Therapeutic Effect Research Articles

Therapeutic Effects of Coenzyme Q10 in the Treatment of Ischemic Stroke.

Ischemic stroke is the second deadly disease worldwide, but current treatment is very limited. The brain, rich in lipids and high in oxygen consumption, is susceptible to damage from oxidative stress after ischemic stroke. Thus, antioxidants are promising neuroprotective agents for treatment and prevention of ischemic stroke. Coenzyme Q10 is the only lipophilic antioxidant that can be synthesized de novo by cells and plays a key role as an electron carrier in the oxidative phosphorylation of the mitochondrial electron transport chain. However, the reduced form of coenzyme Q10 (Ubiquinol) levels are significantly deficient in the brain. The aim of this article is to review the therapeutic effects and mechanisms of coenzyme Q10 in ischemic stroke. Current studies have found that coenzyme Q10 protects and treats ischemic stroke through multiple mechanisms based on the evidence from in vitro experiments, in vivo experiments, and clinical observations. For the first time, we reviewed the neuroprotective effects of coenzyme Q10 in ischemic stroke. Coenzyme Q10 exerts neuroprotective effects after ischemic stroke through anti-oxidative stress, anti-nitrosative stress, anti-inflammation, and anti-cell death. Here, we provided the evidence on the therapeutic and preventive effects of coenzyme Q10 in ischemic stroke and suggested the potential value of coenzyme Q10 as a medication candidate.

Highly sensitive biosensors for real-time monitoring of histamine at acupoint PC6 in rats based on graphene-modified acupuncture needles.

Acupoints are the local initial response sites of acupuncture therapeutic effects. As a biomarker, histamine is released into the acupoint region and plays its role concurrently as acupuncture needles are inserted into acupoints. Hence, real-time monitoring of histamine at acupoints is important to elucidate the effectiveness of the acupoint-activation process in acupuncture. Therefore, we developed highly sensitive acupuncture/Au particles/graphene biosensors by electrodeposition, brushing, and annealing methods based on bare acupuncture needles. We achieved a histamine detection limit of approximately 4.352 (±3.419) × 10-12 mol L-1 and good sensitivity of approximately 6.296 (±3.873) μA μM-1, with satisfactory specificity, repeatability, and stability in vitro, rendering them more competitive and suitable for real-time monitoring in vivo without causing additional damage. Subsequently, we conducted real-time histamine monitoring at non-acupoint and acupoint PC6 in rats, respectively. Our results showed minimal changes at the non-acupoint, whereas a trend of initial increase followed by a decrease was observed at acupoint PC6. The change in histamine concentration at acupoint PC6 reflected its involvement in the acupoint-activation procedure. Moreover, its peak position at ∼18 min could provide guidance for optimizing needle retaining time for maximum therapeutic effect. This work presents the first real-time in vivo monitoring of histamine at acupoints with high sensitivity and underscores the specificity of histamine release between non-acupoint and acupoint PC6, demonstrating great potential for elucidating the acupoint-activation mechanisms in acupuncture. Additionally, this work expands the application of nanomaterials in the integration of medicine and engineering, which is an important aspect of the future development of materials science.

Resolvin E1 and Inhibition of BLT2 Signaling Attenuate the Inflammatory Response and Improve One-Lung Ventilation-Induced Lung Injury.

One-lung ventilation (OLV) is a prevalently used technique to sustain intraoperative pulmonary function. Resolvin E1 (RvE1), a specialized pro-resolving lipid mediator, accelerates the resolution of inflammation in the lungs. However, its therapeutic effects on OLV-induced lung injury remain unclear. We initially developed an OLV rat model and treated it with RvE1. Subsequently, we assessed the wet/dry ratio of the lung tissue, performed hematoxylin and eosin staining, and calculated the ratio of polymorphonuclear cells to white blood cells in the bronchoalveolar lavage fluid. Additionally, we assessed apoptosis, inflammatory factor levels, and lung permeability in the rat lung tissues in the RvE1 treated and untreated groups and explored the molecular mechanisms mediated by RvE1. Our results indicated that RvE1 alleviated lung injury and inflammation and improved lung tissue apoptosis and permeability in OLV rats. Moreover, RvE1 suppressed the expression of the BLT1/2 signaling pathway and its ligands. The use of BLT2 and BLT1 inhibitors (LY255283 and U-75302, respectively) enhanced RvE1's anti-inflammatory effects and reduced lung injury. Furthermore, synergistic treatment with the BLT2 inhibitor and RvE1 provided grater benefits by more effectively inhibiting the NF-kB, p38 MAPK, and ERK pathways. RvE1 and the inhibition of BLT2 signalling reduce the inflammatory response and mitigate OLV-induced lung injury. These findings suggest a novel therapeutic pathway for managing OLV-related complications.

Regulation of Osteogenic and Angiogenic Markers in Alkali Treated Titanium for Hard Tissue Engineering Applications.

Titanium (Ti) and Ti alloys are of great interest in bone and dental tissue engineering applications due to their biocompatibility, corrosion resistance, and close mechanical properties to natural bone. However, the formation of fibrous tissue prevents osteointegration and results in implant loosening. Thus, physical and chemical methods are used to improve the surface properties of Ti. This study aimed to understand the role of alkali treatment conditions, including alkali medium concentration, temperature, rotation speed, and post-heat treatment. Our results showed that alkali treatment using 5 and 10 molar sodium hydroxide solution allows the formation of web-like microstructure. However, a higher concentration of 15 molar resulted in cracks along the surface. Interaction between the human fetal osteoblast cells (hfOBs) and Ti samples showed that heat treatment is necessary for increased cellular proliferation, which was not significantly different at later time points compared to the polished Ti. Alkali heat treatment did not induce inflammatory reactions at later time points. It showed an increase in vascular endothelial growth factor, osteoprotegerin/nuclear factor kappa-В ligand ratio, and osteocalcin expression, which is evidence for accelerated osteoblast cell maturation and bone remodeling in surface-modified samples. Together, these data show that alkali treatment using 5 or 10 molar of NaOH followed by heat treatment may have therapeutic effect and assist with bone tissue integration with Ti implant.

Baseline sensitivity and physiological characteristics of natural product hinokitiol against Sclerotinia sclerotiorum.

Sclerotinia sclerotiorum, a pathogenic fungus of oilseed rape, poses a severe threat to the oilseed rapeseed industry. In this study, we evaluated the potential of the natural compound hinokitiol against S. sclerotiorum by determining its biological activity and physiological characteristics. Our results showed that hinokitiol strongly inhibited the hyphae expansion of S. sclerotiorum, and its effective concentration of hyphae growing inhibition by 50% (EC50) against 103 S. sclerotiorum strains varied from 0.36 to 3.45 μg/mL, with an average of 1.23 μg/mL. Hinokitiol possessed better protective efficacy than therapeutic effects, and it exhibited no cross-resistance between carbendazim. After treatment with hinokitiol, many vesicular protrusions developed on the mycelium with rough surface and thickened cell wall. Moreover, the cell membrane permeability and glycerol content increased, while the oxalic acid declined after hinokitiol treatment. In addition, hinokitiol induced membrane lipid peroxidation and improved the production of reactive oxygen species (ROS) in S. sclerotiorum. Importantly, real-time quantitative polymerase chain reaction showed that cell wall and ROS synthesis-related genes were significantly up-regulated after hinokitiol treatment. This study revealed that hinokitiol has good biological activity against S. sclerotiorum and could be considered as an alternative bio-fungicide for the resistance management in controlling sclerotinia stem rot infected by S. sclerotiorum. These investigations provided new insights into understanding the toxic action of hinokitiol against pathogenic fungi. © 2024 Society of Chemical Industry.

Aficamten and Cardiopulmonary Exercise Test Performance: A Substudy of the SEQUOIA-HCM Randomized Clinical Trial.

Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures. To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates. This was a prespecified analysis from SEQUOIA-HCM, a double-blind, placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO2] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024. Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks. The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-component z score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed. Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory-validated exercise testing at baseline and week 24. Integrated composite exercise performance improved in the aficamten group (mean [SD] z score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z score, -0.19 [0.45]), yielding a placebo-corrected improvement of 0.35 (95% CI, 0.25-0.46; P <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold (all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO2 were more common than large reductions (32% and 2%, respectively) compared with placebo (16% and 11%, respectively). Improvements in both components of the primary outcome, pVO2 and VE/VCO2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05). This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten. ClinicalTrials.gov Identifier: NCT05186818.

Factors Predicting the Effect of a Complex Decongestive Therapy in Patients with Mild Lymphedema Following Mastectomy for Early Stage Breast Cancer.

Background: Complex decongestive therapy (CDT) is being used in breast cancer-related lymphedema (BCRL). The degree of initial edema and bioimpedance analysis (BIA) are known to be related with the therapeutic effect of CDT. D-dimer can indirectly reflect lymphangiogenesis because IL-6 regulates D-dimer and vascular endothelial growth factor, which is the most important lymphangiogenic factor. We assessed whether D-dimer could be used for the prediction of therapeutic effect of CDT, as well as BIA and initial edema. Methods: The participants were patients who took inpatient treatment for BCRL from July 2016 to May 2020. Percent excess volume (PEV) was calculated by dividing the difference in volume of both arms by the edema arm, and the difference in PEV before and after 2 weeks of CDT was defined as the CDT effect. BIA and D-dimer tests were performed before treatment. Results: The single frequency bioimpedance analysis (SFBIA) ratio and D-dimer showed significant correlations with β coefficients of 0.581 and 0.402 (p < 0.01), respectively, and the explanatory power of these models was confirmed to be 0.704.The areas under the curve of initial PEV, SFBIA ratio, D-dimer for determining the CDT effect were identified as 0.849, 0.795, and 0.725, respectively. Conclusions: Initial PEV, SFBIA ratio, and blood D-dimer levels could be used as predictors for CDT treatment effect. Their usefulness order was in the order of initial PEV, SFBIA ratio, and D-dimer. These factors could be used as predictors to establish therapeutic plan in patients with mild lymphedema.

Ultrathin BSA-Stabilized Black Phosphorous Nanoreactor Boosts Mild-Temperature Photothermal Therapy Through Modulation of Cellular Self-Defense Fate.

Mild-temperature photothermal therapy (mild-PTT, 42-45°C) offers a higher level of biosafety. However, its therapeutic effects are compromised by the heat shock response (HSR), a cellular self-defense mechanism, which triggers the overexpression of heat shock proteins (HSPs) with the capacity of repairing the damaged tumor cells. Herein, this work fabricates a novel nanoreactor by incorporating up-conversion nanoparticles (UCNPs), chlorin e6 (Ce6), and glucose oxidase (GOx) onto the ultrathin black phosphorus nanosheet (BPNS) (denoted as GOx-BUC). This nanoreactor amplifies mild-PTT effects under irradiation with an 808nm laser, modulating HSPs-mediated cellular self-defense fate. On one hand, upon irradiation with a 980nm laser, UCNPs can transfer energy to excite Ce6, leading to the generation of ROS burst, which achieves indiscriminate damage to HSPs activity in deeper tumor tissues. On the other hand, GOx can consume glucose, thereby depleting the ATP energy supply and further suppressing HSPs expression. Consequently, GOx-BUC exhibits excellent anti-tumor efficacy under mild temperature in a human colorectal cancer mouse model, resulting in complete tumor inhibition with negligible side effects. This black phosphorous nanoreactor, featuring dual-track HSPs destruction functionality, introduces novel perspectives for enhancing mild-PTT effectiveness while maintaining high biosafety.

STUDY OF COPPER COMPLEXES [Cu(LCF3)2] AND [Cu(Lcur)2]H2O AS RADIOPROTECTIVE COMPOUNDS

One of the first and direct signs of the impact of ionizing radiation (IR) on a cell is the destabilization of chromosomes. Radiation-induced damage to the karyotype is an important indicator both for biological indication of the severity of radiation injuries and for predicting the development of long-term adverse effects of IR. The search for new, effective radioprotective compounds is a priority task of modern radiobiology. In this area, metal-based compounds with high antioxidant activity are of particular interest. The purpose of this work is to determine the possible radioprotective properties of Cu(II) complexes, [Сu(LCF3)2] and [Cu(Lcur)2]H2O, supported by the anions of the β-diketone ligands 1,1,1,5,5,5-hexafluoro-2,4-pentanedione (HLCF3) and 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione or curcumin (HLcur). In this research work we determined survival, life expectancy and cytogenetic parameters: mitotic index, chromosome aberrations and % of polyploid cells in the bone marrow cells of the femur (count in 1000 cells in each preparation). Group I included intact animals; Group II consisted of animals exposed to the radioisotope technetium; Group III consisted of animals that were intraperitoneally injected with copper complex [Cu(LCF3)2] at a dose of 50 mg/kg in a volume of 2 mL one hour before the administration of the Tc isotope (“irradiation + copper compound [Cu(LCF3)2]); Group IV included animals that received the compound [Cu(Lcur)2]H2O before irradiation. The groups with the injection of [Cu(LCF3)2] complex had the highest survival. In terms of chromosomal aberrations and number of polyploid cells, as indicators, a significant difference was found in those irradiated compared with the “irradiation + [Cu(LCF3)2]” group (both after 15 and after 30 days), which indicates the radioprotective property of the compound. In terms of the mitotic index, a tendency towards normalization was noted after 15 days and a significant difference between Groups 2 and 3 by the end of the study (after 30 days), which also proves the beneficial effect of this compound. Analysis of survival and changes in cytogenetic parameters multiregression analysis using both complexes confirms the greatest efficiency of the [Cu(LCF3)2] complex with respect to [Cu(Lcur)2]H2O, because when using [Cu(Lcur)2]H2O in Group IV and comparing it with “pure irradiation” only a tendency toward normalization of cytogenetic parameters was observed. Multiregression analysis of cytogenetic parameters also confirmed the highest efficiency of the [Cu(LCF3)2] compound in comparison with [Cu(Lcur)2]H2O. The results of the research indicate the need to continue work in the direction of searching for agents that have a therapeutic effect in radiation injuries.

Studies on the Preparation of a Microemulsion Formulation of Matricaria Recutita Essential Oil and the Treatment of 2,4-Dinitro-Chlorobenzene- Induced Eczema in Mice by Inhibiting Inflammation.

Eczema, an inflammatory skin disease causing intense itching, is a function of a range of internal and external factors, impacting individuals of all ages and leading to economic loss. Inflammation is the most important manifestation of eczema, and Matricaria recutita essential oil (MREO) extracted from Matricaria recutita possesses excellent antibacterial and anti-inflammatory properties. In this study, Matricaria recutita microemulsions were prepared by the trans-phase emulsification method and their stability was determined by evaluating the relevant indexes. Establishment of 2,4-dinitro-chlorobenzene-induced AD model in mice. Detection of serum indexes of IL-6, IL-17, and TNF-α, and on pathological tissue sections, the HE staining, toluidine blue staining, immunohistochemistry, and observation were performed. The study obtained optimal conditions for the preparation of microemulsion formulations of Matricaria recutita. Through quality evaluation, it was found that the microemulsion increased stability, reduced irritation, and retained anti-inflammatory activity and therapeutic effects on eczema compared to Matricaria recutita essential oil (MREO). Studies have demonstrated that microemulsion formulations of Matricaria recutita and Matricaria recutita significantly down regulate the proinflammatory factors TNF-α, IL-17, and IL-6. It was shown by hematoxylin-eosin (HE) staining that both Matricaria recutita essential oil (MREO) and Matricaria recutita microemulsion (MRME) improved the inflammatory status of eczematous skin tissues in mice. The number of mast cells expressed in the tissues was decreased in the surface-treated group, as shown by toluidine blue staining. Additionally, the number of mast cells expressed in the tissues in the surface-treated group was reduced, as demonstrated by immunohistochemistry. Furthermore, immunohistochemistry revealed that MREO and MRME have immunomodulatory effects on the tissues. The study showed that microemulsion formulations of Matricaria recutita may serve as a novel remedy for eczema.

Advances in stem cell therapy for diabetic foot

Diabetic Foot Ulcers (DFU) represent a grave complication often encountered in the advanced stages of diabetes mellitus. They frequently lead to recurrent hospitalizations and, in severe cases, can result in life-threatening conditions such as infections, gangrene, and even amputation Diabetic foot ulcers (DFU), as a serious complication in the late stage of diabetes mellitus, are prone to lead to repeated hospitalization, and in severe cases, infection, gangrene, and even amputation. Although there are many methods for treating diabetic foot, there is no clear and effective method to reduce the amputation rate of diabetic foot patients. In recent years, advancements in the understanding of stem cell therapy for the treatment of DFU have shed light on its potential as a novel therapeutic approach. In recent years, as the research on stem cell therapy for diabetic foot is gradually deepening, stem cells are expected to become a new therapeutic method for treating DFU in the future. Their therapeutic effects are through promoting angiogenesis, secreting paracrine factors, controlling inflammation, promoting collagen deposition, and regulating immunity, etc. Despite numerous studies confirming the efficacy of stem cell therapy in treating DFU, there is still a need for the establishment of standardized treatment protocols. Although numerous studies have shown that stem cell therapy for DFU is real and effective, there has not yet been a standardized treatment protocol. This article reviews studies related to stem cell therapy for DFU, looking at the mechanism of action, types of stem cells, and modes of administration.

Nanotechnology-Based Drug Delivery Systems for Treating Acute Kidney Injury.

Acute kidney injury (AKI) is a disease that is characterized by a rapid decline in renal function and has a relatively high incidence in hospitalized patients. Sepsis, renal hypoperfusion, and nephrotoxic drug exposure are the main causes of AKI. The major therapy measures currently include supportive treatment, symptomatic treatment, and kidney transplantation. These methods are supportive treatments, and their results are not satisfactory. Fortunately, many new treatments that markedly improve the AKI therapy efficiency are emerging. These include antioxidant therapy, ferroptosis therapy, anti-inflammatory therapy, autophagy therapy, and antiapoptotic therapy. In addition, the development of nanotechnology has further promoted therapeutic effects on AKI. In this review, we highlight recent advances in the development of nanocarriers for AKI drug delivery. Emphasis has been placed on the latest developments in nanocarrier modification and design. We also summarize the applications of different nanocarriers in AKI treatment. Finally, the advantages and challenges of nanocarrier applications in AKI are summarized, and several nanomedicines that have been approved for clinical trials to treat diverse kidney diseases are listed.

Red Bull Energy Drink Impact on Salivary Glands in Wistar Rats: Can Blueberry Extract Reverse the Damage?

Energy drink (ED) consumption has become increasingly popular. Due to a lack of evidence, it was crucial to assess the effects of Red Bull (RB) consumption on the rat submandibular salivary gland and the potential therapeutic impact of blueberry (BB). Thirty rats were randomly assigned to five groups. Group 1 (Control) received distilled water. Group 2 (RB) received RB (10 mL/100 g/day) for 8 weeks. Group 3 (BB) rats were administered BB (500 mg/day for 8 weeks). Group 4 (RB + BB (L)) received RB for 8 weeks, and from the 5th week, were concurrently given BB (250 mg/day) for 4 weeks. Group 5 (RB + BB (H)) received RB for 8 weeks, and from the 5th week, were concurrently given BB (500 mg/day) for 4 weeks. At the end of the experiment, blood samples were collected, the animals were euthanized, and their submandibular salivary glands were harvested. Oxidative stress markers (MDA, GPx, CAT, and SOD) were assessed in both serum and tissue. Inflammatory markers (TNF-α, IL-6, and IL-10) were quantified in tissue. Submandibular gland specimens were prepared for light microscopy, and immunohistochemical staining was performed using anti-α-SMA. RB consumption resulted in a significant increase in MDA, TNF-α, IL-6, and IL-10, while GPx, CAT, and SOD levels decreased significantly. Degenerative changes in the gland’s structure were observed in the RB group. A significant increase in α-SMA immunoreaction was detected in myoepithelial cells. Administration of BB, particularly at a high dose, ameliorated the aforementioned findings. In conclusion, blueberry administration exhibited therapeutic effects due to its antioxidative and anti-inflammatory properties.

Exploring the mechanism of genistein in treating hepatocellular carcinoma through network pharmacology and molecular docking

Abstract Objectives Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with treatment options limited and outcomes often poor, especially in advanced stages. This study explores the therapeutic potential of genistein, a soybean-derived isoflavone, on HCC using network pharmacology to uncover its multi-targeted anti-cancer mechanisms. Methods Potential targets of genistein were predicted using databases such as Super-PRED, PharmMapper, and SwissTargetPrediction. Abnormally expressed genes in HCC tissues were analyzed from TCGA and GEO datasets, with genes linked to the prognosis of HCC patients selected as potential therapeutic targets. GO and KEGG pathway enrichment analyses were conducted for both genistein’s targets and the HCC-related gene set. Key targets were identified through network analysis using Cytoscape software. Molecular docking was performed with Autodock to assess the binding affinity between genistein and these key targets. The therapeutic effects of genistein on HCC were validated through animal experiments and cell line studies. Results This study identified 343 potential targets for genistein in treating hepatocellular carcinoma (HCC). Analyses revealed enrichment in cell cycle regulation pathways through GO and KEGG assessments. Transcriptomic data from HCC datasets unveiled 184 potential therapeutic targets, emphasizing cell cycle regulation. Notably, 12 proteins were identified as targets of both genistein and HCC treatment. Molecular docking studies demonstrated genistein’s strong binding affinity with CDC25C and MELK. In vitro and in vivo validations affirmed genistein’s role in inhibiting HCC proliferation by inducing G2/M phase arrest. This study elucidates genistein’s multi-target mechanism in suppressing HCC cell proliferation, supporting its potential clinical application in HCC treatment. Conclusions This study demonstrates that genistein effectively suppresses the malignant growth of HCC by interfering with the transition from the G2 to M phase, revealing a multifaceted mechanism of action.

The Gut Microbiota Mediates the Protective Effects of Spironolactone on Myocardial Infarction.

Myocardial infarction (MI) is a type of cardiovascular disease that influences millions of human beings worldwide and has a great rate of mortality and morbidity. Spironolactone has been used as a critical drug for the treatment of cardiac failure and it ameliorates cardiac dysfunction post-MI. Despite these findings, whether there is a relationship between the therapeutic effects of spironolactone and the gut microorganism after MI has not been determined. In our research, we used male C57BL/6J mice to explore whether the gut microbiota mediates the beneficial function of spironolactone after myocardial infarction. We demonstrated that deletion of the gut microbiota eliminated the beneficial function of spironolactone in MI mice, displaying exacerbated cardiac dysfunction, cardiac infarct size. In addition, the gut microbiota was altered by spironolactone after sham or MI operation in mice. We also used male C57BL/6J mice to investigate the function of a probiotic in the myocardial infarction. In summary, our findings reveal a precious role of the gut flora in the therapeutic function of spironolactone on MI.

Inflammation-oriented montmorillonite adjuvant enhanced oral delivery of anti-TNF-α nanobody against inflammatory bowel disease

Oral delivery of proteins faces challenges due to the harsh conditions of the gastrointestinal (GI) tract, including gastric acid and intestinal enzyme degradation. Permeation enhancers are limited in their ability to deliver proteins with high molecular weight and can potentially cause toxicity by opening tight junctions. To overcome these challenges, we propose the use of montmorillonite (MMT) as an adjuvant that possesses both inflammation-oriented abilities and the ability to regulate gut microbiota. This adjuvant can be used as a universal protein oral delivery technology by fusing with advantageous binding amino acid sequences. We demonstrated that anti-TNF-α nanobody (VII) can be intercalated into the MMT interlayer space. The carboxylate groups (-COOH) of aspartic acid (D) and glutamic acid (E) interact with the MMT surface through electrostatic interactions with sodium ions (Na+). The amino groups (NH2) of asparagine (N) and glutamine (Q) are primarily attracted to the MMT layers through hydrogen bonding with oxygen atoms on the surface. This binding mechanism protects VII from degradation and ensures its release in the intestinal tract, as well as retaining biological activity, leading to significantly enhanced therapeutic effects on colitis. Furthermore, VII@MMT increases the abundance of short-chain fatty acids (SCFAs)-producing strains, including Clostridia, Prevotellaceae, Alloprevotella, Oscillospiraceae, Clostridia_vadinBB60_group, and Ruminococcaceae, therefore enhance the production of SCFAs and butyrate, inducing regulatory T cells (Tregs) production to modulate local and systemic immune homeostasis. Overall, the MMT adjuvant provides a promising universal strategy for protein oral delivery by rational designed protein.

Precision Treatment of Colon Cancer Using Doxorubicin-Loaded Metal-Organic-Framework-Coated Magnetic Nanoparticles.

Due to the limited efficacy and evident side effects of traditional chemotherapy drugs attributed to their lack of specificity and selectivity, novel strategies are essential for improving cancer treatment outcomes. Here, we successfully engineered Fe3O4 magnetic nanoparticles coated with zeolitic imidazolate framework-8 (ZIF-8). The resulting nanocomposite (Fe3O4@ZIF-8) demonstrates efficient adsorption of a substantial amount of doxorubicin (DOX) due to the porous nature of ZIF-8. The drug-loaded nanoparticles, Fe3O4@ZIF-8/DOX, exhibit significant accumulation at the tumor site in SW620 colon-cancer-bearing mice when guided by an external magnetic field. Within the acidic microenvironment of the tumor, the ZIF-8 framework collapses, releasing DOX and effectively inducing tumor cell death, thereby inhibiting cancer progression while not causing undesired side effects, as confirmed by a variety of in vitro and in vivo characterizations. In comparison to free DOX, Fe3O4@ZIF-8/DOX nanoparticles show superior efficacy in colon cancer treatment. Our findings suggest that Fe3O4@ZIF-8 holds promise as a carrier for small-molecule drug adsorption and its ferromagnetic properties provide drug targeting capabilities, thereby enhancing therapeutic effects on tumors at the same drug dosage. With excellent biocompatibility, Fe3O4@ZIF-8 demonstrates potential as a drug carrier in targeted cancer chemotherapy. Our work suggests that a combination of magnetic targeting and acid-responsiveness holds great promise for advancing targeted cancer therapy in precision nanomedicine.

Zingiber officinale Ameliorates Acute Toxoplasmosis-Induced Pathology in Mice.

Toxoplasma gondii (T. gondii) infects one third of the world's population with significant illness, mainly among immunocompromised individuals and pregnant women. Treatment options for toxoplasmosis are limited which signifies the need for novel, potent, and safe therapeutic options. The goal of this study was to assess the effectiveness of the ethanolic extract of Zingiber officinale (Z. officinale) in treating mice infected with the RH T. gondii strain. Gas Chromatography/Mass Spectrometry (GC/MS) was used to identify components of ethanolic extract of Z. officinale. A total of 80 mice were randomly allocated into four experimental groups that contained 20 mice each. The first group was left uninfected (uninfected control), while three groups were infected with T. gondii RH virulent strain tachyzoites at 2500 tachyzoites/mouse. One infected group was left untreated (infected, untreated), whereas the other two groups were treated orally with either spiramycin (positive control) or Z. officinale ethanolic extract at doses of 200mg/kg and 500mg/kg, respectively for 5 days, starting the day of infection. Ten mice from each group were used to assess mice survival in different groups, whereas the other ten mice in each group were sacrificed on the 5th day post-infectin (dpi) to estimate the treatment efficacy by quantifying liver parasite load, liver function, nitric oxide (NO) production, and levels of antioxidant enzymes. Additionally, histopathological studies were performed to evaluate the therapeutic effect of Z. officinale treatment on toxoplasmosis-induced pathological alterations in liver, brain, and spleen. Treatment with Z. officinale ethanolic extract extended the survival of mice till 9th dpi compared to 7th dpi in infected untreated mice. Higher percentage of mice survived in Z. officinale-treated group compared to spiramycin-treatment group at different time points. Liver parasite loads were significantly lower in Z. officinale extract-treated mice and spiramycin-treated mice compared to infected untreated mice which correlated with significantly lower levels of serum liver enzymes (ALT, AST) and nitric oxide (NO), as well as significantly higher catalase (CAT) antioxidant enzyme activity. Scanning electron microscopy (SEM) examination of tachyzoites from the peritoneal fluid revealed marked damage in tachyzoites from Z. officinale-treated group compared to that from infected untreated mice. Moreover, treatment with Z. officinale ethanolic extract alleviated infection-induced pathological alterations and restored normal tissue morphology of liver, brain, and spleen. Our results demonstrated that Z. officinale treatment reduced parasite burden and reversed histopathological and biochemical alterations in acute murine toxoplasmosis. These findings support the potential utility of Z. officinale as a future effective natural therapeutic for toxoplasmosis. Further studies are needed to determine the effective active ingredient in Z. officinale extract that can be further optimized for treatment of toxoplasmosis.

Supramolecular H-Aggregates of Squaraines with Enhanced Type I Photosensitization for Combined Photodynamic and Photothermal Therapy.

Combined photodynamic and photothermal therapy (PDT and PTT) can achieve more superior therapeutic effects than the sole mode by maximizing the photon utilization, but there remains a significant challenge in the development of related single-molecule photosensitizers (PSs), particularly those with type I photosensitization. In this study, self-assembly of squaraine dyes (SQs) is shown to be a promising strategy for designing PSs for combined type I PDT and PTT, and a supramolecular PS (TPE-SQ7) has been successfully developed through subtle molecular design of an indolenine SQ, which can self-assemble into highly ordered H-aggregates in aqueous solution as well as nanoparticles (NPs). In contrast to the typical quenching effect of H-aggregates on reactive oxygen species (ROS) generation, our results encouragingly manifest that H-aggregates can enhance type I ROS (•OH) generation by facilitating the intersystem crossing process while maintaining a high PTT performance. Consequently, TPE-SQ7 NPs with ordered H-aggregates not only exhibit superior combined therapeutic efficacy than the well-known PS (Ce6) under both normoxic and hypoxic conditions but also have excellent biosafety, making them have important application prospects in tumor phototherapy and antibacterial fields. This study not only proves that the supramolecular self-assembly of SQs is an effective strategy toward high-performance PSs for combined type I PDT and PTT but also provides a different understanding of the effect of H-aggregates on the PDT performance.

GLP-1R-positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice.

Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is approved for obesity treatment, but the specific neuronal sites that contribute to its therapeutic effects remain elusive. Here, we show that GLP-1 receptor-positive (GLP-1R-positive) neurons in the lateral septum (LSGLP-1R) play a critical role in mediating the anorectic and weight-loss effects of liraglutide. LSGLP-1R neurons were robustly activated by liraglutide, and chemogenetic activation of these neurons dramatically suppressed feeding. Targeted knockdown of GLP-1 receptors within the LS, but not in the hypothalamus, substantially attenuated liraglutide's ability to inhibit feeding and lower body weight. The activity of LSGLP-1R neurons rapidly decreased during naturalistic feeding episodes, while synaptic inactivation of LSGLP-1R neurons diminished the anorexic effects triggered by liraglutide. Together, these findings offer critical insights into the functional role of LSGLP-1R neurons in the physiological regulation of energy homeostasis and delineate their instrumental role in mediating the pharmacological efficacy of liraglutide.