Organ Toxicity Research Articles

High Carbonyl Graphene Oxide Suppresses Colorectal Cancer Cell Proliferation and Migration by Inducing Ferroptosis via the System Xc−/GSH/GPX4 Axis

Background/Objectives: Colorectal cancer (CRC) is characterized by a high rate of both incidence and mortality, and its treatment outcomes are often affected by recurrence and drug resistance. Ferroptosis, an iron-dependent programmed cell death mechanism triggered by lipid peroxidation, has recently gained attention as a potential therapeutic target. Graphene oxide (GO), known for its oxygen-containing functional groups, biocompatibility, and potential for functionalization, holds promise in cancer treatment. However, its role in ferroptosis induction in CRC remains underexplored. The objective of this study was to investigate the effects of High Carbonyl Graphene Oxide (HC-GO) on ferroptosis in CRC and elucidate the underlying mechanisms. Methods: In vitro assays were conducted to evaluate the impact of HC-GO on CRC cell proliferation, mitochondrial function, iron accumulation, lipid peroxidation, and reactive oxygen species (ROS) production. The ferroptosis inhibitor Fer-1 was used to confirm the role of ferroptosis in HC-GO’s anti-tumor effects. In vivo, the anti-tumor activity of HC-GO was assessed in a CRC xenograft model, with organ toxicity evaluated. Results: HC-GO significantly inhibited CRC cell proliferation, induced mitochondrial damage, and enhanced iron accumulation, lipid peroxidation, and ROS production. It also downregulated the ferroptosis-inhibiting proteins GPX4 and SLC7A11, which were reversed by Fer-1, confirming the involvement of ferroptosis in HC-GO’s anti-cancer effects. In vivo, HC-GO significantly suppressed tumor growth without noticeable toxicity to vital organs. Conclusions: HC-GO triggered ferroptosis in CRC cells by suppressing the System Xc−/GSH/GPX4 pathway, providing a novel therapeutic strategy for CRC treatment. These findings suggest HC-GO as a promising nanomedicine for clinical application, warranting further investigation to explore its potential in CRC therapy.

Effects of Flurochloridone on the Developmental Toxicity in Zebrafish (Danio rerio) Embryo.

Flurochloridone (FLC) is a selective herbicide that can cause reproductive toxicity in male rats. However, limited information is available regarding the toxicity of FLC in the developmental stages of aquatic organisms. This study aimed to investigate the effects of FLC exposure during embryonic development and elucidate its potential mechanism of action. Zebrafish embryos were exposed to 6.25, 12.5, 25, and 50 μg/mL FLC for 4-144 hpf. The developmental status of embryos was recorded; the indicators of oxidative stress and embryonic apoptosis were determined. We found that FLC exposure caused severe embryonic malformations, such as pericardial edema, spinal curvature, and growth retardation, accompanied by a decreased hatching and survival rate. After exposure until 144 h postfertilization, the median lethal concentration (LC50) of FLC in zebrafish embryos was 36.9 μg/mL. Subsequently, FLC induced the accumulation of reactive oxygen species and malondialdehyde, enhanced the activity of superoxide dismutase, and activated the Keap1-Nrf2 signaling pathway. Further studies confirmed that FLC can induce apoptosis in zebrafish embryos through the activation of caspase. These results suggest that FLC induced developmental toxicity in zebrafish embryos, which provides new evidence regarding FLC toxicity in aquatic organisms and to assess human health risks.

Impact of administration routes and dose frequency on the toxicology of SARS-CoV-2 mRNA vaccines in mice model.

The increasing use of SARS-CoV-2 mRNA vaccines has raised concerns about their potential toxicological effects, necessitating further investigation to ensure their safety. To address this issue, we aimed to evaluate the toxicological effects of SARS-CoV-2 mRNA vaccine candidates formulated with four different types of lipid nanoparticles in ICR mice, focusing on repeated doses and administration routes. We conducted an extensive analysis in which mice received the mRNA vaccine candidates intramuscularly (50 μg/head) twice at 2-week intervals, followed by necropsy at 2 and 14 dpsi (days post-secondary injection). In addition, we performed a repeated dose toxicity test involving three, four, or five doses and compared the toxicological outcomes between intravenous and intramuscular routes. Our findings revealed that all vaccine candidates significantly induced SARS-CoV-2 spike protein-specific IgG and T cell responses. However, at 2 dpsi, there was a notable temporary decrease in lymphocyte and reticulocyte counts, anemia-related parameters, and significant increases in cardiac damage markers, troponin-I and NT-proBNP. Histopathological analysis revealed severe inflammation and necrosis at the injection site, decreased erythroid cells in bone marrow, cortical atrophy of the thymus, and increased spleen cellularity. While most toxicological changes observed at 2 dpsi had resolved by 14 dpsi, spleen enlargement and injection site damage persisted. Furthermore, repeated doses led to the accumulation of toxicity, and different administration routes resulted in distinct toxicological phenotypes. These findings highlight the potential toxicological risks associated with mRNA vaccines, emphasizing the necessity to carefully consider administration routes and dosage regimens in vaccine safety evaluations, particularly given the presence of bone marrow and immune organ toxicity, which, though eventually reversible, remains a serious concern.

Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies.

Chemotherapy (CT) is one of the flagship options for the treatment of cancers worldwide. It involves the use of cytotoxic anticancer agents to kill or inhibit the proliferation of cancer cells. However, despite its clinical efficacy, CT triggers side effect toxicities in several organs, which may impact cancer patient's quality of life and treatment outcomes. While the side effect toxicity is consistent with non-ferroptotic mechanisms involving oxidative stress, inflammation, mitochondrial impairment and other aberrant signalling leading to apoptosis and necroptosis, recent studies show that ferroptosis, a non-apoptotic, iron-dependent cell death pathway, is also involved in the pathophysiology of CT organ toxicity. CT provokes organ ferroptosis via system Xc-/GPX-4/GSH/SLC7A11 axis depletion, ferritinophagy, iron overload, lipid peroxidation and upregulation of ferritin-related proteins. Cisplatin (CP) and doxorubicin (DOX) are common CT drugs indicated to induce ferroptosis in vitro and in vivo. Studies have explored natural preventive and therapeutic strategies using ginger rhizome and its major bioactive compounds, 6-gingerol (6G) and zingerone (ZG), to combat mechanisms of CT side effect toxicity. Ginger extract, 6G and ZG mitigate non-ferroptotic oxidative inflammation, apoptosis and mitochondrial dysfunction mechanisms of CT side effect toxicity, but their effects on CT-induced ferroptosis remain unclear. Systematic investigations are, therefore, needed to unfold the roles of ginger, 6G and ZG on ferroptosis involved in CT side effect toxicity, as they are potential natural agents for the prevention of CT toxicity. This review reveals the ferroptotic and non-ferroptotic toxicity mechanisms of CT and the protective mechanisms of ginger, 6G and ZG against CT-induced, ferroptotic and non-ferroptotic organ toxicities.

Immunomodulatory Effects of Nellikai Thenural Against Thiamethoxam-Induced Toxicity in Carassius auratus

The accumulation of pesticides in aquatic ecosystems poses significant risks to non-target organisms, particularly fish populations. The study evaluated the protective effects of Nellikai Thenural, a traditional Siddha formulation containing Emblica officinalis and honey, against thiamethoxam-induced toxicity in Carassius auratus (goldfish). The experimental design comprised four groups: control, Nellikai Thenural-treated (733 μg), thiamethoxam-exposed (114.84 mg/L), and co-administered (thiamethoxam + Nellikai Thenural) groups. The LC50 value of Nellikai Thenural was determined at 916 μg/ml/kg body weight through brine shrimp lethality assay. Hematological parameters revealed significant alterations in thiamethoxam-exposed fish, with decreased RBC count, hemoglobin levels, and WBC count. The administration of Nellikai Thenural effectively restored these parameters toward normal levels. Biochemical markers, including plasma proteins, immunoglobulins, and tissue-specific enzymes (ALP, ACP, AST), showed marked improvement in the co-administered group compared to thiamethoxam-exposed fish. Behavioral observations indicated reduced stress responses and improved swimming patterns in fish treated with Nellikai Thenural. The findings demonstrate the potential of Nellikai Thenural as a natural immunostimulant and protective agent against pesticide-induced toxicity in aquatic organisms.

Effects of the organochlorine pesticide metabolite p,p’-DDE on the gastrointestinal lipidome in fish: A novel toxicity pathway for a legacy pollutant

Though phased out from use in the United States, environmental contamination by organochlorine pesticides (OCPs) remains a widespread issue, especially around intensive agricultural regions. OCPs, such as dichlorodiphenyltrichloroethane (DDT) and its primary metabolite, dichlorodiphenyldichloroethylene (DDE), have been detected in soils, sediments, surface waters, and biota decades after their discontinued use. As OCPs are persistent and can bioaccumulate in fats, these compounds can transfer and magnify across food webs. Freshwater predatory fish and birds can accumulate high OCP concentrations, leading to a myriad of deleterious impacts on organismal health. Studies have found evidence of reproductive disruption in predatory fish, such as the largemouth bass (LMB; Micropterus salmoides), associated with DDT and DDE exposure. DDE can act through estrogenic pathways and induce the expression of estrogenic signals in male animals; however, the molecular mechanism of disruption is unclear. Recently, metabolomics research has revealed corollary relationships between lipid signals and organic pollutant toxicity. Here, a two-month feeding experiment on LMB was conducted to assess the interactions of DDE (as p,p'-DDE) in food with gut and liver lipid signaling. Targeted lipidomic analysis revealed global alterations in the abundance of tissue lipids, especially cholesteryl esters and phospholipids, in LMB exposed to low levels of p,p'-DDE. Results from these studies indicate that p,p'-DDE may act through disruption of normal lipid homeostasis to cause toxicity in freshwater fish.

Safety assessment of Gami-daebo-tang gagambang used for treating stroke sequelae

Objectives: This study aimed to investigate wheter Gami-daebo-tang gagambang, commonly used for treating stroke sequelae, induces acute toxicity or genetoxicity.Methods: Gami-daebo-tang gagambang contains that the root of <i>Angelica gigas Nakai</i> inducing acute headache and weakness, and the rhizome of <i>Cnidium officinale</i> MAKINO, an herb with potential teratogenicity. Teratogenicity is closely associated with genotoxicity. We analyzed whether Gami-daebo-tang gagambang induces acute toxicity and genotoxicity in accordance with Korean non-clinical test standards and OECD test guidelines TG471, TG473, TG474.Results: When male and female rats were given a single dose of Gami-daebo-tang gagambang, no toxic effects or organ damage were observed at dosages reaching 2,500 mg/kg. The bacterial reverse mutation assay showed no evidence of DNA mutations at concentrations up to 5,000 <i>μ</i>g/plate. In vitro studies indicated that Gami-daebo-tang gagambang did not cause structural or numerical chromosomal aberrations at concentrations as high as 2,000 <i>μ</i>g/mL. Moreover, animal studies demonstrated that the substance did not induce bone marrow toxicity or the formation of micronuclei in erythrocytes at doses up to 2,000 mg/kg.Conclusions: The studies conducted with different models showed that Gami-daebo-tang gagambang did not cause acute toxicity or genotoxicity. This study provides evidence for the safety of Gami-daebo-tang gagambang in terms of acute toxicity and genotoxicity, supporting its potential safe application in treating stroke sequelae.

Dermatological Nanotechnology: Gelatin films with O/W emulsions for skin lesion repair.

The development of films, scaffolds, hydrogels, and other innovations based on biopolymers for the treatment of skin injuries is on the rise. Therefore, it is important to focus on their functionality, influence on human use, and environmental impact. This work investigates the antimicrobial capacity of gelatin films that incorporate O/W emulsions encapsulating bactericidal and healing active ingredients (EA). Their biocompatibility was evaluated in vitro in human skin keratinocyte and murine fibroblast cell cultures, as well as in vivo using the zebrafish model. Finally, its potential to heal wounds was assessed through a keratinocyte cell migration assay. The EA films exhibited antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus. The films were biocompatible with monolayer cultures, without affecting cell viability, metabolic activity, or membrane integrity. The films did not exhibit general toxicological effects in zebrafish nor specific organ toxicity in the heart, liver, or brain. Further, the EA films promoted keratinocyte migration in the wound healing assay. In conclusion, the films could be used as a potential treatment for various types of skin injuries, being safe for both potential human application and the environment after use and disposal.

Empagliflozin-A Sodium Glucose Co-transporter-2 Inhibitor: Overview ofits Chemistry, Pharmacology, and Toxicology.

Empagliflozin is a sodium glucose co-transporter-2 (SGLT2) inhibitor that has gained significant attention in the treatment of type 2 diabetes mellitus. Understanding its chemistry, pharmacology, and toxicology is crucial for the safe and effective use of this medication. This review aims to provide a comprehensive overview of the chemistry, pharmacology, and toxicology of empagliflozin, synthesizing the available literature to present a concise summary of its properties and implications for clinical practice. A systematic search of relevant databases was conducted to identify studies and articles related to the chemistry, pharmacology, and toxicology of empagliflozin. Data from preclinical and clinical studies, as well as post-marketing surveillance reports, were reviewed to provide a comprehensive understanding of the topic. Empagliflozin is a selective SGLT2 inhibitor that works by constraining glucose reabsorption in the kidneys, causing increased urinary glucose elimination. Its unique mechanism of action provides glycemic control, weight reduction, and blood pressure reduction. The drug's chemistry is characterized by its chemical structure, solubility, and stability. Pharmacologically, empagliflozin exhibits favorable pharmacokinetic properties with rapid absorption, extensive protein binding, and renal elimination. Clinical studies have demonstrated its efficacy in improving glycemic control, reducing cardiovascular risks, and preserving renal function. However, adverse effects, for instance, urinary tract infections, genital infections, and diabetic ketoacidosis have been reported. Toxicological studies indicate low potential for organ toxicity, mutagenicity, or carcinogenicity. Empagliflozin is a promising SGLT2 inhibitor that offers an innovative approach to the treatment of type 2 diabetes mellitus. Its unique action mechanism and favorable pharmacokinetic profile contribute to its efficacy in improving glycemic control and reducing cardiovascular risks. While the drug's safety profile is generally favorable, clinicians should be aware of potential adverse effects and monitor patients closely. More study is required to determine the longterm safety and explore potential benefits in other patient populations. Overall, empagliflozin represents a valuable addition to the armamentarium of antidiabetic medications, offering significant benefits to patients suffering from type 2 diabetes mellitus. This study covers all aspects of empagliflozin, including its history, chemistry, pharmacology, and various clinical studies, case reports, and case series.

Evaluating applicability domain of acute toxicity QSAR models for military and industrial chemical risk assessment

Quantitative Structure-Activity Relationship (QSAR) models can be used to predict the risk of novel and emergent chemicals causing adverse health outcomes, avoidance of which is crucial for military operations. While QSAR modeling approaches have been proposed for military and industry risk assessment, the applicability of peer-reviewed tissue-specific QSAR models in military and industrial contexts remain largely unexplored, particularly with respect to specific organ toxicity. We investigated the applicability domain (AD) of acute and sub-chronic tissue-specific QSAR models to evaluate the coverage of military- and industrial-relevant chemicals. Our analysis reveals that military-relevant compounds occupy a similar chemical space as industrial compounds. However, published models for acute target organ toxicity had minimal coverage of the military and industrial chemicals. The published Collaborative Acute Toxicity Modeling Suite (CATMoS) acute oral toxicity model was the notable exception, as it covers a broad range of military and industrial chemicals. Our study underscores the urgent need for development of novel tissue-specific QSAR models, or modification of existing models, to improve chemical risk prediction in both industrial and military applications.

Oral and tumor-targeting mixed micelles based on pegylated biotin and chitosan-based conjugate for breast cancer treatment

Oral drug delivery with tumor-targeting treatment persists as a challenge. In this study, a mixed polymeric micelle (PM) delivery system was designed to overcome the barriers to oral administration for tumor-targeting delivery of paclitaxel (PTX) for breast cancer treatment. D-α-Tocopheryl polyethylene glycol 1000 succinate-modified carboxymethyl chitosan-rhein (TCR) conjugate and Biotin-polyethylene glycol 2000-Biotin (BPB) conjugate were mixed to form TCR-BPB PMs. The particle size and polydispersity index of optimized PTX-loaded TCR-BPB PMs (PTX/TCR-BPB PMs) was 195.90 ± 7.63 nm and 0.08 ± 0.00, with a drug-loading capacity of 41.94 ± 2.47 %. In simulated gastroenteric fluid and blood environments, the PMs presented a sustained-release manner. PTX/TCR-BPB PMs were taken up by Caco-2 and 4T1 cells and displayed strong cytotoxicity in a time- and concentration-dependent manner. PTX/TCR-BPB PMs significantly improved intestinal absorption of PTX. The pharmacokinetics, tissue distribution, and in vivo imaging indicated that PTX/TCR-BPB PMs could enhance oral bioavailability of PTX, prolong the retention time of PTX in the blood, and enhance PTX tumor-targeting ability. PTX/TCR-BPB PMs enhance the antitumor efficacy of PTX and reduce its toxicity in normal organs. Therefore, TCR-BPB PMs are expected to serve as delivery carriers for the oral and tumor-targeting delivery of hydrophobic antitumor drugs.

Oleuropein Protects against the Development of Kidneys Induced by Paracetamol in Albino Male Rats.

Paracetamol treatment is considered one of the treatments used to relieve pain and antipyretic. Therefore, excessive doses and long-term use lead to organ toxicity. Paracetamol treatment is considered one of the treatments used to relieve pain and antipyretic. Therefore, excessive doses and long-term use lead to organ toxicity. The aim of the study was to investigate the protective effect of Oleuropein extracted from olive leaves on the physiological and histological aspects induced by Paracetamol in a rat model. The methods used 25 albino Swiss rats randomly distributed into five groups with the same number. The unit of control is given normal saline. Paracetamol (750 mg/kg) was injected into the group once. In the treatment groups (50 mg/kg, 100 mg/kg, 150 mg/kg). The Administration of Paracetamol's result significantly increased blood urea, creatinine, sodium, and potassium levels, and their blood concentrations decreased with Oleuropein (P 0.05). In addition, Oleuropein extracted from olive leaves relieved some symptoms, including acute vascular congestion caused by a dose of Paracetamol. Compared with paracetamol treatment, there is an infiltration of inflammatory cells and severe nephrotoxicity in the tubules. According to this study, the Oleuropein extracted from olive leaves can be used to prevent kidney damage, and It is not recommended to give Paracetamol, which increases kidney disorders.

Possibilities of Predicting Methotrexate-associated Toxicity in Oncohematology Based on Molecular Genetic Testing Methods

The development of highly effective protocols for the treatment of acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphomas (NHL) followed the path of escalation of doses of cytostatic agents and improvement of supportive care. Methotrexate (MTX), used in high doses (1000–5000 mg/m2), radically changed the results of treatment of ALL and NHL in children, increasing patient survival rates. The downside of the anti-tumor effect of MTX is its organ toxicity, and therefore the development of methods for predicting the development of toxic effects of MTX is an important scientific and practical task. In recent years, the genetic factors of the patient’s organism have been considered as one of the reasons for the individual variability of pharmacokinetic and pharmacodynamic parameters of MTX. Abnormal function of folate cycle enzymes, methotrexate transporter proteins, due to gene polymorphism, may affect the effectiveness and toxicity of the drug. This review summarizes and analyzes the known genetic polymorphisms involved in MTX metabolism. The possibilities of predicting toxicity, as well as the prospects for individualizing therapy, taking into account the results of pharmacogenetic testing, are presented.

Small but mighty: targeted antifungal liposomes of a smaller size are superior in treating cryptococcal meningitis.

Systemic cryptococcosis is fatal even with antifungal interventions. The most effective drug against this disease is amphotericin B (AmB). However, AmB is highly toxic as it binds to fungal ergosterol and also mammalian cholesterol. Liposomal AmB was introduced to the clinic in 1990s because it showed reduced toxicity and longer retention in various organs. However, the dose of AmB required for treatment using liposomal formulation is high and the outcome is far from satisfactory. In our previous work, we generated DectiSomes, dectin-decorated liposomes loaded with AmB that more effectively deliver the drug to the pathogen and enhance antifungal efficacy. However, the improvement in treating systemic cryptococcosis, compared with candidiasis and aspergillosis, is modest. Here, we generated DectiSomes that are half their regular size to improve tissue penetration. We discovered that small DectiSomes are superior in reducing fungal burden in various organs including the brain and in prolonging animal survival.

Antibacterial and Inhibitory Activity of Nora and Mepa Efflux Pumps of Estragole Complexed to β-Cyclodextrin (ES/β-CD) In Vitro Against Staphylococcus aureus Bacteria, Molecular Docking and MPO-Based Pharmacokinetics Prediction.

Background/Objectives: The work investigates the effect of the estragole complex encapsulated in beta-cyclodextrin (ES/β-CD) in modulating bacterial resistance, specifically in Staphylococcus aureus strains expressing NorA and MepA efflux pumps. Efflux pumps are mechanisms that bacteria use to resist antibiotics by expelling them from the cell. Methodology: Several compounds and antibiotics, such as ciprofloxacin and norfloxacin, were used to evaluate the antimicrobial activity and the ability of the ES/β-CD complex to reverse resistance. Methods: The study included scanning electron microscopy assays, minimum inhibitory concentration (MIC) determination, and efflux pump inhibition tests. Results: The ES/β-CD complex did not show significant direct antibacterial activity. However, it modulated the action of norfloxacin, decreasing the MIC when combined with this antibiotic in the 1199B (NorA) strain. These results suggest a potential for synergy but not a direct inhibition of efflux pumps. Conclusion: ES/β-CD can potentiate the efficacy of some antibiotics but does not directly act as an efflux pump inhibitor; it is more of an antibiotic potentiator than a direct solution to bacterial resistance. The molecular docking simulation data suggest its high affinity for forming the ES/β-CD complex. The pharmacokinetic predictions based on MPO suggest that the compound has moderate lipophilicity, highly effective cellular permeability, and low incidence of organic toxicity, pointing to a promising pharmacological principle with controlled daily oral dosing. Conclusions: These results indicate this complex's possible and relevant association as an adjuvant in antibiotic therapy to reduce multidrug-resistant bacteria; however, new in vivo assays are necessary to confirm this effect.

GC/MS Analysis and Protective Effects of Mentha longifolia L. Essential Oil Against Antituberculosis Drug-Induced Organs Toxicity in Wistar Albino Rats.

Mentha longifolia (L.) L., also known as wild mint, is a perennial herbaceous plant that belongs to the Lamiaceae family. This study aimed to investigate the effects of essential oil of M. longifolia (MLEO) on oxidative stress and inflammatory responses in the liver and kidneys in the context of drug-induced liver injury caused by the anti-TB drugs rifampicin, isoniazid, and pyrazinamide (INH-RIF-PZA). The chemical composition of MLEO was characterized using GC/MS analysis, which revealed the presence of pulegone, trans-p-menthan-3-one, piperitenone, and β-caryophyllene as its major volatile constituents. An INH/RIF/PZA mixture was administered to Wistar rats for 30 days, and silymarin was administered as a standard drug. MLEO was administered p.o. at doses of 50 mg and 100 mg/kg b.w. Both doses of the MLEO therapy effectively regulated all biochemical indicators of hepatic impairment and reduced the damage caused by the INH/RIF/PZA mixture. It may be deduced that MLEO has the ability to protect organs against INH/RIF/PZA-induced damage and could potentially be a valuable natural remedy for treating anti-TB-induced liver and kidney injuries.

Changes in Physiological Homeostasis in the Gills of Litopenaeus vannamei Under Carbonate Alkalinity Stress and Recovery Conditions

Carbonate alkalinity (CA) is the major toxic factor that interferes with the survival and growth of shrimp in saline–alkaline water. Gills are the main entry organ for CA toxicity in shrimp. In this study, low-salinity cultured Litopenaeus vannamei were exposed to 5 mmol/L CA stress for 7 days and then recovered for 7 days to explore the physiological changes in the gills under CA stress and recovery conditions at multiple biological levels. The results showed that CA stress increased the activities of antioxidative biochemical indexes (T-AOC, T-SOD, and POD) and the relative expression levels of romo1, nrf2, and gpx genes, while it decreased the relative expression levels of the sod and hsp70 genes. In addition, CA stress also increased the relative expression levels of genes involved in endoplasmic reticulum (ER) stress (bip, ire1, and xbp1), immunity (alf, crus, pen-3, lys, and propo), apoptosis (casp-3), detoxification metabolism (cyp450 and gst), and osmotic adjustment (ca, nka-α, nka-β, vatp, nhe, clc, aqp, tip4, and ccp). Although changes in some of the physiological indexes were reversed after the CA stress was relieved, they still could not effectively recover to the control level. These results reveal that CA stress has a negative impact on physiological homeostasis in the shrimp gills by inducing oxidation and ER stress and by interfering with immunity, apoptosis, detoxification, and osmotic adjustment.

Engineered receptors for soluble cellular communication and disease sensing.

Despite recent advances in mammalian synthetic biology, there remains a lack of modular synthetic receptors that can robustly respond to soluble ligands and in turn activate bespoke cellular functions. Such receptors would have extensive clinical potential to regulate the activity of engineered therapeutic cells, but to date only receptors against cell surface targets have approached clinical translation1. To address this gap, we developed a receptor architecture called synthetic intramembrane proteolysis receptor (SNIPR), that has the added ability to be activated by soluble ligands, both natural and synthetic, with remarkably low baseline activity and high fold activation, through an endocytic, pH-dependent cleavage mechanism. We demonstrate the therapeutic capabilities of the receptor platform by localizing the activity of CAR T cells to solid tumors where soluble disease-associated factors are expressed, bypassing the major hurdle of on-target off-tumor toxicity in bystander organs. We further applied the SNIPR platform to engineer fully synthetic signaling networks between cells orthogonal to natural signaling pathways, expanding the scope of synthetic biology. Our design framework enables cellular communication and environmental interactions, extending the capabilities of synthetic cellular networking in clinical and research contexts.

Generation of BT-Amide, a Bone-Targeted Pyk2 Inhibitor, Effective via Oral Administration, for the Prevention of Glucocorticoid-Induced Bone Loss.

Glucocorticoid-induced osteoporosis (GIOP) is the leading cause of iatrogenic osteoporosis due to the widespread clinical use of glucocorticoids (GC) as immunosuppressants. Previous research identified the proline-rich tyrosine kinase 2, Pyk2, as a critical mediator of GC-induced bone loss, and that blocking Pyk2 could protect the skeleton from adverse GC actions. However, systemic administration of current Pyk2 inhibitors causes harmful side effects, such as skin lesions. To address this, we developed bone-targeted (BT) Pyk2 inhibitors by conjugating them with bisphosphonates (BP), ensuring adherence to the bone matrix and reducing impact on noncalcified tissues. We synthesized BT-Amide by linking a derivative of TAE-226, a Pyk2 inhibitor, with alendronic acid. Oral administration (gavage) of BT-Amide prevented GC-induced bone loss in mice without causing skin lesions, or elevation of any organ toxicity markers. These findings introduce BT-Amide as the first orally effective bone-targeted Pyk2 inhibitor for preventing GC-induced bone loss while minimizing off-target effects.

Green Synthesis of Silver Nanoparticles Using Doxycycline: Evaluation of Antimicrobial Potential and Organ-specific Toxicity

Silver nanoparticles (Ag-NPs) have wide applicability as antimicrobial, biomedical, and anti-cancer drug delivery systems. This study aimed to synthesize Ag-NPs using green methodology to assess their antimicrobial properties and toxicity. Ag-NPs were prepared using doxycycline, an antibiotic serving as a reducing and capping agent. The synthesized Ag-NPs were characterized by ultraviolet-visible spectrophotometry, X-ray diffraction, scanning electron microscopy, and Fourier-transform infrared spectrometry. The antimicrobial efficacy of doxycycline-mediated Ag-NPs was assessed on Candida species in vitro and for toxicity in male albino mice in vivo. The Ag-NPs showed a surface plasmon resonance at 411 nm, indicating a 90 nm average size and spherical shape. Toxicity was tested on mouse organs (liver, kidney, spleen, heart and stomach) using three Ag-NP doses (50, 100, 200 mg/kg) over 14 days. The synthesized Ag-NPs produced large inhibition zones against two well-known fungal species, C. albicans and C. tropicalis, demonstrating their antimicrobial potential. The Ag-NPs showed varying degrees of toxicity in different mouse organs, depending on the administered dose, with more pronounced adverse effects observed at higher concentrations. Periodic administration of Ag-NPs at low-dose volumes holds promise as a safe approach to their use as antimicrobial agents. Low-dose Ag-NPs are minimally toxic and show strong antimicrobial efficacy.