Search Results (479)

Several natural products have been shown to display antiviral activity against the hepatitis B virus (HBV), among a number of other viruses. In a previous study, the hydro-alcoholic extracts (n = 66) of 31 species from the Venezuelan Amazonian rain forest were tested on the hepatoma cell line HepG2.2.15, which constitutively produces HBV. One of the species that exerted inhibitory activity on HBV replication was Senna silvestris. The aim of this study was the bioassay-guided purification of the ethanol fraction of leaves of S. silvestris, which displayed the most significant inhibitory activity against HBV. After solvent extraction and two rounds of reverse-phase HPLC purification, NMR analysis identified salsolinol as the compound that may exert the desired antiviral activity. The purified compound exerted inhibition of both HBV DNA and core HBV DNA. Pure salsolinol obtained from a commercial source also displayed anti-HBV DNA inhibition, with an approximate MIC value of 12 µM. Although salsolinol is widely used in Chinese traditional medicine to treat congestive heart failure, it has also been associated with Parkinson’s disease. More studies are warranted to analyze the effect of changes in its chemical conformation, searching for potent antiviral, perhaps dual agents against HBV and HIV, with reduced toxicity. Full article

Schizophrenia is a challenging multifactorial neuropsychiatric disease that involves interactions between genetic susceptibility and environmental insults. Increasing evidence implicates viral infections as significant environmental contributors, particularly during sensitive neurodevelopmental periods. This review synthesises current findings on the viral hypothesis of schizophrenia, encompassing a wide array of neurotropic viruses, including influenza viruses, herpesviruses (HSV-1 and 2, CMV, VZV, EBV, HHV-6 and 8), hepatitis B and C viruses, HIV, HERVs, HTLV, Zika virus, BoDV, coronaviruses (including SARS-CoV-2), and others. These pathogens can contribute to schizophrenia through mechanisms such as direct microinvasion, persistent central nervous system infection, immune-mediated neuroinflammation, molecular mimicry, and the disturbance of the blood–brain barrier. Prenatal exposure to viral infections can trigger maternal immune activation, resulting in cytokine-mediated alterations in the neurological development of the foetus that persist into adulthood. Genetic studies highlight the role of immune-related loci, including major histocompatibility complex polymorphisms, in modulating susceptibility to infection and neurodevelopmental outcomes. Clinical data also support the “mild encephalitis” hypothesis, suggesting that a subset of schizophrenia cases involve low-grade chronic neuroinflammation. Although antipsychotics have some immunomodulatory effects, adjunctive anti-inflammatory therapies show promise, particularly in treatment-resistant cases. Despite compelling associations, pathogen-specific links remain inconsistent, emphasising the need for longitudinal studies and integrative approaches such as viromics to unravel causal relationships. This review supports a “multi-hit” model in which viral infections interfere with hereditary and immunological susceptibilities, enhancing schizophrenia risk. Elucidating these virus–immune–brain interactions may facilitate the discovery of biomarkers, targeted prevention, and novel therapeutic strategies for schizophrenia. Full article

Background/Objectives: During the repair of a wounded epithelium, keratinocytes become invasive via the epithelial-to-mesenchymal transition (EMT) process. Usually temporary and controlled, EMT persists in a chronically inflamed epithelium and is exacerbated in epithelial dysplasia and dysregulated in invasive carcinomas. Here we investigated the effects that IL-1 beta, IL-6, and IL-8, inflammatory cytokines expressed in specimens from OPMDs and OSCCs, have on NOKs and OSCC cells. Methods: AKT activation and EMT induction were assessed along with cellular invasiveness. Results: IL-1 beta, IL-6, and IL-8 induced EMT in NOKs, ex novo conferring them invasive capacity. The same cytokines exacerbated the constitutive EMT and invasiveness of OSCC cells. Since these phenomena were accompanied by AKT activation, we tested whether they could be influenced by RTV, a long-used anti-HIV drug that was previously found to block the activation of human AKT and exert antitumor effects. We observed that therapeutic amounts of RTV counteract all the above-mentioned tumorigenic activities of ILs. Finally, consistent with the key role that AKT and EMT play in OSCC radio-resistance, RTV increased OSCC cells’ sensitivity to therapeutic doses of ionizing radiation. Conclusions: These preliminary in vitro findings encourage the use of RTV to prevent the malignant evolution of OPMDs, reduce the risk of OSCC metastasis, and improve the outcomes of anti-OSCC radiotherapy. Full article

Ganoderma capense, a member of the Ganoderma genus within the Polyporaceae family, has long been recognized for its high nutritional value and extensive use in traditional medicine. Its primary distribution is in China and South Africa, with the type locality being South Africa. This species is rich in a diverse array of bioactive compounds, including various polysaccharides, glycopeptide macromolecules, and various small-molecule compounds, such as sesquiterpenes, triterpenes, steroids, and alkaloids. Research indicates that these chemical constituents exhibit numerous pharmacological properties, including antioxidant, anti-inflammatory, and anti-tumor activities, as well as inhibition of acetylcholinesterase, reduction in blood lipids, and promotion of neural synapse growth. Apart from its use in traditional Chinese medicine, the components of G. capense are utilized globally for the treatment of a wide range of diseases, including Alzheimer’s disease, febrile convulsions, HIV, and diabetes. This underscores the extensive medical applications of G. capense, emphasizing its significance in contemporary and traditional healthcare. This review summarizes the latest research findings on the bioactive compounds and pharmacological effects of G. capense, compiled from databases such as PubMed, Web of Science, and Elsevier. This study aimed at providing researchers in this field with in-depth scientific insights and guidance, promoting further application and development in the pharmaceutical and food industries, and serving as a reference for subsequent exploration of active substances and the development of new disease treatments. Full article

HIV/AIDS and Mycobacterial tuberculosis (Mtb) are the leading cause of deaths worldwide. Thus, better medicaments are required to manage these diseases. Quinolines have shown great potential due to their broad spectrum of biological activity. Thus, quinoline–1,2,3-triazole–aniline hybrids were synthesised in moderate to good yields. Compounds 11g (IC₅₀ = 0.388 µM), 11h (IC₅₀ = 0.01032 µM) and 11i (IC₅₀ = 0.167 µM) exhibited the most promising in vitro activities against the wild-type HIV-1 subtype B, with 11h being 9-fold more active than AZT (IC₅₀ = 0.0909 µM), the reference drug. Furthermore, compound 11h displayed moderate activity, with a MIC₉₀ of 88μM against Mtb’s H37Rv strain. Cytotoxicity studies on TZM-bl cell lines revealed that most of the tested compounds were generally non-cytotoxic; the selectivity index (SI) for 11h, the front runner, is >2472. Molecular docking studies revealed that 11h interacted with Phe112, Tyr108, Glu283 and Trp86 amino acid residues in the active site of HIV-1. DFT studies revealed that 11h has the ability to donate and accept electrons to and from available orbitals. The predicted ADMET studies showed that these compounds possess drug-likeness, and 11h has the potential for further optimisation as an anti-HIV-1 agent. Full article

In 2022, scientific societies agreed on a document with recommendations for a comprehensive diagnosis of viral hepatitis (B, C, and D). The aim was to evaluate the situation in Spain regarding the comprehensive diagnosis of viral hepatitis in a single blood draw before it is recommended. A panel of experts prepared a structured survey directed at hospitals (public or private with teaching accreditation) with ≥200 beds (sent 20 October 2022, closed 1 December 2022). The response rate was 61% (79/129; 52 hospitals with >500 beds). Among the participating hospitals, all could perform tests for HBsAg, anti-HCV, and HIV serology; 94% could perform PCR testing for HCV, 63% could test for anti-HDV, and 28% could test for HDV-RNA (67% [53/79] outsourced this testing). Point-of-care (POC) testing availability was low (24%), with 84% of these tests being supervised by the reference microbiological laboratory and the results being registered in the patients’ medical history. Ninety percent of the centers carried out the diagnosis in a single step (99% HCV, 70% HBV, 48% HDV, and 44% HBV-HDV). In addition, 77% used some communication strategy when an active infection was encountered (100% HCV, 49% HBV, and 31% HDV). Only 20% had an automated system for scheduling a specialist physician appointment. Most hospitals had the means for a comprehensive diagnosis of viral hepatitis in a single sample, but <50% could test for HBV/HDV. Alerts for continuity of care were available for HCV, but not HBV or HDV. POC device implementation is important for decentralized testing. Full article

An increase in immunoglobulin G4 (IgG4) levels is typically associated with immunological tolerance states and develops after prolonged exposure to antigens. Accordingly, IgG4 is considered an anti-inflammatory antibody with a limited ability to trigger efficient immune responses. Additionally, IgG4 reduces allergic reactions by blocking immunoglobulin E (IgE) activity. In the case of COVID-19, it has been reported that the repeated administration of some vaccines induces high IgG4 levels. The latest research data have revealed a surprising IgE anti-receptor binding domain response after both natural infection and several SARS-CoV-2 vaccines. The presence of IgG4 and IgE in COVID-19 disease suggests that the virus may induce an “allergic-like” response to evade immune surveillance, leading to a shift from T helper 1 (Th1) to T helper 2 (Th2) cells, which promotes tolerance to the virus and potentially contributes to chronic infection. The spike protein from vaccines could also induce such a response. Interestingly, “allergen-like” epitopes and IgE responses have been reported for other viruses, such as influenza, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV). The impact of this viral-induced tolerance will be discussed, concerning long COVID and the protective efficacy of vaccines. Full article

The emergence of HIV strains resistant to the current anti-retroviral drugs has necessitated the search for new anti-retroviral medications. Methanolic and aqueous T. ferdinandiana fruit extracts have potent inhibitory activity against several phases of the HIV-1 replicative cycle. Cell infectivity studies using a non-resistant HIV-1 pseudovirus demonstrated that the methanolic (IC₅₀ 16 µg/mL) and aqueous extracts (IC₅₀ 19 µg/mL) were potent inhibitors of viral infection in a non-replicating HIV-1 assay. Both extracts also inhibited HIV-1 reverse transcriptase (IC₅₀ values of 35 and 33 µg/mL for methanolic and aqueous extracts, respectively) and HIV-1 protease (IC₅₀ values of 19 and 27 µg/mL, respectively) in recombinant enzyme assays. Given their inhibitory activities against multiple phases of HIV-1 replication, T. ferdinandiana fruit extracts may be particularly useful as HIV-1 therapeutics. Furthermore, both extracts displayed good safety profiles and therapeutic indices, indicating their suitability for therapeutic usage. LC-MS metabolomic profiling analysis of the methanolic extract identified several interesting constituents, including a relative abundance of tannins, as well as several flavonoids and stilbenes. All of these compounds have previously been reported to have bioactivities consistent with the anti-HIV-1 activities reported herein. Based on these studies, methanolic and aqueous T. ferdinandiana fruit extracts are promising potential therapies for the prevention, treatment and management of HIV-1. Full article

Backgrounds: The rapid initiation of highly active anti-retroviral therapy (HAART) can control HIV-1 viremia and stabilize the long-term health of people living with HIV-1 (PLWH). Despite this, individuals who are diagnosed late and exhibit poor therapeutic efficacy still pose a great challenge to global HIV management. To address this, we conducted comprehensive multiparametric immune profiling and analyzed its association with disease progression and therapeutic efficacy. Methods: Multicolor flow cytometry was used to characterize the circulating immune cell composition and cellular phenotypes in 40 treatment-naive individuals (16 chronic, 24 newly diagnosed), 26 HAART-treated individuals, and 18 healthy controls. Comparative analyses of T cell subsets, immune activation markers, and viral load signatures were performed, followed by network construction. We carried out principal component analysis and displayed the data by dimensionality reduction. Results: Persistent immune activation, dysregulated regulatory immunity, and aberrant memory differentiation markers were identified in T cells of HIV-1-infected individuals and were associated with disease progression. Additionally, HAART-treated patients which did not fully restore CD4 T cells exhibited higher levels of activated markers, suggesting possible biomarkers of therapeutic efficacy. Conclusions: This study describes changes in immune cell profiles throughout HIV-1 disease progression and explores suitable laboratory predictors for future clinical and therapeutic settings by monitoring pathological immune cell events. Full article

Five previously undescribed tigliane diterpenes (1–4 and 7), along with three known tiglianes (5, 6, and 8) were isolated from the root extract of Euphorbia nicaeensis using chromatographic techniques. The structures of the isolated compounds were determined using spectroscopic techniques. The isolated compounds were tested for anti-HIV activity against HIV-1 NL4.3 and HIV-2 ROD strains. Two derivatives (2 and 8) exhibited significant anti-HIV activity, with IC₅₀ values ranging from 1.10 to 7.47 µM. This study highlights the potential of E. nicaeensis root as a source of novel bioactive tigliane derivatives, warranting further investigation for possible use in HIV treatment. Full article

The persistence of latent HIV-1 proviruses in CD4⁺ T cells is a major obstacle to curing HIV. The “shock and kill” strategy involves reversing latency with latency-reversing agents (LRAs) and selectively inducing cell death in infected cells. However, current LRAs have shown limited efficacy in eliminating the ex vivo HIV reservoir and thus failed in clinical study. In this study, we repurposed PZ703b, a pro-apoptotic protein degrader initially developed for anti-leukemia therapy, to target HIV eradication. PZ703b induced the degradation of Bcl-2 and Bcl-xL, activating the non-canonical NF-kB pathway and caspases cascade, resulting in latency reversal and the selective apoptosis of infected cells. The treatment of ex vivo CD4⁺ T cells from ART-suppressed HIV-1 patients led to approximately a 50% reduction in the replication-competent reservoir. While this result does not reach the threshold required for a complete cure, it demonstrates the potential of a dual degrader of Bcl-2/Bcl-xL in reversing HIV latency and inducing selective cell death. Our study provides a proof-of-concept for using dual degraders of Bcl-2/Bcl-xL as a novel category of LRAs in therapeutic strategies aimed at reducing HIV reservoirs. This approach may pave the way for the further exploration of targeted interventions to eliminate the HIV-inducible reservoir. Full article

Activated immune cells are highly susceptible to human immunodeficiency virus (HIV) infection. Vitamin D (VitD) induces antimicrobial responses and reduces cellular activation. We investigated VitD effects on HIV-1 replication, glucose uptake, and gene regulation using computational and in vitro approaches. CD4⁺ T cells from healthy male donors were treated with VitD and infected with HIV-1. After 72 h, p24 protein was measured to assess viral replication. VitD effects on anti- and pro-HIV genes were analyzed by a Boolean network model based on curated databases and the literature. CCR5 and CXCR4 coreceptor expression, AKT phosphorylation, and glucose uptake were evaluated by flow cytometry, and expression of some model-identified genes was quantified by qPCR. VitD reduced p24 by 53.2% (p = 0.0078). Boolean network modeling predicted that VitD upregulates antiviral, migration, and cell-differentiation related genes, while downregulating genes related to cellular activation, proliferation, glucose metabolism, and HIV replication, notably AKT1, CCNT1, SLC2A1, HIF1A, and PFKL. In vitro, VitD reduced AKT phosphorylation by 26.6% (p = 0.0156), transcription of CCNT1 by 22.7% (p = 0.0391), and glucose uptake by 22.8% (p = 0.0039) without affecting classic antiviral genes or coreceptor expression. These findings suggest an anti-HIV effect of VitD, mediated through AKT and glucose metabolism downmodulation, both involved in cell activation and HIV-1 replication. Full article

Medicinal plants are widely used in Bolivian folk medicine for the treatment of infectious diseases. We have selected one, Clinopodium bolivianum (Benth.) Kuntze, known as “Khoa”, to investigate its potential anti-HIV activity since, traditionally, it has been used to treat other viral infectious diseases. We have carried out an antiviral bioassay-guided fractionation of different extracts of the aerial parts of C. bolivianum. An antiviral crude polysaccharide was obtained, (SBA_S), which is rich in glucose, galactose, mannose, arabinose, xylose, and rhamnose and only has traces of galacturonic acid. SBA_S exhibited antiviral activity with a mechanism of action unrelated to the mannose–lectin DC-SIGN receptors but with a strong viral neutralization activity. In summary, a purified polysaccharide from C. bolivianum has been identified as the main compound responsible for its antiviral activity. SBAs proved to be a neutralizing agent with high antiviral capacity in vitro, so they could be part of new microbicide formulations to prevent HIV transmission. Full article

Background/Objectives: Individuals with HIV on combined antiretroviral therapy (ART) with virologic suppression exhibit chronic immune activation and immune dysfunction. Numerous studies have shown that human milk oligosaccharide (HMO) controls the postnatal transmission of HIV-1, but its effect on adult HIV-1 infection is not known. The purpose of this study was to investigate the anti-HIV activity of Lacto-N-fucopentaose III (LNFPIII) in adult blood-borne macrophages. Methods: Primary human monocyte-derived macrophages from the blood of HIV-seronegative individuals were infected with HIV and treated with or without dextran-conjugated LNFPIII (P3DEX). HIV replication was measured by quantifying the accumulation of HIV Gag p24 in the culture supernatants by ELISA. The quantities of chemokines MIP-1α, MIP-1β, and CCL5 in the culture supernatant were also measured by ELISA. The expression of IL-1β, IL-18, TNFα, IL-10, BECN1, and housekeeping gene HuPO in the macrophages was determined by qRT PCR. The expression of NF-kB, LC3, p62, and β-actin was measured by immunoblotting. Results: We found that P3DEX controls HIV replication without affecting HIV binding and/or internalization by human macrophages. The treatment of HIV-infected macrophages with P3DEX increased the quantity of beta (β)-chemokines MIP-1α, CCL5, and MIP-1β, which are known to have anti-HIV activity. Furthermore, the treatment of HIV-infected macrophages with P3DEX increased autophagic flux in a TLR8-dependent manner and ameliorated the expression of proinflammatory cytokines. These results suggest that P3DEX is a prominent milk-derived sugar that simultaneously augments anti-viral mechanisms and controls immune activation. These findings prudently justify the use and clinical development of P3DEX as a host-directed therapeutic option for people living with HIV. Full article

Polybrominated diphenyl ethers (PBDEs) are natural products with potent antimicrobial and antineoplastic activity. We have previously shown that the polybrominated diphenyl ether bromoxib (4,5,6-tribromo-2-(2′,4′-dibromophenoxy) phenol), isolated from the marine sponge Dysidea species, exhibits a strong cytotoxic potential in leukemia and lymphoma cells by targeting mitochondrial metabolism. Here, using a mass spectrometric thermal proteome profiling (TPP) approach, we observed that bromoxib induces a rapid reduction in the levels of 19 nucleoporins (NUPs) that are part of the nuclear pore complex (NPC). This apparently affected the functionality of the NPC, as evidenced by the bromoxib-mediated inhibition of the nuclear translocation and subsequent gene reporter activity of transcription factors such as nuclear factor of activated T cells (NFAT) and nuclear factor κB (NF-κB). In addition, bromoxib inhibited the nuclear export of the mRNA of the human immunodeficiency virus transactivator of transcription (HIV-Tat) and the subsequent import of the HIV-Tat protein into the nucleus as determined by the decrease in Tat-dependent gene reporter luciferase activity. Inhibition of nuclear mRNA-export also affected expression of the short-lived anti-apoptotic Bcl-2 protein Mcl-1, which has been shown to induce apoptosis. Thus, its ability to target both mitochondrial metabolism and the NPC renders bromoxib a promising anticancer agent. Full article