Severe Side Effects Research Articles

Controlled bioorthogonal activation of Bromodomain-containing protein 4 degrader by co-delivery of PROTAC and Pd-catalyst for tumor-specific therapy

The precise and safe treatment of bioorthogonal prodrug system is hindered by separate administration of prodrug and its activator, which often results in poor therapeutic effects and severe side effects. To address above issues, we herein construct a single bioorthogonal-activated co-delivery system for simultaneous PROTAC prodrug (proPROTAC) delivery and controlled, site-specific activation for tumor-specific treatment. In this co-delivery system (termed AuPLs), prodrug (proPROTAC) and water-soluble Pd-catalyst are first encapsulated by gold nanocubes (AuNCs), which are further coated with a layer of phase-change material (lauric acid/stearic acid, LA/SA). Below 39 °C, the solid state of LA/SA prevents the activation of Pd-mediated bioorthogonal reaction due to the solidification of Pd-catalyst and proPROTAC. Nevertheless, once over 42 °C, the phase change of LA/SA into liquid state, enabled by the photothermal effect of AuNCs, triggers the simultaneous release of proPROTAC and Pd-catalyst and initiates the in situ bioorthogonal reaction for proPROTAC activation. In the tumor-bearing mouse models, the systemic administration of AuPLs results in the accumulation in tumor region, where the photothermal effect activates and controls the tumor-specific bioorthogonal reaction to degrade BRD4 protein, leading to anti-tumor effects with minimized side effects. Overall, the co-delivery proPROTAC and Pd-catalyst and controlled activation by photothermal effects provide a precise way for biorthogonal-based anticancer prodrugs.

DNA damage response-related ncRNAs as regulators of therapy resistance in cancer.

The DNA damage repair (DDR) pathway is a complex signaling cascade that can sense DNA damage and trigger cellular responses to DNA damage to maintain genome stability and integrity. A typical hallmark of cancer is genomic instability or nonintegrity, which is closely related to the accumulation of DNA damage within cancer cells. The treatment principles of radiotherapy and chemotherapy for cancer are based on their cytotoxic effects on DNA damage, which are accompanied by severe and unnecessary side effects on normal tissues, including dysregulation of the DDR and induced therapeutic tolerance. As a driving factor for oncogenes or tumor suppressor genes, noncoding RNA (ncRNA) have been shown to play an important role in cancer cell resistance to radiotherapy and chemotherapy. Recently, it has been found that ncRNA can regulate tumor treatment tolerance by altering the DDR induced by radiotherapy or chemotherapy in cancer cells, indicating that ncRNA are potential regulatory factors targeting the DDR to reverse tumor treatment tolerance. This review provides an overview of the basic information and functions of the DDR and ncRNAs in the tolerance or sensitivity of tumors to chemotherapy and radiation therapy. We focused on the impact of ncRNA (mainly microRNA [miRNA], long noncoding RNA [lncRNA], and circular RNA [circRNA]) on cancer treatment by regulating the DDR and the underlying molecular mechanisms of their effects. These findings provide a theoretical basis and new insights for tumor-targeted therapy and the development of novel drugs targeting the DDR or ncRNAs.

Highly sensitive MXene-based voltammetric sensor for nanomolar clozapine detection

Clozapine is vital for managing schizophrenia and other psychiatric disorders. As a potent medication with risks of severe side effects, accurate detection ensures effective treatment monitoring, patient safety, and optimization of therapeutic outcomes. Herein, niobium carbide two-dimensional transition metal carbides (Nb2CTx MXene) was prepared by etching niobium aluminum carbide (Nb2AlC), which was next partially oxidized by a hydrothermal method to niobium oxide (Nb2O5)/Nb2CTx and ultrasonically bound to carboxylated multi-walled carbon nanotubes (MWCNTs-COOH). It was modified onto a glassy carbon electrode for the detection of the antipsychotic drug clozapine ingested by humans. The morphology and electrochemical properties of MXene-based nanocomposite electrode were verified by scanning electron microscopy, X-ray diffractometry, Raman, cyclic voltammetry and electrochemical impedance characterization methods. The results showed that electrode responded well to clozapine solutions, with good linearity (R2 = 0.9979 and 0.9995) of the peak currents with clozapine concentrations (0.01–1.0 μM and 1.0–10.0 μM) and that this sensor had good immunity, repeatability, reproducibility and stability. The limit of detection was 8.38 nM and the recovery was 92.5 % ~ 106.5 % in real serum and urine samples. The MXene-based sensors offer excellent analytical performance and hold promise for cost-effective generalisation to the detection of nanomolar clozapine in a variety of clinical applications.

Imaging Identifies Superior Inflammation Targeting of M1 Macrophages for Cryo-Shocked Cell Pulmonary Drug Delivery to Treat Acute Lung Injury.

In the realm of combating acute lung injury (ALI) induced by a myriad of triggers including sepsis, pneumonia, aspiration, trauma, and pancreatitis, macrophages emerge as crucial players. However, traditional treatments such as systemic administration of glucocorticoids come with the baggage of severe side effects, curtailing their utility. Enter an innovative solution: a biomimetic drug delivery system fashioned from cryo-shocked macrophages, tailored for pulmonary drug delivery. Positron emission tomography (PET) imaging has shed light on the remarkable targeting abilities of live M1 macrophages, showcasing their unparalleled efficacy in homing in on local inflammatory foci when contrasted with naive, M1, and M2 macrophages. Building upon this foundation, liquid nitrogen-treated (LNT) M1 macrophages are developed, engineered to preserve their inflammation-targeting prowess while sidestepping the release of pro-inflammatory cytokines. This breakthrough allows for the delivery of glucocorticoids directly to inflamed lung tissues, efficiently quelling inflammation and mitigating pulmonary edema while drastically reducing systemic drug exposure. Inspired by the effectiveness of live M1 macrophages, the potential of glucocorticoid-loaded LNT M1 macrophages are harnessed, utilizing them as a stealthy "Trojan horse" in the battle against pneumonia-induced ALI. This innovative approach holds promise as a safe and potent treatment avenue for acute lung injury.

Nano-Medicine for Treatment of Tuberculosis, Promising Approaches Against Antimicrobial Resistance.

Even though the number of effective anti-tuberculosis or anti-mycobacterial agents is increasing, a large number of patients experience severe side effects as a result of these drugs. This hurts the patients' well-being and quality of life. Tumor cells that survive treatment modalities can become chemotherapy resistant at the molecular level. Furthermore, negative effects on normal cells occur concurrently. Strategies that minimize the negative effects on normal cells while efficiently targeting infected cells are required. Nanotherapies, according to recent research, may be one option in this direction. The present study differs from previously published review studies as it concentrates on examining the most recently developed nanoparticles for anti-mycobacterial purposes. Such novel approaches have the potential to reduce harmful side effects and improve patients' health prognoses.Current paper provides a comprehensive analysis of recent advances in nanotherapy systems for the pulmonary delivery of anti-tuberculous drugs. In addition, to low-priced and convenient alternatives for pulmonary delivery, different types of NPs for oral and topical application were also deliberated and summarized in this review.

Unveiling the anticancer potential of Pestalotioprolide E, an unexplored macrolide: Targeting TRXR1-TRX1-ASK1-P38 signaling cascade in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is highly aggressive and metastatic in nature. Existing treatment modalities for TNBC are associated with severe side effects. Thioredoxin reductase (TRXR), the pivotal component of the thioredoxin system, remains overexpressed in various cancer cells including TNBC; promotes cell growth, proliferation, and metastasis, and inhibits apoptosis. Pestalotioprolide E is one of the potent macrolides, a class of secondary metabolites derived from an endophytic fungus Pestalotiopsis microspora with relatively unexplored biological activities. Our study revealed increased expression and activity of TRXR1 in MDA-MB-231 cells compared to the non-cancerous cells. In silico docking analysis and in vitro activity assay demonstrated that Pestalotioprolide E directly interacts with TRXR1 and inhibits its enzymatic activity. This inhibition induces apoptosis via TRX1/ASK1/P38MAPK death signaling cascade and retards metastasis through modulating VEGF, MMP-2, MMP-9, E-cadherin, N-cadherin in MDA-MB-231 cells. Taken together present study establishes TRXR1 as a molecular target for Pestalotioprolide E and its anticancer effect can be attributed to the inhibition of TRXR1 activity in MDA-MB-231.

First evidence in an oversea French department of the deadly risk of protonitazene use: about 5 post mortem cases.

Protonitazene is a synthetic benzoimidazole opioid of the nitazenes class, developed in the 1950s as an effective analgesic, but never released in the market due to severe side effects and major risk of dependence. The laboratory was involved in the determination of the cause of death for 5 subjects deceased in a French department of the Indian Ocean. The 5 victims were male, aged between 20 and 35 years. The first 2 victims were found dead in their prison cell and the 3 other victims were found dead in a squat. Therefore, we have developed and validated a specific procedure to identify and quantify the drug in post mortem specimens using LC-MS/MS. The procedure involves extraction of 0.5 mL fluid at pH 9.5 with a mixture of organic solvents in presence of 20 ng fentanyl-d5 used as internal standard. Linearity of the method was verified from 0.1 to 20 ng/mL in both whole blood and urine (r2 = 0.9983 and 0.9993, respectively). The limit of detection was estimated at 0.05 ng/mL in each matrix. Protonitazene was identified at < LOQ to 0.8 ng/mL, 0.4 to 2.9 ng/mL and 3.0 to 8.0 ng/mL in femoral blood, urine and bile, respectively. Post mortem concentrations were very low, which is consistent with reported high toxicity of protonitazene. As nitazenes represent a growing threat to public health in various parts of the world, this method seems to be a good response to the challenges posed by the identification of this class of substances.

Targeted Chemo-Phototherapy in Red Light with Novel Doxorubicin and Iron(III) Complex-Functionalized Gold Nanoconjugate (Dox-Fe@FA-AuNPs).

The anticancer efficacy of doxorubicin, an anthracycline-based and FDA-approved chemotherapeutic drug, is significantly hindered by acquired chemoresistance and severe side effects despite its potent anticancer properties. To overcome these challenges, we developed an innovative therapeutic formulation that integrates targeted chemotherapy and phototherapy within a single platform using gold nanoparticles (AuNPs). This novel nanoconjugate, designated as Dox-Fe@FA-AuNPs, is co-functionalized with folic acid, doxorubicin, and an iron(III)-phenolate/carboxylate complex, enabling cancer-specific drug activation. Here, we report the synthesis, characterization, and comprehensive physico-chemical and biological evaluations of Dox-Fe@FA-AuNPs. The nanoconjugate exhibited excellent solubility, stability, and enhanced cellular uptake in folate receptor-positive cancer cells. The nanoconjugate was potently cytotoxic against HeLa and MDA-MB-231 cancer cells (HeLa: 105.5±16.52 μg mL-1; MDA-MB-231: 112.0±12.31 μg mL-1; MDA-MB-231 (3D): 156.31±19.35 μg mL-1) while less cytotoxic to the folate(-) cancer cells (MCF-7, A549 and HepG2). The cytotoxicity was attributed to the pH-dependent release of doxorubicin, which preferentially occurs in the acidic tumor microenvironment. Additionally, under red light irradiation, the nanoconjugate generated ROS, inducing caspase-3/7-dependent apoptosis with a photo-index (PI) >50, and inhibited cancer cell migration. Our findings underscore the potential of Dox-Fe@FA-AuNPs as a highly effective and sustainable platform for targeted chemo-phototherapy.

Outcomes of I-125 Low-Dose-Rate Brachytherapy in Patients with Localized Prostate Cancer: A Comprehensive Analysis from a Specialized Tertiary Referral Center.

Low-dose-rate (LDR) brachytherapy with I-125 seeds is one of the most common primary tumor treatments for low-risk and low-intermediate-risk prostate cancer. This report aimed to present an analysis of single-institution long-term results. We analyzed the treatment outcomes of 119 patients with low- and intermediate-risk prostate cancer treated with LDR brachytherapy at our institution between 2014 and 2020. The analysis focused on biochemical recurrence rates (BRFS), overall survival (OS), cumulative local recurrence rate (CLRR), and the incidence of acute and late toxicities. Patient-reported quality of life measures were also evaluated to provide a holistic view on the treatment's impact. The median follow-up period was 46 months. CLRR was 3.3% (4/119), five-year BRFS was 87%, and the five-year OS rate was 95%. Dysuria was the most common acute urinary toxicity, reported in 26.0% of patients as grade 1 and 13.4% as grade 2. As a late side effect, 12.6% of patients experienced mild dysuria. Sexual dysfunction persisted in 6.7% of patients as grade 1, 7.5% as grade 2, and 10.0% as grade 3. LDR brachytherapy in patients with prostate cancer is an effective treatment, with favorable clinical outcomes and manageable toxicity. The low CLRR and high OS rates, as well as low incidence of severe side effects, support the continued use of LDR brachytherapy as a primary treatment modality for localized prostate cancer.

Differential functionality of fluoropyrimidine nucleosides for safe cancer therapy.

Chemotherapies are standard care for most cancer types. Pyrimidine analogs including 5-fluorouracil, cytosine arabinoside, 5-azacytidine, and gemcitabine are effective drugs that are utilized as part of a number of anticancer regimens. However, their lack of cell-specificity results in severe side effects. Therefore, there is a capacity to improve the efficacy of such therapies, while decreasing unwanted side effects. Here, we report that while 5-fluorocytosine is not chemotherapeutic in itself, incorporated into a ribonucleoside and more importantly into an RNA oligonucleotide, it induces cytotoxic effects on cancer cells in vitro . Interestingly, these effects are rescued by both uridine and thymidine. Similarly, in-vitro 2'-deoxy-5-fluorocytidine inhibits the growth of tumor cells but has the advantage of being less toxic to human primary cells compared with 5-fluorocytidine, suggesting that the deoxyribonucleoside could exhibit less side-effects in vivo . Thus, this work indicates that the potency of 5-fluorocytidine and 2'-deoxy-5-fluorocytidine should be further explored. In particular, oligonucleotides incorporating 5-fluorocytosine could be novel chemotherapeutic drugs that could be formulated in cancer-specific particles for safe and efficacious cancer treatments.

Rethinking animal attrition in preclinical research: Expressing causal mechanisms of selection bias using directed acyclic graphs.

Animal attrition in preclinical experiments can introduce bias in the estimation of causal treatment effects, as the treatment-outcome association in surviving animals may not represent the causal effect of interest. This can compromise the internal validity of the study despite randomization at the outset. Directed Acyclic Graphs (DAGs) are useful tools to transparently visualize assumptions about the causal structure underlying observed data. By illustrating relationships between relevant variables, DAGs enable the detection of even less intuitive biases, and can thereby inform strategies for their mitigation. In this study, we present an illustrative causal model for preclinical stroke research, in which animal attrition induces a specific type of selection bias (i.e., collider stratification bias) due to the interplay of animal welfare, initial disease severity and negative side effects of treatment. Even when the treatment had no causal effect, our simulations revealed substantial bias across different scenarios. We show how researchers can detect and potentially mitigate this bias in the analysis phase, even when only data from surviving animals are available, if knowledge of the underlying causal process that gave rise to the data is available. Collider stratification bias should be a concern in preclinical animal studies with severe side effects and high post-randomization attrition.

The relationship between self-reported antipsychotics side effects and depression in Saudi Arabia

BackgroundThe utilization rate of antipsychotics to treat different mental disorders is rising. However, little is known about their side effects’ impact on depression levels. Therefore, the objective of this study was to examine the association between antipsychotic side effects and depression among psychiatric patients treated with antipsychotics. MethodsThis is a prospective, single-center, interview-based, cross-sectional study that examined the association between antipsychotic side effects and depression among adult patients (e.g., ≥18 yrs.) with psychiatric illnesses (e.g., depression, schizophrenia, bipolar disorder) visiting outpatient clinics in a university-affiliated tertiary care center. Antipsychotic side effects were assessed using the Arabic version of the Glasgow Antipsychotic Side-effect Scale (GASS), while depression was assessed using the Arabic version of the 9-item Patient Health Questionnaire (PHQ-9). Univariate and multiple linear regressions were conducted to examine the association between the PHQ-9 and GASS scores. ResultsOne hundred patients met the inclusion criteria and consented to participate. Most of the patients were females (72 %) with a mean age of 38 years. Schizophrenia (37 %) and bipolar disorder (54 %) were the most common mental disorders among the recruited patients. The majority of patients were treated with atypical (e.g., second-generation) antipsychotics (88 %) for at least six months (74 %). Controlling for age, gender, annual family income, education, employment status, marital status, number of comorbidities, duration of treatment with antipsychotics, the type of antipsychotic, and psychiatric illness, higher GASS scores, which indicate more severe antipsychotic side effects, predicted higher PHQ-9 score (e.g., higher levels of depression) (β = 0.419, 95 % CI=[0.307–0.532], p-value < 0.0001). ConclusionEarly identification and management of antipsychotic side effects among psychiatric patients should enhance patient adherence and improve treatment outcomes. Future studies should verify the findings of this study using more robust study designs.

Stimuli-Responsive Covalent Organic Frameworks for Cancer Therapy.

Chemotherapy as a common anticancer therapeutic modality is often challenged by various obstacles such as poor stability, low solubility, and severe side effects of chemotherapeutic agents as well as multidrug resistance of cancerous cells. Nanoparticles in the role of carriers for chemotherapeutic drugs and platforms for combining different therapeutic approaches have effectively participated in overcoming such drawbacks. In particular, nanoparticles able to induce their therapeutic effect in response to specific stimuli like tumor microenvironment characteristics (e.g., hypoxia, acidic pH, high levels of glutathione, and overexpressed hydrogen peroxide) or extrinsic stimulus of laser light bring about more precise and selective treatments. Among them, nanostructures of covalent organic frameworks (COFs) have drawn great interest in biomedical fields during recent years. Possessing large surface area, high porosity, structural stability, and customizable architecture, these biocompatible porous crystalline polymers properly translate to promising platforms for drug delivery and induction of combination therapies. With the focus on stimuli-responsive characteristics of nanoscale COFs, this study aims to propose an overview of their potentiality in cancer treatment on the basis of chemotherapy alone or in combination with sonodynamic, chemodynamic, photodynamic, and photothermal therapies.

Investigation of potential ascorbate peroxidase inhibitors for anti-leishmaniasis therapy.

L eishmaniasis is a prevalent disease that impacts 98 countries and territories, mainly in Africa, Asia, and South America. It can cause substantial illness and death, particularly in its visceral manifestation that can be specifically targeted in the development of medications to combat leishmaniasis. This study has found natural compounds with possible inhibitory activity against APX using a reliable and accurate QSAR model. Despite the severe side effects of current treatments and the absence of an effective vaccination, these compounds show promise as a potential treatment for the disease. Nine hit compounds were found, and subsequent molecular docking was performed. Estradiol cypionate showed the lowest binding energy (- 10.5kcal/mol), thus showing the strongest binding, and also had the strongest binding affinity, with a ΔGTotal of - 26.31 ± 3.01kcal/mol, second only to the control molecule. Additionally, three hits viz. cloxacillin-sodium (- 16.57 ± 2.89kcal/mol), cinchonidine (- 16.04 ± 3.27kcal/mol), and quinine hydrochloride dihydrate (13.38 ± 1.06kcal/mol) also showed significant binding affinity. Multiple interactions between drugs and active site residues demonstrated a substantial binding affinity with the target protein. The identified compounds exhibited drug-like effects and were orally bioavailable based on their ADME-toxicology features. Overall, estradiol cypionate, cloxacillin sodium, cinchonidine, and quinine hydrochloride dihydrate all exhibited inhibitory effects on the APX enzyme of Leishmania donovani. These results suggest that further investigation is needed to explore the potential of developing novel anti-leishmaniasis drugs using these compounds.

Recent Review on Biological Barriers and Host-Material Interfaces in Precision Drug Delivery: Advancement in Biomaterial Engineering for Better Treatment Therapies.

Preclinical and clinical studies have demonstrated that precision therapy has a broad variety of treatment applications, making it an interesting research topic with exciting potential in numerous sectors. However, major obstacles, such as inefficient and unsafe delivery systems and severe side effects, have impeded the widespread use of precision medicine. The purpose of drug delivery systems (DDSs) is to regulate the time and place of drug release and action. They aid in enhancing the equilibrium between medicinal efficacy on target and hazardous side effects off target. One promising approach is biomaterial-assisted biotherapy, which takes advantage of biomaterials' special capabilities, such as high biocompatibility and bioactive characteristics. When administered via different routes, drug molecules deal with biological barriers; DDSs help them overcome these hurdles. With their adaptable features and ample packing capacity, biomaterial-based delivery systems allow for the targeted, localised, and prolonged release of medications. Additionally, they are being investigated more and more for the purpose of controlling the interface between the host tissue and implanted biomedical materials. This review discusses innovative nanoparticle designs for precision and non-personalised applications to improve precision therapies. We prioritised nanoparticle design trends that address heterogeneous delivery barriers, because we believe intelligent nanoparticle design can improve patient outcomes by enabling precision designs and improving general delivery efficacy. We additionally reviewed the most recent literature on biomaterials used in biotherapy and vaccine development, covering drug delivery, stem cell therapy, gene therapy, and other similar fields; we have also addressed the difficulties and future potential of biomaterial-assisted biotherapies.

Graphene oxide nanoribbons conjugated with 1, 2-distearoyl-sn-glycero-3 phosphoethanolamine-poly (ethylene glycol)-transferrin enhanced targeted delivery and cytotoxicity of raloxifene against breast cancer

The clinical utility of raloxifene (RLX), a selective estrogen receptor modulator (SERM), has been compromised by severe side effects and unfavorable drug properties. To address these, a transferrin (Tf) conjugated graphene oxide nanoribbon (GONR) platform was tried for RLX. The stability of GONRs in biological media was improved by surface modification with 1, 2-Distearoyl-sn-glycero-3 phosphoethanolamine-Poly (ethylene glycol) (DSPE-PEG). The Tf molecule was covalently attached to DSPE-PEG (DPT) using EDC-NHS chemistry. The surface of GONR was then modified with DSPE-PEG (DP) or DPT and loaded with RLX (GDP-RLX and GDPT-RLX). The final formulations were characterized for drug loading and stability. The anticancer activities of pure RLX, GDP-RLX, and GDPT-RLX were evaluated and compared in all the in vitro and in vivo studies. In vitro cell line studies showed that GDPT-RLX have significantly high cytotoxicity, cellular uptake, apoptosis induction, G2/M phase arrest, anti-migration properties, and apoptotic protein expression, followed by GDP-RLX and RLX. Pharmacokinetics and tumor biodistribution were also found to be excellent with GDPT-RLX. The in vivo tumor therapy and tumor evaluation outcomes were also consistent with the in vitro data. The Tf conjugated GDPT-RLX represents a promising approach for targeted and sustained delivery of RLX with enhanced therapeutic efficacy.

Predicting T cell receptor functionality against mutant epitopes

Cancer cells and pathogens can evade Tcell receptors (TCRs) via mutations in immunogenic epitopes. TCR cross-reactivity (i.e., recognition of multiple epitopes with sequence similarities) can counteract such escape but may cause severe side effects in cell-based immunotherapies through targeting self-antigens. To predict the effect of epitope point mutations on Tcell functionality, we here present the random forest-based model Predicting T Cell Epitope-Specific Activation against Mutant Versions (P-TEAM). P-TEAM was trained and tested on three datasets with TCR responses to single-amino-acid mutations of the model epitope SIINFEKL, the tumor neo-epitope VPSVWRSSL, and the human cytomegalovirus antigen NLVPMVATV, totaling 9,690 unique TCR-epitope interactions. P-TEAM was able to accurately classify Tcell reactivities and quantitatively predict Tcell functionalities for unobserved single-point mutations and unseen TCRs. Overall, P-TEAM provides an effective computational tool to study Tcell responses against mutated epitopes.

Importance of the Cysteine-Rich Domain of Snake Venom Prothrombin Activators: Insights Gained from Synthetic Neutralizing Antibodies.

Snake venoms are cocktails of biologically active molecules that have evolved to immobilize prey, but can also induce a severe pathology in humans that are bitten. While animal-derived polyclonal antivenoms are the primary treatment for snakebites, they often have limitations in efficacy and can cause severe adverse side effects. Building on recent efforts to develop improved antivenoms, notably through monoclonal antibodies, requires a comprehensive understanding of venom toxins. Among these toxins, snake venom metalloproteinases (SVMPs) play a pivotal role, particularly in viper envenomation, causing tissue damage, hemorrhage and coagulation disruption. One of the current challenges in the development of neutralizing monoclonal antibodies against SVMPs is the large size of the protein and the lack of existing knowledge of neutralizing epitopes. Here, we screened a synthetic human antibody library to isolate monoclonal antibodies against an SVMP from saw-scaled viper (genus Echis) venom. Upon characterization, several antibodies were identified that effectively blocked SVMP-mediated prothrombin activation. Cryo-electron microscopy revealed the structural basis of antibody-mediated neutralization, pinpointing the non-catalytic cysteine-rich domain of SVMPs as a crucial target. These findings emphasize the importance of understanding the molecular mechanisms of SVMPs to counter their toxic effects, thus advancing the development of more effective antivenoms.

Balanced Duality: H2O2-Based Therapy in Cancer and Its Protective Effects on Non-Malignant Tissues.

Conventional cancer therapy strategies, although centered around killing tumor cells, often lead to severe side effects on surrounding normal tissues, thus compromising the chronic quality of life in cancer survivors. Hydrogen peroxide (H2O2) is a secondary signaling molecule that has an array of functions in both tumor and normal cells, including the promotion of cell survival pathways and immune cell modulation in the tumor microenvironment. H2O2 is a reactive oxygen species (ROS) crucial in cellular homeostasis and signaling (at concentrations maintained under nM levels), with increased steady-state levels in tumors relative to their normal tissue counterparts. Increased steady-state levels of H2O2 in tumor cells, make them vulnerable to oxidative stress and ultimately, cell death. Recently, H2O2-producing therapies-namely, pharmacological ascorbate and superoxide dismutase mimetics-have emerged as compelling complementary treatment strategies in cancer. Both pharmacological ascorbate and superoxide dismutase mimetics can generate excess H2O2 to overwhelm the impaired H2O2 removal capacity of cancer cells. This review presents an overview of H2O2 metabolism in the physiological and malignant states, in addition to discussing the anti-tumor and normal tissue-sparing mechanism(s) of, and clinical evidence for, two H2O2-based therapies, pharmacological ascorbate and superoxide dismutase mimetics.

Targeting calcium dependant/cAMP/PKA/CREB pathway and GABAergic transmission by drotaverine and hesperidin for amelioration of tardive dyskinesia

Antipsychotics, commonly used for anxiety and psychosis, are linked to severe side effects like fatal ventricular arrhythmias, sudden cardiac death, and movement disorders, limiting their therapeutic use. This research aimed to explore novel mechanisms to treat psychotic anxiety while minimizing these risks. Drotaverine activates the cAMP/PKA/CREB pathway, while Hesperidin inhibits dopaminergic hyperactivity. Using a reserpine-induced orofacial dyskinesia model, which mimics tardive dyskinesia linked to oxidative stress, reserpine (1 mg/kg, s.c) was administered for three days. Rats were pre-treated with drotaverine (8 mg/kg, p.o) and hesperidin (50 mg/kg, p.o) for five days. Statistical analysis via one-way ANOVA and Dunnett’s test showed that reserpine significantly increased vacuous chewing movements (VCMs), tongue protrusions (TPs), and reduced locomotion and exploration. Pre-treatment with drotaverine and hesperidin reduced VCMs and TPs. Reserpine-treated rats had lower catalase and higher lipid peroxidation (LPO) levels, indicators of oxidative stress, which were reversed by the drugs. Additionally, drotaverine improved cognition by modulating the cAMP/PKA/CREB pathway, and Hesperidin offered neuroprotection through GABAergic transmission. Both drugs, alone or in combination, demonstrate potential as alternative therapies for psychotic anxiety with neuroprotective benefits.