Infections due to Candida spp., they are a threat to global health, with high rates of morbidity and mortality due to their drug resistance, especially in immunocompromised people. Thus, the search for new alternatives is urgent today. In recent years, combined therapy with compounds of natural origin has been proposed as an alternative. Considering the biological potential of isoespintanol (ISO) and continuing with its study, the objective of this research was to assess the effect of ISO in combination with the antifungals, fluconazole (FLZ), amphotericin B (AFB) and caspofungin (CASP), against clinical isolates of C. tropicalis and evaluate the cytotoxic effect of this compound in the acute phase (days 0 and 14) and chronic phase (days 0, 14, 28, 42, 56, 70 and 84), in female mice (Mus musculus) of the Balb/c lineage. The results show that ISO can potentiate the effect of FLZ, AFB and CASP, showing synergism with these antifungals. Evaluation of the mice by direct vision showed no behavioral changes or variation in weight during treatment; furthermore, the analysis of the cytokines IFN-γ and TNF in plasma, peritoneal cavity lavage (PCL) and bronchoalveolar lavage (BAL) indicated that there was no inflammation process and histopathological studies of lung, liver and kidney showed no signs of toxicity caused by ISO; this was consistent with the analysis of oxaloacetic transaminases (GOT) and pyruvic transaminases (GPT), which remained in the standard range. These findings indicate that ISO does not have a cytotoxic effect at the doses evaluated. Our results place ISO as a monoterpene of interest in the search for compounds with pharmacological potential.

The aim of our work was to check if one of the products of natural origin, namely honey bee propolis may be an alternative or supplement to currently used antifungal agents. The activity of 50 ethanolic extracts of propolis (EEPs), harvested in Polish apiaries, was tested on a group of 69 clinical isolates of C. albicans. Most of the EEPs showed satisfactory activity, with minimum fungicidal concentrations (MFC) mainly in the range of 0.08-1.25% (v/v). Eradication of biofilm from polystyrene microtitration plates in 50% (MBEC50) required concentrations in the range of 0.04% (v/v) to more than 1.25% (v/v). High activity was also observed in eradication of biofilm formed by C. glabrata and C. krusei on the surfaces of PVC and silicone catheters. EEPs at subinhibitory concentrations inhibited yeast-to-mycelia morphological transformation of C. albicans in liquid medium and mycelial growth on solid medium. A synergistic effect was observed for the action of EEPs in combination with fluconazole (FLU) and voriconazole (VOR) against C. albicans. In the presence of EEP at concentration as low as 0.02%, the MICs of FLU and VOR were 256 to 32 times lower in comparison to those of the drug alone. Evidences for the fungal cell membrane as the most probable target of EEPs are presented.

Recently many medications are derived from natural substances that have a potential to fight diseases. These bioactive compounds such as curcumin (CUR) and nicotinamide (NIC) have an antioxidant, anti-inflammatory activity and boosting the immune system. Aim: This study aims to evaluate antibacterial and antimelanoma activity of CUR-NIC combination and their liposomal preparation. Method: Activity of CUR-NIC was investigated against skin infection bacteria, Staphylococcus aureus and Pseudomonas aeruginosa. The cytotoxicity assay for melanoma B16 cancer cell line using MTT and migration assays. Results: The CUR and CUR-NIC (1:1) combination and showed an inhibition zone against S. aureus of 18±0.8 mm and MIC 31.25 µg/ml compared to 16 ±0.85 and 62.5 µg/ml, respectively. The cytotoxicity assay for melanoma B16 cancer cell line revealed that the of CUR and NIC combination synergistically reduced cell proliferation with (CI< 1). Indeed, liposomal preparation showed cytotoxic effect of Lip-CUR (IC50= 31.4 ± 3.2), Lip-NIC (IC50=190 ± 7.3) and Lip-CUR-NIC (IC50 8.5 ± 0.3) while CUR showed IC50 of 9.8 ± 2.2µM and NIC (IC50 135.95 ±10.2 µM). Conclusion: synergistic effect when curcumin and nicotinamide are combined, potentially offering a more effective cancer treatment strategy.

Chemical combinations are believed to reduce drug toxicity, delay cancer cell growth, and achieve enhanced efficacy compared with single active drugs. This research investigated the synergistic effect of DOX and Zm-093, a new sulfonamide derivative, on improving the potential for inducing apoptosis in breast cancer (BC) cell lines. First, the Zm-093 compound was synthesized and its structure was confirmed by FT-IR and NMR. Then, the IC50 values for DOX and Zm-093 were calculated to be 1.21 and 51.24 μM, respectively. To investigate the synergistic effect, Compusyn software was utilized to calculate the combination index (CI). Different methods, including western blotting, flow cytometry, and TUNEL, were used to evaluate the potential synergistic effects of these compounds on inducing apoptosis in MCF-7 cells. Combining the indexes obtained at all concentrations revealed synergistic results. The proapoptotic proteins Bax, tBid, and caspase-3, however, increased 2.4, 3.3, and 5.7 times more than those in the control group. Flow cytometry analysis and the TUNEL method in cells treated with DOX and Zm-093 showed that apoptosis was significantly higher than in other groups. The results confirmed the synergistic effect of DOX and ZM-093 on apoptotic factors expression in MCF-7 cells.

Inappropriate expression of histone deacetylase (HDAC6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway are common aberrations observed in cancers. LASSBio-2208, was previously described as a dual inhibitor in the nanomolar range of HDAC6 and PI3Kα, being three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its DMPK in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on MCF-7 (IC50 = 23 µM), CCRF-CEM (IC50 = 8.54 µM) and MOLT-4 (IC50 = 7.15 µM), with no cytotoxic effect on hPBMC. In addition, it has a good antiproliferative effect on MCF-7 cells (IC50 = 5.44 µM), low absorption by PAMPA-GIT and low permeation through the blood-brain barrier by PAMPA-BBB, exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentration corresponding to their CC50 values on MOLT-4 and CCRF-CEM cells.

A study to produce cellulose nanofibrils (CNF) from Kraft cellulose pulp, an optimal enzyme mixture, was defined using a centroid simplex mixture design. The enzyme blend contains 69% endoglucanase and 31% exoglucanase. The central composite rotational design (CCRD) optimized the CNF production process by achieving a higher crystallinity index. It thus corresponded to a solid loading of 15 g/L and an enzyme loading of 0.974. Using the Segal formula, the crystallinity index (CrI) of CNF was determined by X-ray diffraction to be 80.87%. The average diameter of nanocellulose fibers measured by scanning electron microscopy between 550 - 600 nm for the CNF prepared by enzymatic hydrolysis and between 250 - 300 nm for the CNF produced by enzymatic hydrolysis with the optimal enzyme mixture followed by ultrasonic dispersion. Finally, synergistic interactions between the enzymes involved in nanocellulose production were demonstrated, with Colby factor values greater than one.

Cyanex 301 and LIX 63 can seletively extract Pd(II) over Pt(IV) from strong hydrochloric acid solutions. Therefore, solvent extraction experiments have been performed by extractant mixtures containing either Cyanex 301 or LIX 63 and the extraction behavior of Pd(II) was compared. Among the mixture of Cyanex 301, the highest synergistic enhancement coefficient was achieved by mixing Cyanex 301 and TOPO. However, it was very diffiuclt to strip the Pd(II) from the loaded mixture. Among the mixture of LIX 63, the mixture of LIX 63 and Alamine 336/TOPO enhanced the extraction of Pt(II). Although the synergistic coefficient by Cyanex 301 + TOPO was higher than that by LIX 63 + Alamine 336, the Pd(II) in the loaded mixture of LIX 63 and Alamine 336 was easily stripped by thiourea.

Cryptococcus neoformans is a multidrug-resistant human pathogenic yeast responsible for infections in immunocompromised patients. Here, Itraconazole (ITR), a commercial antifungal drug with low effectiveness against C. neoformans, was combined with different synthetic peptides Mo-CBP3-PepII, RcAlb-PepII, RcAlb-PepIII, PepGAT, and PepKAA. The mechanisms of action responsible for the synergistic effect were evaluated for the best combinations by Fluorescence Microscopy (FM). The synthetic peptides enhanced the activity of ITR by 10-fold against C. neoformans. Our results demonstrated that the combinations could induce pore formation in the membrane and overaccumulation of ROS on C. neoformans cells. Our findings indicate that our peptides successfully potentialize the activity of ITR by reducing it by 10-fold to reach antifungal activity against C. neoformans. Therefore, synthetic peptides are potential molecules to act as co-adjuvant agents in treating Cryptococcal infections.

Staphylococcus aureus frequently causes subclinical mastitis around the world with high impact in milk industry and public health. Essential oils (EO) are recognized antimicrobials that can be synergistic with antibiotics. The main objective of this study was evaluating the essential oil (EO) of Melaleuca armillaris as an adjuvant of erythromycin (ERY) for the alternative treatment of bovine mastitis caused by S. aureus. The Minimum Inhibitory and Bactericidal Concentrations (MIC and MBC) of EO, ERY, and its combinations were established against S. aureus at different pHs (7.4, 6.5 and 5.0), emulating extra and intracellular conditions. Sensible (N=3) and resistant (N=3) strains to ERY and S. aureus ATCC 29213 as control were used. Math models were applied to described the antibacterial activity of EO and combinations EO-ERY. The EO was bactericidal against all the strains independently of the pH with a slightly improvement in acid conditions. The synergism between EO and ERY was estimated by the Fractional Inhibitory Concentration Index (FIC) and by mathematical modeling of the bacterial killing data. Synergism was observed with ERY, where combinations had bactericidal activity also even with pH modification. M. armillaris EO is an interesting adjuvant for ERY, being a promissory option for further analysis of intracellular efficacy against S. aureus.

Investigation of the methanol extract of the poroid fungus Fuscoporia torulosa resulted in the isolation of a novel triterpene, fuscoporic acid (1) together with inoscavin A and its previously undescribed Z isomer (2 and 3), 3,4-dihydroxy-benzaldehide (4), osmundacetone (5), senexdiolic acid (6), natalic acid (7), and ergosta-7,22-diene-3-one (8). The structures of fungal compounds were determined on the basis of NMR and MS spectroscopic analysis, as well as molecular modelling studies. Compounds 1, 6-8 were examined for their antibacterial properties on resistant clinical isolates, and cytotoxic activity on human colon adenocarcinoma cell lines. Compound 8 was effective against Colo 205 (IC50 11.65±1.67 µM), Colo 320 (IC50 8.43±1.1 µM) and MRC-5 (IC50 7.92±1.42 µM) cell lines. Potentially synergistic relationship was investigated between 8 and doxorubicin, which revealed a synergism between the examined compounds with a combination index (CI) at the 50% growth inhibition dose (ED50) of 0.521±0.15. Several compounds (1, and 6-8) were tested for P‐glycoprotein modulatory effect in Colo 320 resistant cancer cells, but none of the compounds proved to be effective in this assay. Fungal metabolites 2-5 were evaluated for their antioxidant activity using the oxygen radical absorbance capacity (ORAC) and DPPH assays. Compounds 4 and 5 proved to possess considerable antioxidant effect with EC50 0.25±0.01 (DPPH) and 12.20±0.92 mmol TE/g (ORAC). The current article provides valuable information on both chemical and pharmacological profiles of Fuscoporia torulosa, paving the way for future studies with this species.

Helicobacter pylori infections are still an urgent and hot topic. This is related to the involvement of H. pylori in human diseases (including gastric diseases, gastric adenocarcinoma, mucosa-associated lymphoid tissue lymphoma, and diabetes), the number of which is constantly increasing. At the same time, agents effective against these bacteria are decreasing due to spreading resistance. Our research focused on extracts of the Rubus genus, commonly present in Central and Eastern Europe and very useful in folk medicine. Results have shown that the extract from Rubus idaeus 'Willamette' shoots, and the extract from R. idaeus 'Poranna Rosa' fruits and R. idaeus 'Laszka' R. occidentalis Litacz' fruits prevent the formation of biofilm by H. pylori on intravenous infusions (they reduce living cells, which was detected using triphenyl tetrazolium chloride (TTC) as a dye) at concentrations of 6.65 and 16.65 mg/mL, respectively. However, the living bacteria in the formed biofilm are affected by the extract from the shoots of R. idaeus 'Willamette' and the fruit of R. idaeus 'Poranna Rosa' at a concentration of 16.65 mg/ml, and the remaining extracts at a concentration of 33.3 mg/ml. The results of the study of interactions of extracts from Rubus sp. and the 2 antibiotics against H. pylori planktonic bacteria showed doxycycline synergism with all tested extracts, but only the extract of R. occidentalis 'Litacz' with levofloxacin. The remaining tested extracts showed indifference with levofloxacin. However, studies on the interaction between antibiotics and extracts of R. idaeus 'Willamette' shoot showed synergy with doxycycline and levofloxacin, additivity with amoxicillin and clarithromycin, and indifference with metronidazole. The tests were carried out on fragments of intravenous infusions with TTC as a dye. The tested extracts may be elements of broadly understood anti-H. pylori therapy.

The therapeutic effectiveness of current neurodegenerative diseases treatments is still under debate because of problems with bioavailability and a range of side effects. Fungi, which are increasingly recognized as sources of natural antioxidants and AChE enzyme inhibitors, may thus serve as potent neuroprotective agents. Previous studies have associated the anti-AChE and antioxidant activities of fungi mostly with polysaccharides and phenolic compounds, while other secondary metabolites such as polyamines (PAs) have been neglected. This study aimed to investigate eight edible and medicinal fungi from Serbia, marking the initial investigation into the neuroprotective capabilities of Postia caesia, Clitocybe odora, Clitopilus prunulus, and Morchella elata. Neuroprotective activity was examined using Ellman assay, while antioxidant capacity was tested by conducting DPPH, NO, ABTS and FRAP tests. PAs levels were determined by HPLC coupled with fluorescent detection. Ganoderma applanatum and Lepista nuda exhibited the most robust anti-AChE (98.05 ± 0.83% and 99.94 ± 3.10%, respectively) and antioxidant activities attributed to the synergistic effects of total protein, total phenolic and PAs levels. Furthermore, P. caesia displayed significant AChE inhibition (88.21 ± 4.76%), primarily linked to elevated SPD (62.98 ± 3.19%) and PUT levels (55.87 ± 3.16%). Our results highlight the need of thorough research to comprehend the intricate relationships between distinct fungus species and AChE inhibition. However, it's important to recognize that more research is required to identify the precise substances causing the reported inhibitory effects.

Allylbenzenes (apiol, dillapiol, myristicin and allyltetramethoxybenzene) are individual components of plant essential oils that demonstrate antitumor activity, as well as enhancing effect on cytotoxic drugs such as paclitaxel, doxorubicin, cisplatin, etc. Triphenylphosphine (PPh3) derivatives of allylbenzenes are 2-3 orders of magnitude more potent than allylbenzenes in terms of IC50. Inhibition of efflux pumps has been reported for allylbenzenes, and PPh3 moiety is deemed to be responsible for preferential mitochondrial accumulation and depolarization of mitochondrial membranes. However, due to poor solubility the practical use of these substances has never been an option. Cyclodextrin-based (CD) molecular containers suggested here provided solubilization of allylbenzenes and its PPh3-derivatives. So, in this study we have observed an increase antitumor activity of paclitaxel in the presence of PPh3-derivatives adjuvants by an order of magnitude (in terms of IC50) against adenocarcinomic human alveolar basal epithelial cells A549. At the same time, they are quite powerful cytostatics themselves against A549 cells. On the other hand, the cytotoxic formulations developed show pronounced selectivity of the antiproliferation activity: high against tumor cells line (A549) and low toxicity of these composition was demonstrated on normal cells HEK293T, red blood cells, and sea urchin embryos (a model close to the human genome). On non-cancer HEK293T cells, it was shown that PPh3-derivatives of allylbenzenes at a concentration of 100 µM cause the death of about 20% of cells, while on A549 cancer cells, 85% of cells die. PPh3 derivatives of allylbenzenes, when solubilized in CD molecular containers, show remarkable potential as adjuvants to some of the widely used cytotoxic drugs.

Over the past several decades, the extensive use of pyrethroids has led to the development of resistance in many insect populations, including the economically damaging pest tarnished plant bug (TPB), Lygus lineolaris on cotton. To manage TPB resistance, several commercially formulated pyrethroid-containing binary mixtures, in combination with neonicotinoids or avermectin are recommended for TPB control and resistance management in the Mid-south USA. This study aimed to evaluate the toxicity and resistance risks of four formulated pyrethroid-containing binary mixtures (Endigo, Leverage, Athena, and Hero) on one susceptible and two resistant TPB populations which were field-collected in July (Field-R1) and October (Field-R2), respectively. Based on LC50 values, both resistant TPB populations displayed variable tolerance to the four binary mixtures, with Hero showing the highest resistance and Athena the lowest. Notably, the Field-R2 exhibited 1.5-3-fold higher resistance compared to the Field-R1 for all four binary insecticides. Moreover, both resistant TPB populations demonstrated significantly higher resistance ratios toward Hero and Leverage compared to their corresponding individual pyrethroid, while Endigo and Athena showed similar or lower resistance. This study also utilized the calculated additive index (AI) and co-toxicity coefficient (CTC) analysis, which revealed that the two individual components in Leverage exhibited antagonist effects against the two resistant TPB populations. In contrast, the two individual components in Endigo, Hero and Athena displayed synergistic interactions. Considering that Hero is a mixture of two pyrethroids which can enhance the development of TPB resistance, our findings suggest that Endigo and Athena are likely superior products for slowing down resistance development in TPB populations. This study provides valuable insight for selecting the most effective mixtures to achieve better TPB control through synergistic toxicity analysis, while simultaneously reducing economic and environmental risks associated with resistance development in the insect pest.

Chemotherapy is a standard therapeutic option for triple-negative breast cancer (TNBC); however, its effectiveness is often compromised by drug-related toxicity and resistance development. Herein, we aimed to evaluate whether an improved antineoplastic effect could be achieved in vitro and in vivo in TNBC by combining dovitinib, a multi-kinase inhibitor, with calcitriol, a natural anti-cancer hormone. In vitro, cell proliferation and cell-cycle distribution were studied by sulforhodamine B-assays and flow cytometry. In vivo, dovitinib/calcitriol effects on tumor growth, angiogenesis and endothelium activation were evaluated in xenografted mice by caliper measures, Itgb3-immunohistochemistry and 99mTc-RGD2-tumor uptake. The drug combination elicited a synergistically improved antiproliferative effect in TNBC-derived cells, which allowed a 7-fold dovitinib dose-reduction. Mechanistically, the co-treatment induced cell death and accumulation in S and G2/M phases, while inhibited tumor growth to a greater extent than each compound alone. Tumor uptake of 99mTc-RGD2 was reduced by dovitinib, suggesting angiogenesis inhibition, which was corroborated by decreased endothelial cell growth and tumor vessel density. In summary, calcitriol synergized dovitinib anticancer effects in vitro and in vivo, allowing for a significant dose-reduction of dovitinib, while maintaining its antiproliferative potency. Our results suggest the beneficial convergence of independent antitumor mechanisms of dovitinib and calcitriol to inhibit TNBC-tumor growth.

Potato virus Y (PVY) is one of the most important constraints to potato production worldwide. There is an increasing occurrence of recombinant PVY strains PVYNTN and PVYN-Wi and a decline in the incidence of the nonrecombinant PVYO. We hypothesized that this may be due to the ability of these recombinant strains to antagonize and/or outcompete PVYO in mixed infections. To deter-mine this, we investigated interactions between PVYO and three recombinant PVY strains com-mon in North America: PVYNTN, PVYN-Wi, and PVYN:O. Overall, our study showed that these inter-actions are tissue dependent. Specifically, PVYNTN, the main causal agent of potato tuber necrotic ringspot disease (PTNRD), was found to be more adaptable than PVYO, especially in potato leaves due, at least in part, to the Ny gene that confers hypersensitive resistance (HR) to PVYO. Further-more, PVYN-Wi was found to repress PVYO in potato tubers but act synergistically in potato leaves. The PVYO-induced foliage necrosis in cultivar ‘Ranger Russet’ was observed to be more severe in plants co-infected by PVYN-Wi and PVYN:O, respectively, resulting in plant death. Strikingly, this PVYO -induced necrosis was suppressed by PVYNTN in doubly infected plants. These interactions may, at least partially, explain the decreasing incidence of PVYO in United States potato produc-tion regions, especially given that many cultivars contain the Ny gene, which likely limits PVYO enabling PVYNTN and PVYN-Wi to outcompete. We also found that replication and cell-to-cell movement of these PVY strains in tubers at 4C was similar to levels at ambient temperature.

The search for lower cost materials that reduce pressure drop in fluid transport systems in oil and gas industries to conserve pumping energy is of paramount importance. Polymers are known to reduce pressure drop in pipeline oil-water flows in a process referred to as drag reduction (DR). The effect of partially hydrolysed polyacrylamide, polyethylene oxide, aloe vera mucilage and their mixtures as drag reducing polymers (DRPs) on pressure gradient (pressure drop; Δp) in pipeline oil-water flows was studied. The experiment was carried out in flow rig with 0.02-m diameter straight unplasticised polyvinylchloride (uPVC) pipe, two centrifugal pumps, control valves and two storage tanks. Tap water (ρ = 997 Kg/m³ and µ = 0.89 cP) and diesel (ρ = 832 Kg/m³ and µ = 1.66 cP) were used as the test fluid at ambient condition. The polymer mixture total concentration (MTC) of 30 and 400 ppm at different mixing proportion, mixture Reynolds number (Re_mix) and oil input volume were investigated. The results show increase in pressure gradient with increase in oil input volume in both single-phase water flow and oil-water flow before adding drag reducing polymers (DRPs). But Δp decreased after adding DRPs with increase in Reynolds number (Re) or Re_mix and decrease in the oil-phase Re, vice versa. The results further showed higher reduction in pressure drop by the polymer mixture than in each of the polymer used at the same conditions. The rigidness of the biopolymer was improved by adding synthetic polymers which result to increase in DR efficiency.The search for lower cost materials that reduce pressure drop in fluid transport systems in oil and gas industries to conserve pumping energy is of paramount importance. Polymers are known to reduce pressure drop in pipeline oil-water flows in a process referred to as drag reduction (DR). The effect of partially hydrolysed polyacrylamide, polyethylene oxide, aloe vera mucilage and their mixtures as drag reducing polymers (DRPs) on pressure gradient (pressure drop; Δp) in pipeline oil-water flows was studied. The experiment was carried out in flow rig with 0.02-m diameter straight unplasticised polyvinylchloride (uPVC) pipe, two centrifugal pumps, control valves and two storage tanks. Tap water (ρ = 997 Kg/m³ and µ = 0.89 cP) and diesel (ρ = 832 Kg/m³ and µ = 1.66 cP) were used as the test fluid at ambient condition. The polymer mixture total concentration (MTC) of 30 and 400 ppm at different mixing proportion, mixture Reynolds number (Re_mix) and oil input volume were investigated. The results show increase in pressure gradient with increase in oil input volume in both single-phase water flow and oil-water flow before adding drag reducing polymers (DRPs). But Δp decreased after adding DRPs with increase in Reynolds number (Re) or Re_mix and decrease in the oil-phase Re, vice versa. The results further showed higher reduction in pressure drop by the polymer mixture than in each of the polymer used at the same conditions. The rigidness of the biopolymer was improved by adding synthetic polymers which result to increase in DR efficiency.

Current research in the field of antimicrobials is focused on the development of novel antibiotics and antimicrobial agents to counteract the huge dilemma that the human population is mainly facing in regards to the rise of bacterial resistance and biofilm infections. Host Defense peptides (HDPs) are a promising group of molecules for antimicrobial development as they share unique characteristics suitable for antimicrobial activity including their broad spectrum of activity and potency against bacteria. AamAP1 is a novel HDP that was identified through molecular cloning from the venom of the North African scorpion Androctonus amoeruxi. In vitro antimicrobial assays revealed that the peptide displays moderate activity against different strains of Gram-positive and Gram-negative bacteria. Additionally, the peptide proved to be highly hemolytic and displaying significantly high toxicity against mammalian cells. In our study, a novel synthetic peptide analogue named A3 was designed from the naturally occurring scorpion venom host defense peptide. The design strategy depended on modifying the amino acid sequence of the parent peptide in order to increase its net positive charge, percentage helicity and optimize other physico-chemical parameters involved theoretically in HDPs activity. Accordingly, A3 was evaluated for its in vitro antimicrobial and anti-biofilm activity individually and in combination with four different types of conventional antibiotics against clinical isolates of multi-drug resistant (MDR) Gram-positive bacteria. A3 was also evaluated for its cytotoxicity against mammalian cells. A3 displayed potent and selective in vitro antimicrobial activities against a wide range of MDR Gram-positive bacteria. Our results also showed that combining A3 with conventional antibiotics displayed a synergistic mode of action which resulted in decreasing the MIC value for A3 peptide as low as 0.125 µM. These effective concentrations were associated with negligible toxicities on mammalian cells. In conclusion, A3 exhibits enhanced activity and selectivity when compared with the parent natural scorpion venom peptide. The combination of A3 with conventional antibiotics may be pursued as a potential novel treatment strategy against MDR and biofilm forming bacteria.

Combination antiviral therapy may be helpful in the treatment of SARS-CoV-2 infection, however no clinical trial data are available and combined use of direct acting antivirals (DAA) and monoclonal antibodies (mAb) has been reported only anecdotally. To assess the cooperative effects of dual drug combinations in vitro, we used a VERO E6 cell based in vitro system with the ancestral B.1 or the highly divergent BQ.1.1 virus to test pairwise combinations of the licensed DAA, including nirmatrelvir (NRM), remdesivir (RDV) and the active metabolite of molnupiravir (EIDD-1931) as well the combination of RDV with four licensed mAbs (sotrovimab, bebtelovimab, cilgavimab, tixagevimab; tested only with the susceptible B.1 virus). According to SynergyFinder 3.0 summary and weighted scores, all the combinations had an additive effect. Within DAA/DAA combinations, paired scores with the B.1 and BQ.1.1 variants were comparable. In the post-hoc analysis weighting synergy by concentrations, several cases of highly synergistic scores were detected at specific drug concentrations, both for DAA/DAA and for RDV/mAb combinations. This was supported by in vitro confirmation experiments showing a more than linear shift of a drug effective concentration (IC50) at increasing concentrations of the companion drug, although the effect was prominent with DAA/DAA combinations but minimal or null with RDV/mAb combinations. These results support a cooperative effects of dual drug combinations in vitro, which should be further investigated in animal models before introduction into the clinic.

In this study, Li-Al-OH layered double hydroxide (LDH), which was prepared by solvent-free one-step mechanochemical reaction of LiOH and Al(OH)₃, was applied to remove boron from aqueous solution. Dry-grinding for 3 h at a rotational speed of 500 rpm, Li/Al molar 1/2 was the optimum condition to prepare highly crystalline of Li-Al LDH phase with no evident impure phases. Two milling products with Li/Al molar ratio at 1/2 and 2/2 were evaluated for boron adsorption. The results confirmed that Li/Al molar ratio 2/2 sample showed high boron adsorption capacity due to the physical adsorption of Li-Al-OH LDH and chemical synergism of phase gel Al(OH)₃. The adsorption isotherms, described by the Langmuir model, indicated maximum monolayer boron uptake capacity 45.45 mg/g, implying competitive adsorption capacity of the material in our experiment.

MicroRNAs (miRNA) exert regulatory actions via base-pairing with their binding sites on target mRNAs. Cooperative-binding, i.e., synergism, among binding sites on a mRNA is biochemically well-characterized. We studied whether this synergism is reflected in global relationship between miRNA-mediated regulatory activity and miRNA-binding-site count on the target mRNAs, i.e., leading to a non-linear relationship between the two. Recently, using our own and public datasets, we have enquired into miRNA regulatory actions: first, we analyzed the power-law distribution pattern of miRNA binding sites; second, strikingly, mRNAs for core miRNA regulatory apparatus proteins have extra-ordinarily high binding site counts, forming self-feedback-control loops; third, we revealed that tumor suppressor mRNAs generally have more sites than oncogene mRNAs; and fourth, we characterized enrichment of miRNA target mRNAs in translationally less-active polysomes relative to more-active polysomes. In these four studies, obvious correlation was observed qualitatively between the extent to which a mRNA is miRNA-regulated and its binding sites count. This paper summarizes the used datasets. We also re-analyzed the correlation by comparative linear and non-linear regression analyses. The results support a non-linear, instead of linear, relationship between the two parameters, conceivably a transcriptome-level reflection of cooperative-binding/synergism among miRNA binding sites on a target mRNA.

Alkaloid-based urea derivatives were produced with high yield through the reaction of anabasine and cytisine with isoxazolylphenylcarbamates in boiling benzene. Their antitumor ac-tivity in combination with the commonly used six anticancer drugs namely cyclophosphane, fluorouracil, etoposide, cysplatine, ribomustine with different mechanisms of action was investi-gated. Based on the quantum chemical calculations data and molecular docking, hypotheses have been put forward to explain their mutual influence when affecting on the С6 rat glioma model cells.

Infections caused by KPC-producing K. pneumoniae continue to pose a significant clinical challenge due to emerging resistance to new antimicrobials. We investigated the association between two drugs whose roles have been repurposed against multidrug-resistant bacteria: fosfomycin and temocillin. Temocillin exhibits unusual stability against KPC enzymes, while fosfomycin acts as a potent “synergizer”. We conducted in vitro antimicrobial activity studies on 100 clinical isolates of KPC-producing K. pneumoniae using a combination of fosfomycin and temocillin. The results demonstrated synergistic activity in 91% of the isolates. Subsequently, we assessed the effect on Galleria mellonella larvae using 5 different KPC-Kp isolates. The addition of fosfomycin to temocillin increased larvae survival from 73 to 97% (+Δ 32%; isolate 1), from 93 to 100% (+Δ 7%; isolate 2), from 63 to 86% (+Δ 36%; isolate 3), from 63 to 90% (+Δ 42%; isolate 4), and from 93 to 97% (+Δ 4%; isolate 10), respectively. Among the temocillin-resistant KPC-producing K. pneumoniae isolates (24 isolates), the addition of fosfomycin reduced temocillin MIC values below the resistance breakpoint in all isolated except one. Temocillin combined with fosfomycin emerges as a promising combination against KPC-producing K. pneumoniae, warranting further clinical evaluation.

The promising antimicrobial activity of essential oils (EOs) led researchers to use them in combination with antimicrobial drugs in order to reduce drug toxicity, side effects, and resistance with single agents. In Pancalieri (Turin, Italy), there is a local production of Mentha x piperita worldwide known as “Mentha of Pancalieri”. The EO from this Mentha is considered as one of the best peppermint EO in the world. In our research, we assessed the antifungal activity of “Mentha of Pancalieri” EO either alone or in combination with azole drugs (fluconazole, itraconazole, ketoconazole) against a wide panel of yeast and dermatophyte clinical isolates. The EO was analyzed by GC-MS and its antifungal properties were evaluated by MIC/MFC parameters, according to the CLSI guidelines, with some modifications. The interaction of peppermint EO with azoles was evaluated through the chequerboard and isobologram methods. Results suggest this EO exerts a fungicidal activity against yeasts, and a fungistatic activity against dermatophytes. Interaction studies with azoles indicate mainly synergistic profiles between itraconazole and peppermint EO vs. Candida spp., Cryptococcus neoformans and Trichophyton mentagrophytes. Peppermint of Pancalieri EO may act as a potential antifungal agent and may serve as a natural adjuvant for fungal infection treatment.

This study explored the potential synergism within chlorhexidine-silver nanoparticles conjugates against Influenza type A, Staphylococcus aureus, Escherichia coli, and Candida albicans. Silver nanoparticles (SN) were obtained by the reduction of silver ions with green tea total phenolic extract and conjugated with chlorhexidine (Cx). The particles were characterized by UV-Vis and FTIR spectroscopies, dynamic light scattering, X-ray diffraction, and transmission electron microscopy. A stable negatively-charged nano-silver colloid (ζ=-50.01) was obtained with an average hydrodynamic diameter of 92.34 nm. In the presence of chlorhexidine, the spectral data and the shift of the zeta potential to positive values (ζ=+44.59) revealed the successful sorption of the drug onto the silver surface. The conjugates (SN-Cx) demonstrated potentiation in the effects against S. aureus and C. albicans, and synergism against E. coli with minimal inhibitory concentrations of SN 5.5 µg/mL+Cx 8.8 µg/mL. The SN showed excellent, increasing with time, virucidal properties, and low toxicity. The coupling of the cationic chlorhexidine with nano-silver, however, did not reduce its intrinsic cytotoxicity on various cell lines (MDCK, BJ, and А549). The newly-synthesized antimicrobial agent presented with an extended and promising therapeutic spectrum and needs to be further evaluated on relevant to the designated route of administration three-dimensional cell models (e.g., nasal, bronchial, dermal, ocular, etc.).