiperazine phenylahistin (halimide) isolated from marine and terrestrial Aspergillus sp. … Analyses allowed identifying desferrioxamines, fatty acid amides, diketopiperazines, xanthurenic acid, the cyclic octapeptides surugamides, and two potentially new surugamide A analogs. …

Advances in Peptidomimetics for Next-Generation Therapeutics: Strategies, Modifications, and Applications.

Over the past two decades, peptide drug discovery has experienced a remarkable renaissance, with organic chemistry and biotechnology emerging as pivotal tools for developing peptidomimetics that exhibit improved stability, specificity, and bioavailability compared to conventional peptides. This review systematically examines methodologies for modifying peptide backbones to achieve targeted properties, highlighting recent advances facilitated by modern biotechnological innovations for novel molecular transformations. Additionally, the review emphasizes the practical applications of peptides and

Anticancer natural products from the Middle East and North Africa: biodiversity, mechanisms, and translational challenges.

Cancer remains one of the leading causes of morbidity and mortality worldwide, imposing substantial clinical, societal, and economic burdens. Despite major advances in surgical oncology, systemic chemotherapy, radiation therapy, molecularly targeted therapeutics, and immune checkpoint inhibition, contemporary cancer treatment remains constrained by dose-limiting toxicities, intratumoral and intertumoral heterogeneity, and the inexorable emergence of multifaceted drug resistance mechanisms. These persistent therapeutic challenges have reinstated interest in natural products (NPs) as evolutionar

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… Beyond the mechanistically characterized compounds above, fungal-derived natural products of structurally heterogeneous classes, including cytochalasins, phomazines, diketopiperazines, and non-ribosomal peptides, further illustrate the chemical breadth and anticancer potential of fungal secondary metabolites … AGM12-1 | Egypt (soil) | Diketopiperazines | Cyclic dipeptides | Hepatocellular; colon cancer | Cytotoxicity; PKS/NRPS biosynthetic activity | ( 225 ) Terrestrial arid systems and biogeographically structured phytochemical innovation In MENA’s arid and semi-arid areas, plants are subjected to chronic …

FmocFF Peptide Hydrogel Is a Promising Matrix for Encapsulation and Controlled Release of the Anticancer Peptide Drug Bortezomib.

One major public health issue is cancer chemotherapy; despite constant progress in the area, administration of anticancer drugs to patients is often associated with serious side effects. It is therefore imperative to develop vehicles for encapsulation and controlled delivery of such drugs. Anticancer drugs include small peptide drugs, such as Bortezomib (BTZ). Self-assembling peptides have been recently reported as promising drug delivery agents. The research reported here proposes the encapsulation of BTZ into peptide hydrogels formed by the self-assembling FmocFF dipeptide as delivery vehicl

Histone Deacetylases as Epigenetic Targets for Treating Parkinson's Disease.

Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that is increasingly becoming a global threat to the health and life of the elderly worldwide. Although there are some drugs clinically available for treating PD, these treatments can only alleviate the symptoms of PD patients but cannot completely cure the disease. Therefore, exploring other potential mechanisms to develop more effective treatments that can modify the course of PD is still highly desirable. Over the last two decades, histone deacetylases, as an important group of epigenetic targets, have attracted muc