Pathogenic bacteria infection is a major public health problem due to the high morbidity and mortality rates, as well as the increased expenditure on patient management. Although there are several ...options for antimicrobial therapy, their efficacy is limited because of the occurrence of drug-resistant bacteria. Many conventional antibiotics have failed to show significant amelioration in overall survival of infectious patients. Nanomedicine for delivering antibiotics provides an opportunity to improve the efficiency of the antibacterial regimen. Nanosystems used for antibiotic delivery and targeting to infection sites render some benefits over conventional formulations, including increased solubility, enhanced stability, improved epithelium permeability and bioavailability, prolonged antibiotic half-life, tissue targeting, and minimal adverse effects. The nanocarriers' sophisticated material engineering tailors the controllable physicochemical properties of the nanoparticles for bacterial targeting through passive or active targeting. In this review, we highlight the recent progress on the development of antibacterial nanoparticles loaded with antibiotics. We systematically introduce the concepts and amelioration mechanisms of the nanomedical techniques for bacterial eradication. Passive targeting by modulating the nanoparticle structure and the physicochemical properties is an option for efficient drug delivery to the bacteria. In addition, active targeting, such as magnetic hyperthermia induced by iron oxide nanoparticles, is another efficient way to deliver the drugs to the targeted site. The nanoparticles are also designed to respond to the change in environment pH or enzymes to trigger the release of the antibiotics. This article offers an overview of the benefits of antibacterial nanosystems for treating infectious diseases.
Aims
Sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2i) have off‐target effects on haemoconcentration and anti‐inflammation. The impact of SGLT‐2i on the risk of venous thromboembolism (VTE) in ...patients with diabetes mellitus (DM) remains unclear. This study aimed to evaluate the risk of newly diagnosed VTE in patients with DM using SGLT‐2i in comparison to dipeptidyl peptidase‐4 inhibitors (DPP‐4i) or glucagon‐like peptide‐1 receptor agonists (GLP‐1RA).
Materials and Methods
In this nationwide retrospective cohort study, we used data from Taiwan's National Health Insurance Research Database. Patients with diabetes aged 20 years or older who received SGLT‐2i, DPP‐4i, or GLP‐1RA between 1 May 2016, and 31 December 2020, were included. The risks of VTE in SGLT‐2i users were compared with those of DPP‐4i and GLP‐1RA users. A Cox regression model with stabilised inverse probability of treatment weighting was used to calculate hazard ratio (HR) for VTE risk. Additionally, a meta‐analysis of relevant articles published before 23 May 2023, was conducted.
Results
Data from 136,530 SGLT‐2i, 598,280 DPP‐4i, and 5760 GLP‐1RA users were analysed. SGLT‐2i use was associated with a lower risk of VTE than DPP‐4i (HR, 0.70; 95% CI, 0.59–0.84; p < 0·001), but not with GLP‐1RA (HR, 1.39; 95% CI, 0.32–5.94; p = 0.66). Our meta‐analysis further supported these findings (SGLT‐2i vs. DPP‐4i: HR, 0.71; 95% CI, 0.62–0.82; p < 0·001; SGLT‐2i vs. GLP‐1RA: HR, 0.91; 95% CI, 0.73–1.15; p = 0.43), suggesting the robustness of our retrospective analysis.
Conclusions
In patients with DM, SGLT‐2i was associated with a lower risk of VTE compared to DPP‐4i, but not GLP‐1RA.
The molecular packing motifs within crystalline domains should be a key determinant of charge transport in thin‐film transistors (TFTs) based on small organic molecules. Despite this implied ...importance, detailed information about molecular organization in polycrystalline thin films is not available for the vast majority of molecular organic semiconductors. Considering the potential of fused thiophenes as environmentally stable, high‐performance semiconductors, it is therefore of interest to investigate their thin film microstructures in relation to the single crystal molecular packing and OTFT performance. Here, the molecular packing motifs of several new benzod,d′thieno3,2‐b;4,5‐b′dithiophene (BTDT) derivatives are studied both in bulk 3D crystals and as thin films by single crystal diffraction and grazing incidence wide angle X‐ray scattering (GIWAXS), respectively. The results show that the BTDT derivative thin films can have significantly different molecular packing from their bulk crystals. For phenylbenzod,d′thieno3,2‐b;4,5‐b′dithiophene (P‐BTDT), 2‐biphenylbenzod,d′thieno‐3,2‐b;4,5‐b′dithiophene (Bp‐BTDT), 2‐naphthalenylbenzod,d′thieno3,2‐b;4,5‐b′dithiophene (Np‐BTDT), and bisbenzod,d′thieno3,2‐b;4,5‐b′dithiophene (BBTDT), two lattices co‐exist, and are significantly strained versus their single crystal forms. For P‐BTDT, the dominance of the more strained lattice relative to the bulk‐like lattice likely explains the high carrier mobility. In contrast, poor crystallinity and surface coverage at the dielectric/substrate interface explains the marginal OTFT performance of seemingly similar PF‐BTDT films.
The thin film molecular packing motifs of several new benzod,dthieno3,2‐b;4,5‐bdithiophene (BTDT) derivatives have different molecular packings from their bulk crystals. Co‐existence of strained lattices with their single crystal forms is speculated to have a significant effect on organic thin‐film transistor (OTFT) performance.
COVID-19 is threatening human health worldwide but no effective treatment currently exists for this disease. Current therapeutic strategies focus on the inhibition of viral replication or using ...anti-inflammatory/immunomodulatory compounds to improve host immunity, but not both. Traditional Chinese medicine (TCM) compounds could be promising candidates due to their safety and minimal toxicity. In this study, we have developed a novel
bioinformatics workflow that integrates multiple databases to predict the use of honeysuckle (
) and Huangqi (
) as potential anti-SARS-CoV-2 agents. Using extracts from honeysuckle and Huangqi, these two herbs upregulated a group of microRNAs including
,
, and
, which are critical to reduce the pathogenesis of SARS-CoV-2. Moreover, these herbs suppressed pro-inflammatory cytokines including IL-6 or TNF-α, which were both identified in the cytokine storm of acute respiratory distress syndrome, a major cause of COVID-19 death. Furthermore, both herbs partially inhibited the fusion of SARS-CoV-2 spike protein-transfected BHK-21 cells with the human lung cancer cell line Calu-3 that was expressing ACE2 receptors. These herbs inhibited SARS-CoV-2 M
activity, thereby alleviating viral entry as well as replication. In conclusion, our findings demonstrate that honeysuckle and Huangqi have the potential to be used as an inhibitor of SARS-CoV-2 virus entry that warrants further
analysis and functional assessment of miRNAs to confirm their clinical importance. This fast-screening platform can also be applied to other drug discovery studies for other infectious diseases.
Despite advances in chemotherapies and targeted drugs, colorectal cancer (CRC) remains challenging to treat due to drug resistance. Emerging evidence indicates that cancer-associated fibroblasts ...(CAFs) facilitate the generation of cancer stem-like cells (CSCs) and drug resistance. Glycogen synthase kinase-3 (GSK) associated signaling pathways have been implicated in the generation of CSCs and represent a target for therapeutics development.
Gamma-mangostin (gMG) isolated from Garcinia mangostana was evaluated for its ability to downregulate GSK3β-associated signaling in CRC cells and overcome CAF-induced 5-fluorouracil resistance and CSC generation.
Bioinformatics analysis, in silico molecular docking, in vitro assays, including cell viability tests, colony- and tumor sphere-formation assays, transwell migration assays, ELISA, SDS-PAGE, Western blotting, miR expression, qPCR, and flow cytometry, as well as in vivo mouse xenograft models were used to evaluate the antitumor effects of gMG.
Bioinformatics analyses indicated that GSK3β/CDK6/β-catenin mRNA signature was significantly higher in colon cancer patients. Additional algorithms predicted a higher miR-26b level was associated with significantly higher survival in CRC patients and GSK3β and CDK6 as targets of miR-26b-5p. To validate these findings in vitro, we showed that CAF-cocultured CRC cells expressed an increased expression of GSK3β, β-catenin, CDK6, and NF-κB. Therapeutically, we demonstrated that gMG treatment suppressed GSK3β-associated signaling pathways while concomitantly increased the miR-26b-5p level. Using a xenograft mouse model of CAFs cocultured HCT116 tumorspheres, we showed that gMG treatment reduced tumor growth and overcame CAF-induced 5-fluorouracil resistance.
Pharmacological intervention with gMG suppressed CRC carcinogenesis and stemness via downregulating GSK3/β-catenin/CDK6 and upregulating the miR-26b-5p tumor suppressor. Thus, gMG represents a potential new CRC therapeutic agent and warrants further investigation.
Display omitted
Keloid is a type of disfiguring pathological scarring unique to human skin. The disorder is characterized by excessive collagen deposition. Immune cell infiltration is a hallmark of both normal and ...pathological tissue repair. However, the immunopathological mechanisms of keloid remain unclear. Recent studies have uncovered the pivotal role of both innate and adaptive immunity in modulating the aberrant behavior of keloid fibroblasts. Several novel therapeutics attempting to restore regulation of the immune microenvironment have shown variable efficacy. We review the current understanding of keloid immunopathogenesis and highlight the potential roles of immune pathway-specific therapeutics.
Perivascular adipose tissue (PVAT)-derived relaxing factor (PVATRF) significantly regulates vascular tone. Its chemical nature remains unknown. We determined whether palmitic acid methyl ester (PAME) ...was the PVATRF and whether its release and/or vasorelaxing activity decreased in hypertension.
Using superfusion bioassay cascade technique, tissue bath myography, and gas chromatography/mass spectrometry, we determined PVATRF and PAME release from aortic PVAT preparations of Wistar Kyoto rats and spontaneously hypertensive rats. The PVAT of Wistar Kyoto rats spontaneously and calcium dependently released PVATRF and PAME. Both induced aortic vasorelaxations, which were inhibited by 4-aminopyridine (2 mmol/L) and tetraethylammonium 5 and 10 mmol/L but were not affected by tetraethylammonium 1 or 3 mmol/L, glibenclamide (3 μmol/L), or iberiotoxin (100 nmol/L). Aortic vasorelaxations induced by PVATRF- and PAME-containing Krebs solutions were not affected after heating at 70°C but were equally attenuated after hexane extractions. Culture mediums of differentiated adipocytes, but not those of fibroblasts, contained significant PAME and caused aortic vasorelaxation. The PVAT of spontaneously hypertensive rats released significantly less PVATRF and PAME with an increased release of angiotensin II. In addition, PAME-induced relaxation of spontaneously hypertensive rats aortic smooth muscle diminished drastically, which was ameliorated significantly by losartan.
We found that PAME is the PVATRF, causing vasorelaxation by opening voltage-dependent K+ channels on smooth muscle cells. Diminished PAME release and its vasorelaxing activity and increased release of angiotensin II in the PVAT suggest a noble role of PVAT in pathogenesis of hypertension. The antihypertensive effect of losartan is attributed partly to its reversing diminished PAME-induced vasorelaxation.
Acute lung injury (ALI) is a life-threatening respiratory condition characterized by severe inflammation and lung tissue damage, frequently causing rapid respiratory failure and long-term ...complications. The microRNA let-7a-5p is involved in the progression of lung injury, inflammation, and fibrosis by regulating immune cell activation and cytokine production. This study aims to use an innovative cellular electroporation platform to generate extracellular vesicles (EVs) carring let-7a-5p (EV-let-7a-5p) derived from transfected Wharton's jelly-mesenchymal stem cells (WJ-MSCs) as a potential gene therapy for ALI.
A cellular nanoporation (CNP) method was used to induce the production and release of EV-let-7a-5p from WJ-MSCs transfected with the relevant plasmid DNA. EV-let-7a-5p in the conditioned medium were isolated using a tangential flow filtration (TFF) system. EV characterization followed the minimal consensus guidelines outlined by the International Society for Extracellular Vesicles. We conducted a thorough set of therapeutic assessments, including the antifibrotic effects using a transforming growth factor beta (TGF-β)-induced cell model, the modulation effects on macrophage polarization, and the influence of EV-let-7a-5p in a rat model of hyperoxia-induced ALI.
The CNP platform significantly increased EV secretion from transfected WJ-MSCs, and the encapsulated let-7a-5p in engineered EVs was markedly higher than that in untreated WJ-MSCs. These EV-let-7a-5p did not influence cell proliferation and effectively mitigated the TGF-β-induced fibrotic phenotype by downregulating SMAD2/3 phosphorylation in LL29 cells. Furthermore, EV-let-7a-5p regulated M2-like macrophage activation in an inflammatory microenvironment and significantly induced interleukin (IL)-10 secretion, demonstrating their modulatory effect on inflammation. Administering EVs from untreated WJ-MSCs slightly improved lung function and increased let-7a-5p expression in plasma in the hyperoxia-induced ALI rat model. In comparison, EV-let-7a-5p significantly reduced macrophage infiltration and collagen deposition while increasing IL-10 expression, causing a substantial improvement in lung function.
This study reveals that the use of the CNP platform to stimulate and transfect WJ-MSCs could generate an abundance of let-7a-5p-enriched EVs, which underscores the therapeutic potential in countering inflammatory responses, fibrotic activation, and hyperoxia-induced lung injury. These results provide potential avenues for developing innovative therapeutic approaches for more effective interventions in ALI.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Honeysuckle (
Thunb) is a traditional Chinese medicine (TCM) with an antipathogenic activity. MicroRNAs (miRNAs) are small non-coding RNA molecules that are ubiquitously expressed in cells. ...Endogenous miRNA may function as an innate response to block pathogen invasion. The miRNA expression profiles of both mice and humans after the ingestion of honeysuckle were obtained. Fifteen overexpressed miRNAs overlapped and were predicted to be capable of targeting three viruses: dengue virus (DENV), enterovirus 71 (EV71) and SARS-CoV-2. Among them,
was examined to be capable of targeting the EV71 RNA genome by reporter assay and Western blotting. Moreover, honeysuckle-induced
suppression of EV71 RNA and protein expression as well as viral replication were investigated both in vitro and in vivo. We demonstrated that
targeted EV71 at the predicted sequences using luciferase reporter plasmids as well as two infectious replicons (pMP4-y-5 and pTOPO-4643). The suppression of EV71 replication and viral load was demonstrated in two cell lines by luciferase activity, RT-PCR, real-time PCR, Western blotting and plaque assay. Furthermore, EV71-infected suckling mice fed honeysuckle extract or inoculated with
showed decreased clinical scores and a prolonged survival time accompanied with decreased viral RNA, protein expression and virus titer. The ingestion of honeysuckle attenuates EV71 replication and related pathogenesis partially through the upregulation of
expression both in vitro and in vivo. Our previous report and the current findings imply that both honeysuckle and upregulated
can execute a suppressive function against the replication of DENV and EV71. Taken together, this evidence indicates that honeysuckle can induce the expression of
and that this miRNA as well as 11 other miRNAs have great potential to prevent and suppress EV71 replication.
Alopecia is one of the most common adverse effects of chemotherapy. It reduces the patient's self-esteem and quality of life and the effect of therapy. Scalp cooling is the only verified current ...method for prevention but success is not guaranteed, particularly after receiving anthracycline-based combinations. Low-level light therapy has been clinically proven to inhibit the progress of androgenic alopecia. A previous study using human subjects shows limited benefits for low-level light therapy for patients who suffer chemotherapy-induced alopecia but an increase in the number of probes and the optimization of light sources may improve the efficacy. This study determines the efficacy of low-level light therapy for the prevention of chemotherapy-induced hair loss for patients with breast cancer using a randomized controlled trial.
One hundred six eligible breast cancer patients were randomly distributed into a low-level light therapy group and a control group, after receiving chemotherapy. Subjects in the low-level light therapy group received 12 courses of intervention within 4 weeks. Subjects in the control group received no intervention but were closely monitored. The primary outcome is measured as the difference in the hair count in a target area between the baseline and at the end of week 4, as measured using a phototrichogram (Sentra scalp analyzer). The secondary outcomes include the change in hair count at the end of week 1, week 2, and week 3 and hair width at the end of week 1, week 2, week 3, and week 4, as measured using a phototrichogram, and the change in distress, the quality of life, and self-esteem due to chemotherapy-induced alopecia, at the end of week 4, as measured using a questionnaire.
This study improves cancer patients' quality of life and provides clinical evidence.
Registered at ClinicalTrials.gov- NCT05397457 on 1 June 2022.
PDF
