Marcio José Poças-Fonseca

The incidence of drug-resistant Candida infections is increasing globally, emphasizing the need for novel antifungal strategies. Photodynamic therapy (PDT), which generates reactive oxygen species through appropriate light-activated photosensitizers, represents a promising alternative for superficial infections. This study investigated the effect of the epigenetic drugs sodium butyrate (NaBut) and hydralazine (HLZ) combined with PDT on the growth of Candida spp. The minimum inhibitory concentrations (MICs) for NaBut, HLZ and PDT alone were assessed against C . albicans , C . parapsilosis , C . glabrata and C . tropicalis . Candida cells were then exposed to sub-inhibitory concentrations of NaBut or HLZ (50% or 75% MIC), incubated with the aluminum-phthalocyanine chloride nanoemulsion (AlPc‑NE) photosensitizer, and irradiated at 660 nm. C . glabrata was the species most susceptible to NaBut (128 mM) and HLZ (0.46 mM), followed by C . albicans (256 mM NaBut, 1.5 mM HLZ). The C . albicans cells were the most susceptible to PDT alone (12.5 nM AlPc‑NE), followed by C . parapsilosis (25 nM AlPc‑NE). Previous exposure to HLZ significantly increased the efficacy of PDT on inhibiting the growth of these last two species. These findings may contribute to the development of new therapeutic strategies against superficial Candida infections.

Background/Objectives: Actinobacteria are one of the largest bacterial phyla. These microbes produce bioactive compounds, such as antifungals, antibiotics, immunological modulators, and anti-tumor agents. Studies on actinobacteria isolated from the Brazilian Savannah biome (Cerrado) are scarce and mostly address metagenomics or the search for hydrolytic enzyme-producing microbes. Solanum lycocarpum (lobeira) is a tree widely employed in regional gastronomy and pharmacopeia in Central Brazil. Methods: In this work, 60 actinobacteria isolates were purified from the rhizosphere of S. lycocarpum. Eight Streptomyces spp. isolates were selected for in vitro antifungal activity against Cryptococcus neoformans H99, the C. neoformans 89-610 fluconazole-tolerant strain, C. gattii NIH198, Candida albicans, C. glabrata, and C. parapsilosis. The ability of the aqueous extracts of the isolates to induce the in vitro secretion of tumor necrosis factor (TNF-α), nitric oxide (NO), interleukin-6 (IL-6), and IL-10 by murine macrophages was also evaluated. Results: All extracts showed antifungal activity against at least two yeast species. Streptomyces spp. LAP11, LDB2, and LDB17 inhibited C. neoformans growth by 40–93%. Most extracts (except LAP2) also inhibited C. gattii. None inhibited C. albicans, but all inhibited C. glabrata (40–90%). Streptomyces sp. LAP8 extract increased nitric oxide production by approximately 347-fold in murine macrophages, while LDB11 extract suppressed LPS-induced TNF-α production by 70% and simultaneously increased IL-10 secretion, suggesting immunosuppressive potential. Conclusions: The results revealed that Cerrado actinobacteria-derived aqueous extracts are potential sources of antifungal and immunomodulatory biocompounds.

Background/Objectives: Curcumin has antimicrobial activity, and its mechanism of action involves changing histone acetylation. Our group has shown that histone deacetylases (HDACs) inhibitors increase the sensibility of Cryptococcus neoformans to certain antifungal treatments. Therefore, the aim of this work was to investigate whether curcumin pretreatment increases the effect of photodynamic therapy (PDT) mediated by aluminum phthalocyanine in nanoemulsion (AlPc-NE) against C. neoformans. Methods: The minimum inhibitory concentrations (MIC) of AlPc-NE and curcumin, along with the 72-h growth curve of cells exposed to the combined treatments, were evaluated in the C. neoformans reference strain H99. Additionally, further analysis was performed using HDAC gene deletion mutant strains, hda1Δ and hos2Δ. Results: Curcumin reduces the effect of PDT on C. neoformans reference strain H99, likely due to its antioxidant properties. In the hda1Δ strain, 50% MIC of curcumin reduced the effect of PDT, but this effect was not observed in response to 75% MIC of curcumin. Conversely, in the hos2Δ strain, pretreatment with curcumin at 75% MIC enhanced the efficacy of PDT in combination with 50% MIC of AlPc-NE. Conclusions: These results indicate that curcumin inhibits C. neoformans. Moreover, at lower concentrations, curcumin protects cells against oxidant damage, while at higher concentrations, it may trigger epigenetic mechanisms that compromise cell viability. In conclusion, both curcumin and PDT are active against C. neoformans, with HDACs affecting their efficacy, and the effectiveness of the combined treatment depends on the concentration of both curcumin and AlPc-NE.

The research on actinobacteria isolated from traditional medicinal plants is limited. Here, four new Streptomyces isolates (Ha1, Pp1, UzK and UzM) were obtained from the rhizospheres of Helianthus annuus, Pongamia pinnata and Ziziphus mauritiana, frequently utilized in Indian traditional medicine. The Streptomyces isolates aqueous extracts were studied alone against the growth of the Cryptococcus neoformans H99 reference strain, the fluconazole-tolerant T1-5796 and 89–610 strains, three histone deacetylase (HDAC) genes mutant strains, C. gattii NIH198, Candida albicans, C. glabrata, C. parapsilosis and C. tropicalis to determine minimum inhibitory concentration (MIC). Next, the extracts were employed in combination with aluminium-phthalocyanine chloride nanoemulsion-mediated photodynamic therapy to evaluate a possible interaction. We demonstrated that the C. neoformans T1-5796 fluconazole-tolerant strain was more severely inhibited by the Pp1 isolate extract (MIC: 6 mg mL⁻¹) than H99, which was not inhibited. Growth inhibition of the HDAC null mutants was more prominent for the extract of the UzM isolate, showing inhibition at 2 mg mL⁻¹. The UzM extract was also the most effective in hindering the Candida species proliferation, with MIC values ranging from 10 to 40 mg mL⁻¹. The four Streptomyces extracts, especially UzK and UzM, significantly enhanced the antifungal effect of the photodynamic therapy. Our results indicate these Streptomyces isolates as sources of novel metabolites which could potentiate the effect of photodynamic therapy in controlling yeasts superficial infections.

Melanoma, the most aggressive form of skin cancer, presents a major clinical challenge due to its tendency to metastasize and recalcitrance to traditional therapies. Despite advances in surgery, chemotherapy, and radiotherapy, the outlook for advanced melanoma remains bleak, reinforcing the urgent need for more effective treatments. Photodynamic therapy (PDT) has emerged as a promising alternative, leading to targeted tumor destruction with minimal harm to surrounding tissues. In this study, the direct and abscopal antitumor effects of PDT in a bilateral murine melanoma model were evaluated. Although only one of the two tumors was treated, effects were observed in both. Our findings revealed significant changes in systemic inflammation and alterations in CD4⁺ and CD8⁺ T cell populations in treated groups, as evidenced by blood analyses and flow cytometry. High-throughput RNA sequencing (RNA-Seq) further unveiled shifts in gene expression profiles in both treated and untreated tumors. This research sheds light on the novel antitumor and abscopal effects of nanoemulsion of aluminum chloride phthalocyanine (AlPcNE)-mediated PDT in melanoma, highlighting the potential of different PDT protocols to modulate immune responses and to achieve more effective and targeted cancer treatments.

Most studies regarding the use of fungi as enzyme producers for biomass deconstruction have focused on mesophile species, whereas the potential of thermophiles has been evaluated less. This study revealed, through genome and transcriptome analyses, the genetic repertoire of the biotechnological relevant thermophile fungus Humicola grisea .

Pathogenic microbes are exposed to a number of potential DNA-damaging stimuli during interaction with the host immune system. Microbial survival in this situation depends on a fine balance between the maintenance of DNA integrity and the adaptability provided by mutations. In this study, we investigated the association of the DNA repair response with the virulence of Cryptococcus neoformans, a basidiomycete that causes life-threatening meningoencephalitis in immunocompromised individuals. We focused on the characterization of C. neoformansAPN1 and APN2 putative genes, aiming to evaluate a possible role of the predicted Apurinic/apyrimidinic (AP) endonucleases 1 and 2 of the base excision repair (BER) pathway on C. neoformans response to stress conditions and virulence. Our results demonstrated the involvement of the putative AP-endonucleases Apn1 and Apn2 in the cellular response to DNA damage induced by alkylation and by UV radiation, in melanin production, in tolerance to drugs and in virulence of C. neoformans in vivo. We also pointed out the potential use of DNA repair inhibitor methoxy-amine in combination with conventional antifungal drugs, for the development of new therapeutic approaches against this human fungal pathogen. This work provides new information about the DNA damage response of the highly important pathogenic fungus C. neoformans.