Polymyxins are the last line of defense against multidrug-resistant (MDR) Gram-negative bacterial infections. However, this last resort has been threatened by the emergence of superbugs carrying the mobile colistin resistance gene-1 (mcr-1). Given the high concentration of matrix metalloproteinase 3 (MMP-3) in bacterial pneumonia, limited plasma accumulation of colistin (CST) in the lung, and potential toxicity of ionic silver (Ag+), we designed a feasible clinical transformation platform, an MMP-3 high-performance lung-targeted bio-responsive delivery system, which we named \"CST&Ag@CNMS\". This system exhibited excellent lung-targeting ability (>80% in lungs), MMP-3 bio-responsive release property (95% release on demand), and synergistic bactericidal activity in vitro (2-4-fold minimum inhibitory concentration reduction). In the mcr-1+ CST-resistant murine pneumonia model, treatment with CST&Ag@CNMS improved survival rates (70% vs. 20%), reduced bacteria burden (2-3 log colony-forming unit [CFU]/g tissue), and considerably mitigated inflammatory response. In this study, CST&Ag@CNMS performed better than the combination of free CST and AgNO3. We also demonstrated the superior biosafety and biodegradability of CST&Ag@CNMS both in vitro and in vivo. These findings indicate the clinical translational potential of CST&Ag@CNMS for the treatment of lung infections caused by CST-resistant bacteria carrying mcr-1.

Copper and iron are the basic metal elements that have attracted much attention in industry. Prussian blue (PB) is a significant class of metal-organic frameworks (MOFs); however, the lack of such linkages between the structure and properties, as well as properties differences, limits their potential applications. In this paper, the Cu-based Prussian blue nanocubes with and without Fe doping were synthesized. With the increasing reaction time, the morphology of the Cu-based Prussian blue nanocubes without Fe doping (PB:Cu NCs) changes from cuboidal to circular, and finally grows back to cuboidal. However, Cu-based Prussian blue nanocubes with Fe doping (PB: CuFe NCs) grow directly from the cube and eventually collapse. The nanocubes show a notable red shift with the tunable spectra from 400 nm to 700 nm. Compared with PB: Cu NCs, the PB: CuFe NCs have higher temperature rise under 808 nm irradiation and better photothermal efficacy. The catalytic efficiency of PB: CuFe NCs changes with the pH and reaches its maximum value of 1.021 mM with a pH of 5.5. The enhanced catalytic reaction by the near-infrared radiation plasmonic photothermal effect is also confirmed. This work highlights the potential of the developed PB: Cu and PB: CuFe NCs for photothermal-enhanced co-catalysis nanomaterials.

The rising prevalence of antibiotic-resistance is currently a grave issue; hence, novel antimicrobial agents are being explored and developed to address infections resulting from multiple drug-resistant pathogens. Biogenic CuO, ZnO, and WO3 nanoparticles can be considered as such agents. Clinical isolates of E. coli, S. aureus, methicillin-resistant S. aureus (MRSA), and Candida albicans from oral and vaginal samples were treated with single and combination metal nanoparticles incubated under dark and light conditions to understand the synergistic effect of the nanoparticles and their photocatalytic antimicrobial activity. Biogenic CuO and ZnO nanoparticles exhibited significant antimicrobial effects under dark incubation which did not alter on photoactivation. However, photoactivated WO3 nanoparticles significantly reduced the number of viable cells by 75% for all the test organisms, thus proving to be a promising antimicrobial agent. Combinations of CuO, ZnO, and WO3 nanoparticles demonstrated synergistic action as a significant increase in their antimicrobial property (>90%) was observed compared to the action of single elemental nanoparticles. The mechanism of the antimicrobial action of metal nanoparticles both in combination and in isolation was assessed with respect to lipid peroxidation due to ROS (reactive oxygen species) generation by measuring malondialdehyde (MDA) production, and the damage to cell integrity using live/dead staining and quantitating with the use of flow cytometry and fluorescence microscopy.

Nanomaterials are increasingly being used for crop growth, especially as a new paradigm for plant disease management. Among the other nanomaterials, silver nanoparticles (AgNPs) draw a great deal of attention because of their unique features and multiple usages. Rapid expansion in nanotechnology and utilization of AgNPs in a large range of areas resulted in the substantial release of these nanoparticles into the soil and water environment, causing concern for the safety of ecosystems and phytosanitary. In an attempt to find an effective control measure for sweet potato soft rot disease, the pathogen Dickeya dadantii was exposed to AgNPs, the cell-free culture supernatant (CFCS) of Bacillus amyloliquefaciens alone, and both in combination. AgNPs were synthesized using CFCS of Bacillus amyloliquefaciens strain A3. The green synthesized AgNPs exhibited a characteristic surface plasmon resonance peak at 410-420 nm. Electron microscopy and X-ray diffraction spectroscopy determined the nanocrystalline nature and 20-100 nm diameters of AgNPs. Release of metal Ag+ ion from biosynthesized AgNPs increases with time. AgNPs and CFCS of B. amyloliquefaciens alone exhibited antibacterial activity against the growth, biofilm formation, swimming motility, and virulence of strain A3. The antibacterial activities elevated with the elevation in AgNPs and CFCS concentration. Similar antibacterial activities against D. dadantii were obtained with AgNPs at 50 µg·mL-1, 50% CFCS alone, and the combination of AgNPs at 12 µg·mL-1 and 12% CFCS of B. amyloliquefaciens. In planta experiments indicated that all the treatments reduced D. dadantii infection and increased plant growth. These findings suggest that AgNPs along with CFCS of B. amyloliquefaciens can be applied to minimize this bacterial disease by controlling pathogen-contaminated sweet potato tuber with minimum Ag nano-pollutant in the environment.

Nanoparticle drug delivery systems have proved anti-tumor effects; however, they are not widely used in tumor therapy due to insufficient ability to target specific sites, multidrug resistance to anti-tumor drugs, and the high toxicity of the drugs. With the development of RNAi technology, nucleic acids have been delivered to target sites to replace or correct defective genes or knock down specific genes. Also, synergistic therapeutic effects can be achieved for combined drug delivery, which is more effective for overcoming multidrug resistance of cancer cells. These combination therapies achieve better therapeutic effects than delivering nucleic acids or chemotherapeutic drugs alone, so the scope of combined drug delivery has also been expanded to three aspects: drug-drug, drug-gene, and gene-gene. This review summarizes the recent advances of nanocarriers to co-delivery agents, including i) the characterization and preparation of nanocarriers, such as lipid-based nanocarriers, polymer nanocarriers, and inorganic delivery carriers; ii) the advantages and disadvantages of synergistic delivery approaches; iii) the effectual delivery cases that are applied in the synergistic delivery systems; and iv) future perspectives in the design of nanoparticle drug delivery systems to co-deliver therapeutic agents.

UNASSIGNED: Schizophrenia (SZ) is a severe chronic mental disorder with increased risk of hepatitis B virus (HBV) infection, which is incurable currently and induces various negative emotions and psychological pressures in patients to exacerbate mental disorders. To facilitate the therapeutic design for SZ patients complicated with HBV infection (SZ + HBV), it is helpful to first elucidate the metabolic perturbations in SZ + HBV patients.
UNASSIGNED: In this study, metabolic profiles of the serum samples from four groups of participants comprising healthy controls (HC, n = 72), HBV infection (n = 52), SZ patients (n = 37), and SZ + HBV (n = 41) patients were investigated using a high-resolution 1H NMR-based metabolomics approach.
UNASSIGNED: Distinguishable metabolic profiles were found in the four groups. In comparison with HC, HBV infection induced increased levels of citrate and succinate to perturbate the tricarboxylic acid cycle and succinate-related pathways. Similar to SZ cases, SZ + HBV patients exhibited decreased glucose but increased citrate, pyruvate, and lactate, suggesting the occurrence of disturbance in glucose metabolism. Moreover, in comparison with HC, several serum amino acid levels in SZ + HBV patients were significantly altered. Our findings suggest that Warburg effect, energy metabolism disorders, neurotransmitter metabolism abnormalities, mitochondrial dysfunction and several disturbed pathways in relation to tyrosine and choline appear to play specific and central roles in the pathophysiology of SZ + HBV. Apart from replicating metabolic alterations induced by SZ and HBV separately (e.g., in energy metabolism and Warburg effect), the specific metabolic abnormalities in the SZ + HBV group (e.g., several tyrosine- and choline-related pathways) highlighted the existence of a synergistic action between SZ and HBV pathologies. Current study revealed the metabolic alterations specific to the interaction between SZ and HBV pathologies, and may open important perspectives for designing precise therapies for SZ + HBV patients beyond the simple combination of two individual treatments.

BACKGROUND: Bemisia tabaci Gennadius (Hemiptera: Aleyrodidae) is a serious pest of crops in different regions of the world. Our recent studies on the joint application of Akanthomyces attenuatus (a pathogenic insect fungus) and matrine (a botanical insecticide) against B. tabaci have shown promising results. Using RNA sequencing (RNA-Seq), we identified differentially expressed genes involved in whitefly responses to single or mixed applications of A. attenuatus and matrine.
METHODS: In this study, we compared the transcriptome profiles of B. tabaci treated with individual and combined treatments of A. attenuatus and matrine to determine variations in gene expression among whiteflies in response to different treatments.
RESULTS: Transcriptomic data analysis showed differential expression of 71, 1194, and 51 genes in response to A. attenuatus (BtA), matrine (BtM), and A. attenuatus + matrine (BtAM) treatment, respectively. A total of 65 common differentially expressed genes (DEGs) were identified between whiteflies treated with A. attenuatus (BtA) and matrine (BtM). A comparison of DEGs across the three treatments (BtA, BtM, and BtAM) revealed two common DEGs. The results also revealed that AMPK signaling, apoptosis, and drug metabolism pathways are likely involved in whitefly defense responses against A. attenuatus and matrine infection. Furthermore, a notable suppression of general metabolism and immune response genes was observed in whiteflies treated with A. attenuatus + matrine (BtAM) compared to whiteflies treated with individual A. attenuatus (BtA) or matrine (BtM) treatments.
CONCLUSIONS: Dynamic changes in the number of differentially expressed genes were observed in B. tabaci subjected to different treatments (BtA, BtM, and BtAM). To the best of our knowledge, this is the first report on the molecular interactions between whitefly and individual or combined treatments of A. attenuatus and matrine. These results will further improve our knowledge of the infection mechanism and complex biochemical processes involved in the synergistic action of A. attenuatus and matrine against B. tabaci.

Neurological disorders such as Alzheimer\'s disease, Parkinson\'s disease, dementia, epilepsy, depression, migraine etc. are affecting more and more elderly people\'s day by day. Conventional route of administration to treat these diseases has to face a major hindrance that is blood brain and blood-cerebrospinal fluid (CSF) barrier to achieve desired concentration of drug at the site of action for therapeutic effect. Hence, intranasal route of delivery is considered as promising and alternative route to achieve desired goals. In last four decades, brain targeting strategies are widely studied and considered having great potential by researchers; especially intranasal delivery owing to its benefits. Various nano formulations such as nanoemulsions, nanosuspensions, hydrogels, in situ gels, dendrimers and lipidic formulations are studied widely. Lipid nano formulations especially second generation nanostructured lipid carriers offer greater advantages in terms of stability, fabrication techniques, scalability, drug loading and drug targeting. Nanostructured lipid carrier (NLCs) constitute of two major components viz solid lipid and liquid lipid in a specific ratio. In this review, authors have discussed about the possible synergistic actions of oils/liquid lipids with synthetic drugs resulting into great therapeutic benefits.

UNASSIGNED: Preclinical studies have demonstrated the possible anticancer effects of statins, but the synergistic effect of concomitant statin use with standard chemotherapy protocols in patients with breast cancer has not yet been investigated.
UNASSIGNED: The current study aimed to evaluate the efficacy of concomitant pitavastatin use with neoadjuvant chemotherapy protocols in patients with breast cancer.
UNASSIGNED: This study was a randomized controlled clinical trial. A total of 70 adult female patients with pathologically-proven invasive breast cancer were randomized to receive or not receive pitavastatin (2 mg) oral tablets once daily concomitantly with standard neoadjuvant chemotherapy protocols for 6 months. The primary outcomes of this study were changes in tumor size and changes to the Ki67 index. In addition, secondary outcomes were changes in cyclin D1 and cleaved caspase-3 serum levels. This study was registered at ClinicalTrials.gov (Identifier: NCT04705909).
UNASSIGNED: Patients in the pitavastatin group showed significantly higher median (IQR) reductions in tumor size [-19.8 (-41.5, 9.5)] compared to those in the control group [-5.0 (-15.5, 0.0), p = 0.0009]. The change in Ki67 from baseline to the end of therapy was similar between the two groups (p = 0.12). By the end of therapy, the cyclin D1 levels in the pitavastatin group were significantly decreased [median (IQR) change of - 10.0 (-20.2, -2.9) from baseline], whereas the control group showed an increase in cyclin D1 levels [14.8 (4.1, 56.4)]. The median (IQR) caspase-3 was elevated in the pitavastatin group 1.6 (0.2, 2.2), and decreased in the control group (-0.2 (-1.1, 0.0), p = 0.0002).Subgroup analysis of the pitavastatin group revealed that patients with positive human epidermal growth receptor 2 (HER2) had higher median (IQR) reductions in Ki67 [-35.0 (-70.0, -12.5)] than those with negative HER2 [2.5 (-15.0, 10.0), p = 0.04]. All patients who achieved a complete pathological response (n = 9) exhibited an HER2-neu positive receptor at baseline.
UNASSIGNED: Concomitant use of pitavastatin with standard neoadjuvant chemotherapy protocols may improve neoadjuvant chemotherapy responses in patients with breast cancer.

Increasing rates of cancer incidence and the toxicity concerns of existing chemotherapeutic agents have intensified the research to explore more alternative routes to combat tumor. Luteolin, a flavone found in numerous fruits, vegetables, and herbs, has exhibited a number of biological activities, such as anticancer and anti-inflammatory. Luteolin inhibits tumor growth by targeting cellular processes such as apoptosis, cell-cycle progression, angiogenesis and migration. Mechanistically, luteolin causes cell death by downregulating Akt, PLK-1, cyclin-B1, cyclin-A, CDC-2, CDK-2, Bcl-2, and Bcl-xL, while upregulating BAX, caspase-3, and p21. It has also been reported to inhibit STAT3 signaling by the suppression of STAT3 activation and enhanced STAT3 protein degradation in various cancer cells. Therefore, extensive studies on the anticancer properties of luteolin reveal its promising role in chemoprevention. The present review describes all the possible cellular interactions of luteolin in cancer, along with its synergistic mode of action and nanodelivery insight.