TiO2-ZnPc nanoparticles functionalized with folic acid as a target photosensitizer for photodynamic therapy against glioblastoma cells.

The use of TiO2 as a photosensitizer in photodynamic therapy is limited due to TiO2 generates reactive oxygen species only under UV irradiation. The TiO2 surface has been modified with different functional groups to achieve activation at longer wavelengths (visible light). This work reports the synthesis, characterization, and biological toxicity assay of TiO2 nanoparticles functionalized with folic acid and combined with a zinc phthalocyanine to obtain a nano-photosensitizer for its application in photodynamic therapy for glioblastoma cancer treatment. The nano-photosensitizer was prepared using the sol-gel method. Folic acid and zinc phthalocyanine were added during the hydrolysis and condensation of titanium butoxide, which was the TiO2 precursor. The samples obtained were characterized by several microscopy and spectroscopy techniques. An in vitro toxicity test was performed using the MTT assay and the C6 cellular line. The results of the characterization showed that the structure of the nanoparticles corresponds mainly to the anatase phase. Successful functionalization with folic acid and an excellent combination with phthalocyanine was also achieved. Both folic acid-functionalized TiO2 and phthalocyanine-functionalized TiO2 had no cytotoxic effect on C6 cells (even at high concentrations) in comparison to Cis-Pt, which was very toxic to C6 cells. The materials behaved similarly to the control (untreated cells). The cell viability and light microscopy images suggest that both materials could be considered biocompatible and mildly phototoxic in these cells when activated by light.

Aspergillusidone G Potentiates the Anti-Inflammatory Effects of Polaprezinc in LPS-Induced BV2 Microglia: A Bioinformatics and Experimental Study.

Neuroinflammation is one of the main mechanisms involved in the progression of neurodegenerative diseases (NDs), and microglial activation is the main feature of neuroinflammation. Polaprezinc (Pol), a chelator of L-carnosine and zinc, is widely used as a clinical drug for gastric ulcers. However, its potential effects on NDs remain unexplored. In LPS-induced BV-2 microglia, we found that Pol reduced the generation of NO and ROS and revealed inhibited expression of iNOS, COX-2, and inflammatory factors such as IL-6, TNF-α, and 1L-1ß by Pol using qRT-PCR and Western blotting. These effects were found to be associated with the suppression of the NF-κB signaling pathway. Moreover, we evaluated the potential synergistic effects of aspergillusidone G (Asp G) when combined with Pol. Remarkably, co-treatment with low doses of Asp G enhanced the NO inhibition by Pol from approximately 30% to 80% in LPS-induced BV2 microglia, indicating a synergistic anti-inflammatory effect. A bioinformatics analysis suggested that the synergistic mechanism of Asp G and Pol might be attributed to several targets, including NFκB1, NRF2, ABL1, TLR4, and PPARα. These findings highlight the anti-neuroinflammatory properties of Pol and its enhanced efficacy when combined with Asp G, proposing a novel therapeutic strategy for managing neuroinflammation in NDs.

Lead and calcium crosstalk tempted acrosome damage and hyperpolarization of spermatozoa: signaling and ultra-structural evidences.

BACKGROUND: Exposure of humans and animals to heavy metals is increasing day-by-day; thus, lead even today remains of significant public health concern. According to CDC, blood lead reference value (BLRV) ranges from 3.5 µg/dl to 5 µg/dl in adults. Recently, almost 2.6% decline in male fertility per year has been reported but the cause is not well established. Lead (Pb2+) affects the size of testis, semen quality, and secretory functions of prostate. But the molecular mechanism(s) of lead toxicity in sperm cells is not clear. Thus, present study was undertaken to evaluate the adverse effects of lead acetate at environmentally relevant exposure levels (0.5, 5, 10 and 20 ppm) on functional and molecular dynamics of spermatozoa of bucks following in vitro exposure for 15 min and 3 h. RESULTS: Lead significantly decreased motility, viable count, and motion kinematic patterns of spermatozoa like curvilinear velocity, straight-line velocity, average path velocity, beat cross frequency and maximum amplitude of head lateral displacement even at 5 ppm concentration. Pb2+ modulated intracellular cAMP and Ca2+ levels in sperm cells through L-type calcium channels and induced spontaneous or premature acrosome reaction (AR) by increasing tyrosine phosphorylation of sperm proteins and downregulated mitochondrial transmembrane potential. Lead significantly increased DNA damage and apoptosis as well. Electron microscopy studies revealed Pb2+ -induced deleterious effects on plasma membrane of head and acrosome including collapsed cristae in mitochondria. CONCLUSIONS: Pb2+ not only mimics Ca2+ but also affects cellular targets involved in generation of cAMP, mitochondrial transmembrane potential, and ionic exchange. Lead seems to interact with Ca2+ channels because of charge similarity and probably enters the sperm cell through these channels and results in hyperpolarization. Our findings also indicate lead-induced TP and intracellular Ca2+ release in spermatozoa which in turn may be responsible for premature acrosome exocytosis which is essential feature of capacitation for fertilization. Thus, lead seems to reduce the fertilizing capacity of spermatozoa even at 0.5 ppm concentrations.

A Novel Multi-Effect Photosensitizer for Tumor Destruction via Multimodal Imaging Guided Synergistic Cancer Phototherapy.

Background: How to ingeniously design multi-effect photosensitizers (PSs), including multimodal imaging and multi-channel therapy, is of great significance for highly spatiotemporal controllable precise phototherapy of malignant tumors. Methods: Herein, a novel multifunctional zinc(II) phthalocyanine-based planar micromolecule amphiphile (ZnPc 1) was successfully designed and synthesized, in which N atom with photoinduced electron transfer effect was introduced to enhance the near-infrared absorbance and nonradiative heat generation. After simple self-assembling into nanoparticles (NPs), ZnPc 1 NPs would exhibit enhanced multimodal imaging properties including fluorescence (FL) imaging (FLI) /photoacoustic (PA) imaging (PAI) /infrared (IR) thermal imaging, which was further used to guide the combined photodynamic therapy (PDT) and photothermal therapy (PTT). Results: It was that under the self-guidance of the multimodal imaging, ZnPc 1 NPs could precisely pinpoint the tumor from the vertical and horizontal boundaries achieving highly efficient and accurate treatment of cancer. Conclusion: Accordingly, the integration of FL/PA/IR multimodal imaging and PDT/PTT synergistic therapy pathway into one ZnPc 1 could provide a blueprint for the next generation of phototherapy, which offered a new paradigm for the integration of diagnosis and treatment in tumor and a promising prospect for precise cancer therapy.

Lead Acetate-Injected Mice is an Animal Model for Extrapolation of Calcifying Response to Humans Due to Low Involvement of Bone Resorption.

Vascular calcification affects the prognosis of patients with renal failure. Bisphosphonates are regarded as candidate anti-calcifying drugs because of their inhibitory effects on both calcium-phosphate aggregation and bone resorption. However, calcification in well-known rodent models is dependent upon bone resorption accompanied by excessive bone turnover, making it difficult to estimate accurately the anti-calcifying potential of drugs. Therefore, models with low bone resorption are required to extrapolate anti-calcifying effects to humans. Three bisphosphonates (etidronate, alendronate, and FYB-931) were characterised for their inhibitory effects on bone resorption in vivo and calcium-phosphate aggregation estimated by calciprotein particle formation in vitro. Then, their effects were examined using two models inducing ectopic calcification: the site where lead acetate was subcutaneously injected into mice and the transplanted, aorta obtained from a donor rat. The inhibitory effects of bisphosphonates on bone resorption and calcium-phosphate aggregation were alendronate > FYB-931 > etidronate and FYB-931 > alendronate = etidronate, respectively. In the lead acetate-induced model, calcification was most potently suppressed by FYB-931, followed by alendronate and etidronate. In the aorta-transplanted model, only FYB-931 suppressed calcification at a high dose. In both the models, no correlation was observed between calcification and bone resorption marker, tartrate-resistant acid phosphatase (TRACP). Results from the lead acetate-induced model showed that inhibitory potency against calcium-phosphate aggregation contributed to calcification inhibition. The two calcification models, especially the lead acetate-induced model, may be ideal for the extrapolation of calcifying response to humans because of calcium-phosphate aggregation rather than bone resorption as its mechanism.

A Nanoencapsulated Ir(III)-Phthalocyanine Conjugate as a Promising Photodynamic Therapy Anticancer Agent.

Despite the potential of photodynamic therapy (PDT) in cancer treatment, the development of efficient and photostable photosensitizing molecules that operate at long wavelengths of light has become a major hurdle. Here, we report for the first time an Ir(III)-phthalocyanine conjugate (Ir-ZnPc) as a novel photosensitizer for high-efficiency synergistic PDT treatment that takes advantage of the long-wavelength excitation and near infrared (NIR) emission of the phthalocyanine scaffold and the known photostability and high phototoxicity of cyclometalated Ir(III) complexes. In order to increase water solubility and cell membrane permeability, the conjugate and parent zinc phthalocyanine (ZnPc) were encapsulated in amphoteric redox-responsive polyurethane-polyurea hybrid nanocapsules (Ir-ZnPc-NCs and ZnPc-NCs, respectively). Photobiological evaluations revealed that the encapsulated Ir-ZnPc conjugate achieved high photocytotoxicity in both normoxic and hypoxic conditions under 630 nm light irradiation, which can be attributed to dual Type I and Type II reactive oxygen species (ROS) photogeneration. Interestingly, PDT treatments with Ir-ZnPc-NCs and ZnPc-NCs significantly inhibited the growth of three-dimensional (3D) multicellular tumor spheroids. Overall, the nanoencapsulation of Zn phthalocyanines conjugated to cyclometalated Ir(III) complexes provides a new strategy for obtaining photostable and biocompatible red-light-activated nano-PDT agents with efficient performance under challenging hypoxic environments, thus offering new therapeutic opportunities for cancer treatment.

Synthesis, characterization and biological applications of substituted indolo[2,1-b]quinazolin-12(6H)-one based rhenium(I) organometallic compounds.

The Re(I) organometallic compounds [(Re(CO)3L1-6 )Cl], where Ligand(L) = Tryptanthrin derivatives were prepared and characterized by various spectroscopic techniques. To assess the binding capacities and binding manner, tests of Calf thymus DNA under the impact of organometallic complexes were conducted using absorption titration and viscosity measuring techniques. Data from the research mentioned above point to an intercalation type of binding, which was verified by the docking study. Swiss ADME tools carried out an ADME study. The work focuses on computing the molecular orbital energies for the synthesized compounds using the density functional theory (DFT). The compounds were tested against the MCF-7 cell line to determine their anticancer effects. It was observed that their IC50 values were equivalent to those of the standard medication, indicating that they had a similar antiproliferative impact.

Inhibitory effect of organogermanium compound 3-(trihydroxygermyl)propanoic acid on fructose-induced glycation of amino compounds.

3-(Trihydroxygermyl)propanoic acid (THGP), a hydrolysate of poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132, also known as repagermanium), can inhibit glycation between glucose/ribose and amino compounds. In addition, THGP may inhibit glycation by inhibiting reactions that occur after Amadori rearrangement and inducing the reversible solubilization of AGEs. In this study, we first investigated the effects and mechanisms on the glycation of fructose and amino compounds by THGP, as a greater reactivity was obtained with fructose than with glucose. Unlike other anti-glycation materials, THGP can form a complex with fructose, the initial compound of glycation. THGP also inhibited the production of AGEs and suppressed the reduction of fructose in a reaction between fructose and arginine. These results indicate that THGP forms a complex with cyclic fructose possessing a cis-diol structure at a reducing end, and that it suppresses the ring-opening of fructose and the progress of the initial glycation reaction. We next tried to evaluate the suppressive effect of glucosyl hesperidin (GHes) and THGP on the reaction of glycation between fructose and collagen. Both compounds effectively reduced the production of AGEs individually, and the combination of them led to a synergistic suppression. Therefore, through combination with other antiglycation materials, THGP may cooperatively exhibit glycation-inhibitory effects and be able to suppress the AGE production.

Multifunctional Organometallic Compounds Active against Infective Trypanosomes: Ru(II) Ferrocenyl Derivatives with Two Different Bioactive Ligands.

Human African trypanosomiasis (HAT, sleeping sickness) and American trypanosomiasis (Chagas disease) are endemic zoonotic diseases caused by genomically related trypanosomatid protozoan parasites (Trypanosoma brucei and Trypanosoma cruzi, respectively). Just a few old drugs are available for their treatment, with most of them sharing poor safety, efficacy, and pharmacokinetic profiles. Only fexinidazole has been recently incorporated into the arsenal for the treatment of HAT. In this work, new multifunctional Ru(II) ferrocenyl compounds were rationally designed as potential agents against these pathogens by including in a single molecule 1,1'-bis(diphenylphosphino)ferrocene (dppf) and two bioactive bidentate ligands: pyridine-2-thiolato-1-oxide ligand (mpo) and polypyridyl ligands (NN). Three [Ru(mpo)(dppf)(NN)](PF6) compounds and their derivatives with chloride as a counterion were synthesized and fully characterized in solid state and solution. They showed in vitro activity on bloodstream T. brucei (EC50 = 31-160 nM) and on T. cruzi trypomastigotes (EC50 = 190-410 nM). Compounds showed the lowest EC50 values on T. brucei when compared to the whole set of metal-based compounds previously developed by us. In addition, several of the Ru compounds showed good selectivity toward the parasites, particularly against the highly proliferative bloodstream form of T. brucei. Interaction with DNA and generation of reactive oxygen species (ROS) were ruled out as potential targets and modes of action of the Ru compounds. Biochemical assays and in silico analysis led to the insight that they are able to inhibit the NADH-dependent fumarate reductase from T. cruzi. One representative hit induced a mild oxidation of low molecular weight thiols in T. brucei. The compounds were stable for at least 72 h in two different media and more lipophilic than both bioactive ligands, mpo and NN. An initial assessment of the therapeutic efficacy of one of the most potent and selective candidates, [Ru(mpo)(dppf)(bipy)]Cl, was performed using a murine infection model of acute African trypanosomiasis. This hit compound lacks acute toxicity when applied to animals in the dose/regimen described, but was unable to control parasite proliferation in vivo, probably because of its rapid clearance or low biodistribution in the extracellular fluids. Future studies should investigate the pharmacokinetics of this compound in vivo and involve further research to gain deeper insight into the mechanism of action of the compounds.

Exploring antimalarial potential: Conjugating organometallic moieties with organic fragments for enhanced efficacy.

In the search for novel ligands with efficacy against various diseases, particularly parasitic diseases, molecular hybridization of organometallic units into biologically active scaffolds has been hailed as an appealing strategy in medicinal chemistry. The conjugation to organometallic fragments can be achieved by an appropriate linker or by directly coordinating the existing drugs to a metal. The success of Ferroquine (FQ, SR97193), an effective chloroquine-ferrocene conjugate currently undergoing the patient-exploratory phase as a combination therapy with the novel triaminopyrimidine ZY-19489 for malaria, has sparked intense interest in organometallic compound drug discovery. We present the evolution of organometallic antimalarial agents over the last decade, focusing on the parent moiety's class and the type of organometallics involved. Four main organometallic antimalarial compounds have been chosen based on conjugated organic moieties: existing antimalarial drugs, other clinical drugs, hybrid drugs, and promising scaffolds of thiosemicarbazones, benzimidazoles, and chalcones, in particular. The presented insights contribute to the ongoing discourse on organometallic compound drug development for malaria diseases.

Synthesis, characterization, DNA interaction, molecular docking, and α-amylase and α-glucosidase inhibition studies of a water soluble Zn(II) phthalocyanine.

In this study, 2(3),9(10),16(17),23(24)-tetrakis-[(N-methyl-(1-benzylpiperidin-4-yl)oxy)phthalocyaninato]zinc(II) iodide (ZnPc-2) was synthesized and characterized using spectral methods (FT-IR, 1H-NMR, UV-Vis and mass spectroscopy). The interaction of ZnPc-2 with DNA was investigated by using the UV/Vis titrimetric method, thermal denaturation profile, agarose gel electrophoresis and molecular docking studies. Additionally, the antidiabetic activity of ZnPc-2 was revealed spectroscopically by studying α-amylase and α-glucosidase inhibition activities. The spectroscopic results indicated that ZnPc-2 effectively binds to calf thymus-DNA (CT-DNA) with a Kb value of 7.5 × 104 M-1 and interacts with CT-DNA via noncovalent binding mode. Gel electrophoresis results also show that ZnPc-2 binds strongly to DNA molecules and exhibits effective nuclease activity even at low concentrations. Furthermore, docking studies suggest that ZnPc-2 exhibits a stronger binding tendency with DNA than the control compounds ethidium bromide and cisplatin. Consequently, due to its strong DNA binding and nuclease activity, ZnPc-2 may be suitable for antimicrobial and anticancer applications after further toxicological tests. Additionally, antidiabetic studies showed that ZnPc-2 had both α-amylase and α-glucosidase inhibition activity. Moreover, the α-glucosidase inhibitory effect of ZnPc-2 was approximately 3500 times higher than that of the standard inhibitor, acarbose. Considering these results, it can be said that ZnPc-2 is a moderate α-amylase and a highly effective α-glucosidase inhibitor. This suggests that ZnPc-2 may have the potential to be used as a therapeutic agent for the treatment of type 2 diabetes.

Green synthesis and characterization of AgNPs, liposomal loaded AgNPs and ZnPcS4 photosensitizer for enhanced photodynamic therapy effects in MCF-7 breast cancer cells.

Breast cancer remains a formidable challenge in oncology despite significant advancements in treatment modalities. Conventional therapies such as surgery, chemotherapy, radiation therapy, and hormonal therapy have been the mainstay in managing breast cancer for decades. However, a subset of patient's experiences treatment failure, leading to disease recurrence and progression. Therefore, this study investigates the therapeutic potential of green-synthesized silver nanoparticles (AgNPs) using an African medicinal plant (Dicoma anomala methanol root extract) as a reducing agent for combating breast cancer. AgNPs were synthesized using the bottom-up approach and later modified with liposomes (Lip) loaded with photosensitizer (PS) zinc phthalocyanine tetrasulfonate (Lip@ZnPcS4) using thin film hydration method. The successful formation and Lip modification of AgNPs, alongside ZnPcS4, were confirmed through various analytical techniques including UV-Vis spectroscopy, Fourier-transform infrared spectroscopy (FT-IR), high-resolution transmission electron microscopy (HR-TEM), scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS). Following a 24 h treatment period, MCF-7 cells were assessed for viability using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT viability assay), cell death analysis using mitochondrial membrane potential (MMP) (ΔΨm), Annexin V-fluorescein isothiocyanate (FITC)-propidium iodide (PI) kit, and caspase- 3, 8 and 9 activities. The experiments were repeated four times (n = 4), and the results were analyzed using SPSS statistical software version 27, with a confidence interval set at 0.95. The synthesized nanoparticles and nanocomplex, including AgNPs, AgNPs-Lip, Lip@ZnPcS4, and AgNPs-Lip@ZnPcS4, exhibited notable cytotoxicity and therapeutic efficacy against MCF-7 breast cancer cells. Notably, the induction of apoptosis, governed by the upregulation of apoptotic proteins i.e., caspase 8 and 9 activities. In addition, caspase 3 was not expressed by MCF-7 cells in both control and experimental groups. Given the challenging prognosis associated with breast cancer, the findings underscore the promise of liposomal nanoformulations in cancer photodynamic therapy (PDT), thus warranting further exploration in clinical settings.

Susceptibility of Leishmania to novel pentavalent organometallics: Investigating impact on DNA and membrane integrity in antimony(III)-sensitive and -resistant strains.

The aim the present study was to investigate the impact of novel pentavalent organobismuth and organoantimony complexes on membrane integrity and their interaction with DNA, activity against Sb(III)-sensitive and -resistant Leishmania strains and toxicity in mammalian peritoneal macrophages. Ph3M(L)2 type complexes were synthesized, where M = Sb(V) or Bi(V) and L = deprotonated 3-(dimethylamino)benzoic acid or 2-acetylbenzoic acid. Both organobismuth(V) and organoantimony(V) complexes exhibited efficacy at micromolar concentrations against Leishmania amazonensis and L. infantum but only the later ones demonstrated biocompatibility. Ph3Sb(L1)2 and Ph3Bi(L1)2 demonstrated distinct susceptibility profiles compared to inorganic Sb(III)-resistant strains of MRPA-overexpressing L. amazonensis and AQP1-mutated L. guyanensis. These complexes were able to permeate the cell membrane and interact with the Leishmania DNA, suggesting that this effect may contribute to the parasite growth inhibition via apoptosis. Taken altogether, our data substantiate the notion of a distinct mechanism of uptake pathway and action in Leishmania for these organometallic complexes, distinguishing them from the conventional inorganic antimonial drugs.

Enhancing antitumor efficacy of NIR-I region zinc phthalocyanine@upconversion nanoparticle through lysosomal escape and mitochondria targeting.

Accurately visualizing the intracellular trafficking of upconversion nanoparticles (UCNPs) loaded with phthalocyanines and achieving precise photodynamic therapy (PDT) using near-infrared (NIR) laser irradiation still present challenges. In this study, a novel NIR laser-triggered upconversion luminescence (UCL) imaging-guided nanoparticle called FA@TPA-NH-ZnPc@UCNPs (FTU) was developed for PDT. FTU consisted of UCNPs, folic acid (FA), and triphenylamino-phenylaniline zinc phthalocyanine (TPA-NH-ZnPc). Notably, TPA-NH-ZnPc showcases aggregation-induced emission (AIE) characteristic and NIR absorption properties at 741 nm, synthesized initially via molybdenum-catalyzed condensation reaction. The UCL emitted by FTU enable real-time visualization of their subcellular localization and intracellular trafficking within ovarian cancer HO-8910 cells. Fluorescence images revealed that FTU managed to escape from lysosomes due to the "proton sponge" effect of TPA-NH-ZnPc. The FA ligands on the surface of FTU further directed their transport and accumulation within mitochondria. When excited by a 980 nm laser, FTU exhibited UCL and activated TPA-NH-ZnPc, consequently generating cytotoxic singlet oxygen (1O2), disrupted mitochondrial function and induced apoptosis in cancer cells, which demonstrated great potential for tumor ablation.

Natural resistance to meglumine antimoniate is associated with treatment failure in cutaneous leishmaniasis caused by Leishmania (Viannia) panamensis.

The multifactorial basis of therapeutic response can obscure the relation between antimicrobial drug susceptibility and clinical outcome. To discern the relationship between parasite susceptibility to meglumine antimoniate (SbV) and therapeutic outcome of cutaneous leishmaniasis, risk factors for treatment failure were considered in evaluating this relationship in ninety-one cutaneous leishmaniasis patients and corresponding clinical strains of Leishmania (Viannia) panamensis. Parasite susceptibility to 32 µg SbV/mL (plasma Cmax) was evaluated in primary human macrophages, PBMCs, and U937 macrophages. Early parasitological response to treatment was determined in lesions of a subgroup of patients, and pathogenicity of Sb-resistant and sensitive clinical strains was compared in BALB/c mice. Parasite survival in cell models and patient lesions was determined by qRT-PCR of Leishmania 7SLRNA transcript. Parasite loads in BALB/c mice were quantified by limiting dilution analysis. The disparate Sb-susceptibility of parasite subpopulations distinguished by isoenzyme profiles (zymodemes) was manifest in all cell models. Notably, Sb-resistance defined by parasite survival, was most effectively discerned in U937 macrophages compared with primary human host cells, significantly higher among strains from patients who failed treatment than cured and, significantly associated with treatment failure. Each unit increase in transformed survival rate corresponded to a 10.6-fold rise in the odds of treatment failure. Furthermore, treatment failure was significantly associated with naturally Sb-resistant zymodeme 2.3 strains, which also produced larger lesions and parasite burdens in BALB/c mice than Sb-sensitive zymodeme 2.2 strains. The confounding effect of host risk factors for treatment failure in discerning this association was evidenced in comparing strains from patients with and without the defined risk factors for treatment failure. These results establish the association of natural resistance to meglumine antimoniate with treatment failure, the importance of host risk factors in evaluating drug susceptibility and treatment outcome, and the clinical and epidemiological relevance of natural Sb-resistance in L. (V.) panamensis subpopulations.

Modulation of heat shock protein expression and cytokine levels in MCF-7 cells through photodynamic therapy.

In this study, we assess the impact of photodynamic therapy (PDT) using aluminum phthalocyanine tetrasulfonate (AlPcS4) on the viability and cellular stress responses of MCF-7 breast cancer cells. Specifically, we investigate changes in cell viability, cytokine production, and the expression of stress-related genes. Experimental groups included control cells, those treated with AlPcS4 only, light-emitting diode (LED) only, and combined PDT. To evaluate these effects on cell viability, cytokine production, and the expression of stress-related genes, techniques such as 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, enzyme-linked immunosorbent assays (ELISA), and real-time quantitative PCR (RT‒qPCR) were employed. Our findings reveal how PDT with AlPcS4 modulates mitochondrial activity and cytokine responses, shedding light on the cellular pathways essential for cell survival and stress adaptation. This work enhances our understanding of PDT's therapeutic potential and mechanisms in treating breast cancer.

Salvaging donated kidneys from prolonged warm ischemia during ex vivo hypothermic oxygenated perfusion.

Prolonged warm ischemic is the main cause discarding donated organs after cardiac death. Here, we identified that prolonged warm ischemic time induced disseminated intravascular coagulation and severe capillary vasospasm after cardiac death of rat kidneys. Additionally, we found a significant accumulation of fibrinogen in a hypoxic cell culture of human umbilical vein epithelial cells and in isolated kidneys exposed to prolonged warm ischemic following flushing out of blood. However, pre-flushing the kidney with snake venom plasmin in a 90-minute warm ischemic model maximized removal of micro thrombi and facilitated the delivery of oxygen and therapeutic agents. Application of carbon monoxide-releasing CORM-401 during ex vivo hypothermic oxygenated perfusion achieved multipath protective effects in prolonged warm ischemic kidneys. This led to significant improvements in perfusion parameters, restoration of the microcirculation, amelioration of mitochondrial injury, oxidative stress, and apoptosis. This benefit resulted in significantly prolonged warm ischemic kidney recipient survival rates of 70%, compared with none in those receiving ex vivo hypothermic oxygenated perfusion alone. Significantly, ex vivo hypothermic oxygenated perfusion combined with cytoprotective carbon monoxide releasing CORM-401 treatment meaningfully protected the donated kidney after cardiac death from ischemia-reperfusion injury by reducing inflammation, oxidative stress, apoptosis, and pathological damage. Thus, our study suggests a new combination treatment strategy to potentially expand the donor pool by increasing use of organs after cardiac death and salvaging prolonged warm ischemic kidneys.

CuPc-Fe@BSA nanocomposite: Intracellular acid-sensitive aggregation for enhanced sonodynamic and chemo-therapy.

Due to their rigid π-conjugated macrocyclic structure, organic sonosensitizers face significant aggregation in physiological conditions, hindering the production of reactive oxygen species (ROS). An acid-sensitive nanoassembly was developed to address this issue and enhance sonodynamic therapy (SDT) and emission. Initially, copper phthalocyanine (CuPc) was activated using a H2SO4-assisted hydrothermal method to introduce multiple functional groups (-COOH, -OH, and -SO3H), disrupting strong π-π stacking and promoting ROS generation and emission. Subsequently, negatively charged CuPc-SO4 was incorporated into bovine serum albumin (BSA) to form CuPc-Fe@BSA nanoparticles (10 nm) with Fe3+ ions serving as linkers. In acidic conditions, protonation of CuPc-SO4 and BSA weakened the interactions, leading to Fe3+ release and nanostructure dissociation. Protonated CuPc-SO4 tended to self-aggregate into nanorods. This acidity-sensitive aggregation is vital for achieving specific accumulation within the tumor microenvironment (TME), thereby enhancing retention and SDT efficacy. Prior to this, the nanocomposites demonstrated cycling stability under neutral conditions. Additionally, the released Fe ions exhibited mimicry of glutathione peroxidase and peroxidase activity for chemotherapy (CDT). The synergistic effect of SDT and CDT increased intracellular oxidative stress, causing mitochondrial injury and ferroptosis. Furthermore, the combined therapy induced immunogenic cell death (ICD), effectively activating anticancer immune responses and suppressing metastasis and recurrence.

Dissimilar effect of organometallic ruthenium complexes on the viability of MDR and non-MDR experimental models.

Ruthenium complexes containing triphenylphosphine diamide ligands were prepared, characterized, and tested for their biological activity against various cancer cell lines and the malaria parasite, Plasmodium falciparum. The effect of M (mono-substituted) and B (bis-substituted) complexes on the human cervical carcinoma (HeLa) cell line was investigated using the MTT assay. Five (B2, B3, B5, B6, and B13) of the 24 synthesized ruthenium complexes showed significant effects with IC50 values ranging between 0.3 and 2.3 µM. Evaluation of the potential biomolecular targets of B2 and B13 by fluorescence spectroscopy revealed relevant interactions with BSA and only a weak affinity for ctDNA. Complexes M2, B2, M13 and B13 were selected for further biological characterization. Their effect on the viability of two ovarian cancer cell lines was compared to normal cell lines, denoting their selectivity. Upon treatment of four different drug-resistant gynaecological cancer cell lines, differing in their multidrug-resistant phenotypes, the efficacy of the bis-substituted complexes was shown to be greater than their mono-substituted counterparts. The non-MDR cells are sensitive to all the tested complexes, compared to MDR cells which are less sensitive. Upon investigation of complexes M2, M13, B2, and B13 against sensitive and multidrug-resistant parasite strains of P. falciparum, the bis-substituted complexes were again shown to be the most potent, with submicromolar activity against both strains. Furthermore, the resistance indexes for the complexes were approximately equal to 1, which is at least 5-fold lower than chloroquine diphosphate, suggesting the ability of these complexes to retain their activity in resistant forms of the parasite.

Dual Antimicrobial-Anticancer Potential, Hydrolysis, and DNA/BSA Binding Affinity of a Novel Water-Soluble Ruthenium-Arene Ethylenediamine Schiff base (RAES) Organometallic.

The need for a systematic approach in developing new metal-based drugs with dual anticancer-antimicrobial properties is emphasized by the vulnerability of cancer patients to bacterial infections. In this context, a novel organometallic assembly was designed, featuring ruthenium(II) coordination with p-cymene, one chlorido ligand, and a bidentate neutral Schiff base derived from 4-methoxybenzaldehyde and N,N-dimethylethylenediamine. The compound was extensively characterized in both solid-state and solution, employing single crystal X-ray diffraction, nuclear magnetic resonance, infrared, ultraviolet-visible spectroscopy, and density functional theory, alongside Hirshfeld surface analysis. The hydrolysis kinetic was thoroughly investigated, revealing the important role of the chloro-aqua equilibrium in the dynamics of binding with deoxyribonucleic acid and bovine serum albumin. Notably, the aqua species exhibited a pronounced affinity for deoxyribonucleic acid, engaging through electrostatic and hydrogen bonding interactions, while the chloro species demonstrated groove-binding properties. Interaction with albumin revealed distinct binding mechanisms. The aqua species displayed covalent binding, contrasting with the ligand-like van der Waals interactions and hydrogen bonding observed with the chloro specie. Molecular docking studies highlighted site-specific interactions with biomolecular targets. Remarkably, the compound exhibited wide spectrum moderate antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans, coupled with low micromolar cytotoxic activity against human colorectal adenocarcinoma cells and significant activity against human leukemic monocyte lymphoma cells. The presented findings encourage further development of this compound, promising avenues for its evolution into a versatile therapeutic agent targeting both infectious diseases and cancer.