Antiviral activity of porphyrins and porphyrin-like compounds against tick-borne encephalitis virus: Blockage of the viral entry/fusion machinery by photosensitization-mediated destruction of the viral envelope.

Tick-borne encephalitis virus (TBEV), the causative agent of tick-borne encephalitis (TBE), is a medically important flavivirus endemic to the European-Asian continent. Although more than 12,000 clinical cases are reported annually worldwide, there is no anti-TBEV therapy available to treat patients with TBE. Porphyrins are macrocyclic molecules consisting of a planar tetrapyrrolic ring that can coordinate a metal cation. In this study, we investigated the cytotoxicity and anti-TBEV activity of a large series of alkyl- or (het)aryl-substituted porphyrins, metalloporphyrins, and chlorins and characterized their molecular interactions with the viral envelope in detail. Our structure-activity relationship study showed that the tetrapyrrole ring is an essential structural element for anti-TBEV activity, but that the presence of different structurally distinct side chains with different lengths, charges, and rigidity or metal cation coordination can significantly alter the antiviral potency of porphyrin scaffolds. Porphyrins were demonstrated to interact with the TBEV lipid membrane and envelope protein E, disrupt the TBEV envelope and inhibit the TBEV entry/fusion machinery. The crucial mechanism of the anti-TBEV activity of porphyrins is based on photosensitization and the formation of highly reactive singlet oxygen. In addition to blocking viral entry and fusion, porphyrins were also observed to interact with RNA oligonucleotides derived from TBEV genomic RNA, indicating that these compounds could target multiple viral/cellular structures. Furthermore, immunization of mice with porphyrin-inactivated TBEV resulted in the formation of TBEV-neutralizing antibodies and protected the mice from TBEV infection. Porphyrins can thus be used to inactivate TBEV while retaining the immunogenic properties of the virus and could be useful for producing new inactivated TBEV vaccines.

Antimalarials Targeting the Malaria Parasite Cation ATPase P. falciparum ATP4 (PfATP4).

Malaria, caused by parasites of the Plasmodium species and transmitted through the bites of infected female Anopheles mosquitoes, is still a fatal and dangerous disease in mainly tropical and subtropical regions. The widespread resistance of P. falciparum to antimalarial drugs forces the search for new molecules with activity against this parasite. While a large number of compounds can inhibit P. falciparum growth in vitro, unfortunately, only a limited number of targets have been identified so far. One of the most promising approaches has been the identification of effective inhibitors of P-type cation-transporter ATPase 4 (PfATP4) in P. falciparum. PfATP4 is a Na+ efflux pump that maintains a low cytosolic Na+ in the parasite. Thus, upon treatment with PfATP4 inhibitors, the parasites rapidly accumulate Na+, which triggers processes leading to parasite death. PfATP4 is present in the parasite plasma membrane but is absent in mammals; its exclusivity thus makes it a good antimalarial drug target. The current review presents PfATP4 function in the context of the pharmacological influence of its inhibitors. In addition, compounds with inhibitory activities belonging to spiroindolones, dihydroisoquinolones, aminopyrazoles, pyrazoleamides, and 4-cyano-3-methylisoquinolines, are also reviewed. Particular emphasis is placed on the results of preclinical and clinical studies in which their effectiveness was tested. PfATP4-associated antimalarials rapidly cleared parasites in mouse models and preliminary human trials. These findings highlight a fundamental biochemical mechanism sensitive to pharmacological intervention that can form a medicinal chemistry approach for antimalarial drug design to create new molecules with potent PfATP4 inhibitory activity.

Ciclosporin A Cationic Emulsion 0.1% for the Management of Dry Eye Disease: Facts That Matter for Eye-Care Providers.

Dry eye disease (DED) is a chronic inflammatory disease of the ocular surface requiring long-term therapy. Severe forms of DED generally do not respond to tear substitutes alone or combined, and often require treatment with topical anti-inflammatory agents to break the vicious circle of inflammation. This review summarises data from randomised controlled trials and real-world evidence on the efficacy and safety of ciclosporin A 0.1% cationic emulsion (Ikervis®) for the management of DED. Improvements in clinical signs and symptoms were reported from as early as 4 weeks after treatment initiation, although it can take a few months to reach the full benefits. Treatment periods of up to 12 months provide sustained benefit to patients. In the most responsive patients, treatment discontinuation is possible with no further substantial relapse over 12 months in over 65% of patients. Transient local ocular effects are the most commonly reported adverse events.

Wnt/ß-catenin inhibitor pyrivinium attenuates cisplatin-induced acute kidney injury by possibly reducing platinum uptake and accumulation mediated by reduced organic cation transporter-2 expressions.

Aberrant activation of Wnt/ß-catenin induces renal dysfunction by initiating pro-apoptotic cascades, fibrosis, oxidative and inflammatory burden. This study tested the therapeutic effects of Wnt/ß-catenin inhibitor pyrvinium against cisplatin-induced acute kidney injury (AKI) in rats. Cisplatin was administered at a single dose of 5 mg/kg (i.p.) and renal cisplatin accumulation and uptake in cortical slices were determined after the fifth day by atomic absorption spectroscopy. Levels of pro-inflammatory cytokines were checked by ELISA, and organic cation transporter-2 (OCT-2) transcription and expression in renal tissue were evaluated by RT-PCR and immunohistochemical technique. Cisplatin administration produced renal dysfunction manifested as increase in serum creatinine, blood urea nitrogen, proteinuria, reduced clearance and electrolyte imbalance. Oxidative stress indices, pro-inflammatory cytokines, fibronectin, and caspase-3 activity were elevated in cisplatin-challenged rats. Moreover, increased renal OCT-2 transcription and immunostaining were detected in cisplatin kidneys which resulted in platinum accumulation. Additional docking studies depicted strong interaction between the ß-catenin and OCT-2 protein. These manifestations induced mitochondrial dysfunction, histological damage and fibrosis. Notably, Wnt/ß-catenin inhibitor pyrvinium (60 µg/kg; p.o.) treatment reduced the renal OCT-2 gene transcription causing a decline in platinum levels. Thus, the present study concludes that Wnt/ß-catenin inhibition attenuates cisplatin-induced AKI in rats, partly by down-regulating OCT-2 expression.

[Current status of persistent chronic hyperkalaemia in France: An expert consensus based on a Delphi approach]. / État des lieux sur l'hyperkaliémie chronique persistante en France : consensus d'experts par une approche Delphi.

INTRODUCTION: In France, no consensus document on the management of persistent hyperkalaemia is currently available. Variability in clinical practices has been observed. METHODS: A consensus statement on the definition and the management of persistent hyperkalaemia was developed by a Delphi panel of French nephrologists between December 2019 (26 voting participants among 40 invited panellists in first round) and June 2020 (20 voting participants among 26 panellists in second round). RESULTS: Persisting hyperkalaemia not controlled with current treatment strategies may be defined as the occurrence of two or more hyperkalaemia episodes within a year despite the administration of cation-exchange resins or loop diuretics during the same year. Some patient characteristics (diabetes, chronic kidney disease from stage 3B to stage 5 without dialysis, chronic heart failure) are associated with an increased risk of developing persistent hyperkalaemia. There is a medical need for the management of persistent hyperkalaemia in patients treated with renin-angiotensin-aldosterone system inhibitors that is not met by current treatment strategies (including available cation-exchange resins). CONCLUSIONS: The panel expressed a need for new treatment strategies validated by clinical trials.

Role of interleukin-6 in antigen-specific mucosal immunoglobulin A induction by cationic liposomes.

The COVID-19 pandemic, caused by a highly virulent and transmissible pathogen, has proven to be devastating to society. Mucosal vaccines that can induce antigen-specific immune responses in both the systemic and mucosal compartments are considered an effective measure to overcome infectious diseases caused by pathogenic microbes. We have recently developed a nasal vaccine system using cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium-propane and cholesteryl 3ß-N-(dimethylaminoethyl)carbamate in mice. However, the comprehensive molecular mechanism(s), especially the host soluble mediator involved in this process, by which cationic liposomes promote antigen-specific mucosal immune responses, remain to be elucidated. Herein, we show that intranasal administration of cationic liposomes elicited interleukin-6 (IL-6) expression at the site of administration. Additionally, both nasal passages and splenocytes from mice nasally immunized with cationic liposomes plus ovalbumin (OVA) were polarized to produce IL-6 when re-stimulated with OVA in vitro. Furthermore, pretreatment with anti-IL-6R antibody, which blocks the biological activities of IL-6, attenuated the production of OVA-specific nasal immunoglobulin A (IgA) but not OVA-specific serum immunoglobulin G (IgG) responses. In this study, we demonstrated that IL-6, exerted by nasally administered cationic liposomes, plays a crucial role in antigen-specific IgA induction.

Use of dietary supplements containing polyvalent cations and antacids among people with HIV and its impact on viral suppression.

Dietary supplements and medications containing polyvalent cations can interact with integrase strand transfer inhibitors (INSTIs) and decrease exposure to INSTIs. In this cross-sectional study of 513 people with HIV (PWH) who were on stable antiretroviral therapy, 57.5% and 6.6% reported concurrent use of dietary supplements and antacids, respectively. In the multivariable analysis, the use of antacids, but not dietary supplements containing polyvalent cations, was associated with HIV viremia in PWH who received INSTI-based ART.

Efficacy and toxicity of particle radiotherapy in WHO grade II and grade III meningiomas: a systematic review.

OBJECTIVEAdjuvant radiotherapy has become a common addition to the management of high-grade meningiomas, as immediate treatment with radiation following resection has been associated with significantly improved outcomes. Recent investigations into particle therapy have expanded into the management of high-risk meningiomas. Here, the authors systematically review studies on the efficacy and utility of particle-based radiotherapy in the management of high-grade meningioma.METHODSA literature search was developed by first defining the population, intervention, comparison, outcomes, and study design (PICOS). A search strategy was designed for each of three electronic databases: PubMed, Embase, and Scopus. Data extraction was conducted in accordance with the PRISMA guidelines. Outcomes of interest included local disease control, overall survival, and toxicity, which were compared with historical data on photon-based therapies.RESULTSEleven retrospective studies including 240 patients with atypical (WHO grade II) and anaplastic (WHO grade III) meningioma undergoing particle radiation therapy were identified. Five of the 11 studies included in this systematic review focused specifically on WHO grade II and III meningiomas; the others also included WHO grade I meningioma. Across all of the studies, the median follow-up ranged from 6 to 145 months. Local control rates for high-grade meningiomas ranged from 46.7% to 86% by the last follow-up or at 5 years. Overall survival rates ranged from 0% to 100% with better prognoses for atypical than for malignant meningiomas. Radiation necrosis was the most common adverse effect of treatment, occurring in 3.9% of specified cases.CONCLUSIONSDespite the lack of randomized prospective trials, this review of existing retrospective studies suggests that particle therapy, whether an adjuvant or a stand-alone treatment, confers survival benefit with a relatively low risk for severe treatment-derived toxicity compared to standard photon-based therapy. However, additional controlled studies are needed.

Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile: Synthesis, antibacterial evaluation and an in vivo C. difficile infection model.

Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited; this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C. difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 µg/mL against methicillin-resistant Staphylococcus aureus and 8 µg/mL against C. difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 µg/mL), Pseudomonas aeruginosa (8 µg/mL) and Klebsiella pneumoniae (16 µg/mL); additionally, compound 50 displayed reduced haemolytic activity (<13%) in an in vitro haemolysis assay. Membrane-disruption assays were conducted on selected derivatives to confirm the membrane-active mechanism of action inherent to the synthesized amphiphilic compounds. A comparative solubility assay was developed and utilized to optimize the aqueous solubility of the compounds for in vivo studies. The biaryl peptidomimetics 28 and 67 were found to exhibit significant efficacy in an in vivo murine model of C. difficile infection by reducing the severity and slowing the onset of disease.

Therapeutic effects and anti-metastasis effects of cationic liposomes against pancreatic cancer metastasis in vitro and in vivo.

The anti-metastatic effects of cationic liposomes (CL) composed of 87 mol% dimyristoylphosphatidylcholine (DMPC), 8 mol% O,O'-ditetradecanoyl-N-(α-trimethylammonioacetyl) diethanolamine chloride (2C14ECl) and 5 mol% polyoxyethylene(21) dodecyl ether (C12(EO)21) was investigated for human pancreatic cancer (BxPC-3) cells. The inhibitory effect of CL on the migration of BxPC-3 cells was observed based on a wound scratch assay. CL suppressed pseudopodium formation of BxPC-3 cells. The anti-invasive effect of CL against BxPC-3 cells was observed via a Matrigel invasion assay. The anti-invasive effect of CL for BxPC-3 cells was found to occur through the inhibition of MMP2, MMP9, and MMP14. Overall, the results of this study revealed for the first time, the therapeutic effects and anti-metastasis activity of CL in xenograft mouse models for peritoneal metastasis of human pancreatic cancer.

Inhibition of glioma growth by a GOLPH3 siRNA-loaded cationic liposomes.

PURPOSE: GOLPH3 has been shown to be involved in glioma proliferation. In this study, we aimed to demonstrate that GOLPH3 can serve as a target for glioma gene therapy. METHODS: During the experiment, cationic liposomes with angiopep-2 (A2-CL) were used to deliver siGOLPH3 crossing the blood-brain barrier and reaching the glioma. RESULTS: At the cellular level, the A2-CL/siGOLPH3 could silence GOLPH3 and then effectively inhibited the proliferation of cells. In vivo experiments, using U87-GFP-Luci-bearing BALB/c mouse models, we demonstrated that A2-CL could deliver GOLPH3-siRNA specifically to glioma and effectively inhibit glioma growth. CONCLUSIONS: This study shows that GOLPH3 has great potential as a target for the gene therapy of glioma and is of great value in precise medical applications.

Can neutral dietary cation-anion difference (DCAD) decrease occurrence of clinical periparturient hypocalcaemia in dairy cattle?

BACKGROUND: Adjusting the dietary cation-anion difference (DCAD) is one of the most efficient ways to stimulate calcium homeostasis in periparturient dairy cattle. However, adjusting DCAD to the recommended negative values (-100 to -150 mEq/kg) is associated with decreased food intake and metabolic acidosis. The critical conditions of the animals at peripartum (i.e. drastic hormonal changes, decreased appetite and negative energy balance) can be detrimental to the health, productivity and welfare of the animals if combined with decreased feed intake caused by unpalatable acidogenic salts. METHODS: In a cross-sectional study, we analysed the ration of eight small to large dairy herds with intensive husbandry systems, including 6949 dry cows. Sodium, potassium, chlorine and sulfur concentrations in the feed were determined and DCAD was calculated. The DCAD of the ration of the farms ranged from -33.5 to +24.7 mEq/kg. Parturient paresis (PP, or milk fever) prevalence was investigated and correlated to DCAD values. RESULTS: Clinical PP occurrence in the dairies of this investigation on average declined by 87% (ranging from a 97% decline to 5% increase). This indicates that adjusting DCAD at neutral values (0 ± 30 mEq/kg range) may both lower the PP prevalence and increase ration palatability by lowering acidogenic salts in the ration. CONCLUSIONS: Further research is recommended to investigate the effects of neutral DCAD on subclinical hypocalcaemia and food intake of the cattle.

Osteochondral Angiogenesis and Promoted Vascularization: New Therapeutic Target.

The control of the different angiogenic process is an important point in osteochondral regeneration. Angiogenesis is a prerequisite for osteogenesis in vivo; insufficient neovascularization of bone constructs after scaffold implantation resulted in hypoxia and cellular necrosis. Otherwise, angiogenesis must be avoided in chondrogenesis; vascularization of the cartilage contributes to structural damage and pain. Finding a balance between these processes is important to design a successful treatment for osteochondral regeneration. This chapter shows the most important advances in the control of angiogenic process for the treatment of osteochondral diseases focused on the administration of pro- or anti-angiogenic factor and the design of the scaffold.

Cationic gas-filled microbubbles for ultrasound-based nucleic acids delivery.

The use of ultrasound has gained great interest for nucleic acids delivery. Ultrasound can reach deep tissues in non-invasive manner. The process of sonoporation is based on the use of low-frequency ultrasound combined with gas-filled microbubbles (MBs) allowing an improved delivery of molecules including nucleic acids in the insonified tissue. For in vivo gene transfer, the engineering of cationic MBs is essential for creating strong electrostatic interactions between MBs and nucleic acids leading to their protection against nucleases degradation and high concentration within the target tissue. Cationic MBs must be stable enough to withstand nucleic acids interaction, have a good size distribution for in vivo administration, and enough acoustic activity to be detected by echography. This review aims to summarize the basic principles of ultrasound-based delivery and new knowledge acquired in these recent years about this method. A focus is made on gene delivery by discussing reported studies made with cationic MBs including ours. They have the ability for efficient delivery of plasmid DNA (pDNA), mRNA or siRNA. Last, we discuss about the key challenges that have to be faced for a fine use of this delivery system.

Exceptionally High Proton and Lithium Cation Gas-Phase Basicity of the Anti-Diabetic Drug Metformin.

Substituted biguanides are known for their biological effect, and a few of them are used as drugs, the most prominent example being metformin (1,1-dimethylbiguanide, IUPAC name: N,N-dimethylimidodicarbonimidic diamide). Because of the presence of hydrogen atoms at the amino groups, biguanides exhibit a multiple tautomerism. This aspect of their structures was examined in detail for unsubstituted biguanide and metformin in the gas phase. At the density functional theory (DFT) level {essentially B3LYP/6-311+G(d,p)}, the most stable structures correspond to the conjugated, push-pull, system (NR2)(NH2)C═N-C(═NH)NH2 (R = H, CH3), further stabilized by an internal hydrogen bond. The structural and energetic aspects of protonation and lithium cation adduct formation of biguanide and metformin was examined at the same level of theory. The gas-phase protonation energetics reveal that the more stable tautomer is protonated at the terminal imino C═NH site, still with an internal hydrogen bond maintaining the structure of the neutral system. The calculated proton affinity and gas-phase basicity of the two molecules reach the domain of superbasicity. By contrast, the lithium cation prefers to bind the less stable, not fully conjugated, tautomer (NR2)C(═NH)-NH-C(═NH)NH2 of biguanides, in which the two C═NH groups are separated by NH. This less stable form of biguanides binds Li+ as a bidentate ligand, in agreement with what was reported in the literature for other metal cations in the solid phase. The quantitative assessment of resonance in biguanide, in metformin and in their protonated forms, using the HOMED and HOMA indices, reveals an increase in electron delocalization upon protonation. On the contrary, the most stable lithium cation adducts are less conjugated than the stable neutral biguanides, because the metal cation is better coordinated by the not-fully conjugated bidentate tautomer.

π-Delocalized Lipophilic Cations as New Candidates for Antimalarial, Antitrypanosomal and Antileishmanial Agents: Synthesis, Evaluation of Antiprotozoal Potency, and Insight into Their Action Mechanisms.

The search for new drugs that could treat tropical protozoan diseases, such as malaria or neglected tropical diseases (NTDs), motivates many medicinal chemists. New classes of antiprotozoal drugs that act through a novel mechanism of action must be developed. This review presents our efforts toward finding new candidate treatments for malaria, American trypanosomiasis, human African trypanosomiasis and leishmaniasis based on π-delocalized lipophilic cations (DLCs). DLCs, such as rhodacyanines, azarhodacyanines, ß-carbolinium salts, and phenoxazinium salts, displayed strong antiprotozoal activities with highly selective indices. Several DLCs displayed moderate to excellent in vivo efficacies against Plasmodium berghei when administered intraperitoneally or orally. This review also discusses chemical biology approaches to understanding the mechanism of action underlying the antimalarial rhodacyanines.

Efficient Packaging of Plasmid DNA Using a pH Sensitive Cationic Lipid for Delivery to Hepatocytes.

Plasmid DNA (pDNA) is expected to be a new class of medicine for treating currently incurable diseases. To deliver these nucleic acids, we developed a liposomal delivery system we have called a multifunctional envelope-type nano device (MEND). In this report, we demonstrate that a MEND containing a pH-sensitive cationic lipid, YSK05 (YSK-MEND), efficiently delivered pDNA via systemic injection, and that its expression was highly dependent on the encapsulation state of the pDNA. In the preparation, the pH, ionic strength, and sodium chloride (NaCl) concentration of the lipid/pDNA mixture strongly affected the encapsulation efficiency of pDNA. Additionally, the transgene expression of luciferase in the liver by the injected YSK-MEND was dependent on the encapsulation state of pDNA rather than the nature of the YSK-MEND. Confocal laser scanning microscopy findings revealed that injection of the YSK-MEND led to homogenous gene expression in the liver compared to injection via the hydrodynamic tail vein (HTV). Concerning the safety of the YSK-MEND, a transient increase in the activity of liver enzymes was observed. However, no significant adverse events were observed. Taken together, the YSK-MEND represents a potentially attractive therapy for the treatment of various hepatic diseases.

In vivo toxicity of cationic micelles and liposomes.

This study investigated toxicity of nanocarriers comprised of cationic polymer and lipid components often used in gene and drug delivery, formulated as cationic micelles and liposomes. Rats were injected intravenously with 10, 25 or 100 mg/kg and sacrificed after 24 or 48 h, or 24 h after the last of three intravenous injections of 100 mg/kg every other day. Histological evaluation of liver, lung and spleen, clinical chemistry parameters, and hematology indicated little effect of treatment. DNA strand breaks were increased in the lung and spleen. Further, in the dose response study we found unaltered expression levels of genes in the antioxidant response (HMOX1) and repair of oxidized nucleobases (OGG1), whereas expression levels of cytokines (IL6, CXCL2 and CCL2) were elevated in lung, spleen or liver. The results indicate that assessment of genotoxicity and gene expression add information on toxicity of nanocarriers, which is not obtained by histology and hematology. FROM THE CLINICAL EDITOR: This study investigates the toxicity of cationic micelles and liposomes utilized as nanocarriers in gene and drug delivery, demonstrating its effects on the lungs, spleen and liver.

Therapeutic effects of cationic hybrid liposomes on the hepatic metastasis of colon carcinoma along with apoptosis in vivo.

Therapeutic effects of cationic hybrid liposomes (HL) composed of 87 mol% dimyristoyl-phosphatidylcholine (DMPC), 5 mol% polyoxyethylene (21) dodecyl ether (C12(EO)21) and 8 mol% O,O'-ditetradecanoyl-N-(α-trimethyl-ammonioacetyl) diethanolamine chloride (2C14ECl) on the metastasis of human colon carcinoma (HCT116) cells were examined in vivo. Cationic HL having a hydrodynamic diameter less than 150 nm were preserved for one month. Therapeutic effects were obtained in the hepatic metastasis mouse models of HCT116 cells after the intravenous injection of cationic HL. The histological analysis indicated the induction of apoptosis in the liver section of the hepatic metastasis mouse models treated with cationic HL in vivo. Therapeutic effects of cationic HL without any drugs on the hepatic metastasis were revealed for the first time on the basis of histological analyses in vivo.