Sorbicillinoid HSL-2 inhibits the infection of influenza A virus via interaction with the PPAR-γ/NF-κB pathway.

BACKGROUND: Drug resistance is an important factor in the fight against influenza A virus (IAV). Natural products offer a rich source of lead compounds for the discovery of novel antiviral drugs. In a previous study, we isolated the sorbicillinoid polyketide HSL-2 from the mycelium of fungus Trichoderma sp. T-4-1. Here, we show that this compound exerts strong antiviral activity against a panel of IAVs. METHODS: The immunofluorescence and qRT-PCR assays were used to detect the inhibitory effect of HSL-2 toward the replication of influenza virus and IAV-induced expression of the pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1ß. RESULTS: The results indicated that HSL-2 inhibited influenza virus replication, and it significantly inhibited IAV-induced overexpression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß through modulating the PPAR-γ/NF-κB pathway. Notably, this effect was decreased when cells were transfected with PPAR-γ siRNA or treated with the PPAR-γ inhibitor T0070907. In addition, HSL-2 was able to attenuate lung inflammatory responses and to improve lung lesions in a mouse model of IAV infection. CONCLUSIONS: In this paper, we identified a microbial secondary metabolite, HSL-2, with anti-influenza virus activity. This report is the first to describe the antiviral activity and mechanism of action of HSL-2, and it provides a new strategy for the development of novel anti-influenza virus drugs from natural sources.

Advancements in the ERK1/2 Signaling Pathway Affecting Male Reproduction.

Male infertility, age-related changes, and tumors have been increasingly studied in the field of male reproductive health due to the emergence of environmental stressors, declining fertility rates, and aging populations. Numerous studies have demonstrated that the ERK1/2 signaling pathway plays a significant role in male reproduction. The ERK1/2 pathway is associated with several signaling pathways and has a complex interplay that influences the spermatogenic microenvironment, sperm viability, gonadal axis regulation, as well as resistance to testicular aging and tumors. Moreover, the ERK1/2 pathway directly or indirectly regulates testicular somatic cells, which are crucial for maintaining spermatogenesis and microenvironment regulation. Given the critical role of the ERK1/2 signaling pathway in male reproductive health, comprehensive exploration of its multifaceted effects on male reproduction and underlying mechanisms is necessary. This study aims to provide a solid foundation for in-depth research in the field of male reproduction and further enhance the reproductive health of males.

In Vitro Antibacterial Activity of a Novel Acid-Activated Antimicrobial Peptide against Streptococcus mutans.

BACKGROUND: Dental caries is an oral disease associated with infection by microbial biofilm. The metabolic activity of cariogenic bacteria results in a pH decrease in the plaque biofilm, causing tooth demineralization. This acidic environment favors the growth of cariogenic bacteria that are highly resistant to strong acids, which, in turn, produce more acid resulting in a further decrease in the pH of the plaque biofilm. Therefore, the strategy of utilizing the acidic dental plaque microenvironment to prevent and treat dental caries has become a hot research topic in recent years, such as the development of pH-sensitive drug delivery systems. AIMS: Design of a new acid-activated antibacterial peptide. OBJECTIVES: To design and synthesis an acid targeted antimicrobial peptide with the GWHHFFHFFHFF sequence. METHODS: Minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) testing confirmed its antibacterial activity. Propidium iodide (PI) staining was used to detect nucleic acid leakage. Determination of anti-biofilm activity by biofilm inhibition assay. A phototoxicity study confirmed the phototoxicity of PPIX-P12. RESULTS: MIC and MBC testing confirmed that P12 possessed acid-activated anti-Streptococcus mutans activity. Bactericidal kinetic experiments and propidium iodide (PI) staining experiments showed that P12 killed planktonic S. mutans UA159 cells leading to the leakage of nucleic acids in the acidic medium. Moreover, P12 showed acid-activated anti-biofilms at the early and mature biofilm stages. P12 was conjugated with the phototherapeutic agent protoporphyrin IX (PpIX) to construct the protoporphyrin derivative PpIX-P12. In vitro experiments revealed that PpIX-P12 displayed better antibacterial activity in pH 5.5 medium than in pH 7.2 medium. CONCLUSION: In conclusion, we designed an acid-activated AMP, which had no antimicrobial activity at neutral pH, but had antimicrobial activity at an acidic pH.

A Hybrid Antimicrobial Peptide Targeting Staphylococcus aureus with a Dual Function of Inhibiting Quorum Sensing Signaling and an Antibacterial Effect.

Community-associated methicillin-resistant Staphylococcus aureus (MRSA) is now a major cause of bacterial infection. Antivirulence therapy does not stimulate evolution of a pathogen toward a resistant phenotype, providing a novel method to treat infectious diseases. Here, we used a cyclic peptide of CP7, an AIP-III variant that specifically inhibited the virulence and biofilm formation of Staphylococcus aureus (S. aureus) in a nonbiocidal manner, to conjugate with a broad-spectrum antimicrobial peptide (AMP) via two N-termini to obtain a hybrid AMP called CP7-FP13-2. This peptide not only specifically inhibited the production of virulence of S. aureus at low micromolar concentrations but also killed S. aureus, including MRSA, by disrupting the integrity of the bacterial cell membrane. In addition, CP7-FP13-2 inhibited the formation of the S. aureus biofilm and showed good antimicrobial efficacy against the S. aureus-infected Kunming mice model. Therefore, this study provides a promising strategy against the resistance and virulence of S. aureus.

Phenolic compound SG-1 from Balanophora harlandii and its derivatives exert anti-influenza A virus activity via activation of the Nrf2/HO-1 pathway.

Influenza A virus (IAV) is one of the leading causes of respiratory illness and continues to cause pandemics around the world. Against this backdrop, drug resistance poses a challenge to existing antiviral drugs, and hence, there is an urgent need for developing new antiviral drugs. In this study, we obtained a phenolic compound SG-7, a derivative of natural compound 2-hydroxymethyl-1,4-hydroquinone, which exhibits inhibitory activity toward a panel of influenza viruses and has low cellular toxicity. Mechanistic studies have shown that SG-7 exerts its anti-IAV properties by acting on the virus itself and modulating host signaling pathways. Namely, SG-7 targets the HA2 subunit of hemagglutinin (HA) to block the fusion of viral-cellular membranes and inhibits IAV-induced oxidative stress and overexpression of pro-inflammatory factors by activating the Nrf2/HO-1 pathway and reducing NF-κB activation. In addition, SG-7 can enhance type I IFN antiviral response by inducing Nrf2 expression. Importantly, SG-7 showed the ability to inhibit viral replication in the lungs of IAV-infected mice and reduce their mortality. Therefore, SG-7 may be a promising lead compound for anti-influenza drug development.

New sesquiterpene from a soil fungus of Trichoderma sp.

Sixteen secondary metabolites, including one new sesquiterpene (1, named isocyclonerodiol oxide), seven known sesquiterpenes (2-8), two sorbicillinoid polyketides (15, 16), and six known other compounds (9-14) were isolated from the fermentation broth of Trichoderma sp. T-4-1. The structure of 1 was determined by 1 D, 2 D NMR (HMBC, HSQC, 1H-1H COSY, NOESY), and HRESIMS spectra. In addition, sesquiterpenes and sorbicillinoid polyketides showed significant antiviral activities.