Significant Side Effects Research Articles

Immunosuppressive Therapy, Puberty and Growth Outcomes in Pediatric Kidney Transplant Recipients: A Pragmatic Review.

Kidney transplantation in children with end-stage kidney disease significantly enhances survival and quality of life but poses unique challenges related to chronic immunosuppressive therapy. In fact, despite being essential for preventing organ rejection, immunosuppressive therapy can have significant side effects specific to pediatric patients, such as adverse impacts on physiological growth, puberty, and fertility. The resulting short stature and delayed or incomplete pubertal development can profoundly affect young patients' psychological and social well-being, impacting self-esteem and overall quality of life, and may significantly hamper compliance and therapeutic adherence. Most studies on immunosuppression in pediatric kidney transplant recipients focus on general side effects and outcomes like long-term graft survival or acute complications. On the other side, there is limited evidence in the current literature on the specific issues of growth, puberty, and fertility in this patient population. In this pragmatic review, we aimed to summarize the most relevant information available on these critical aspects of post-transplant management in pediatric patients, also providing some practical indications on management strategies for minimizing these often neglected but still important complications.

Blue light-driven cell cycle arrest in thyroid cancer via Retinal-OPN3 complex

BackgroundPapillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy, with a rising incidence. Traditional treatments, such as thyroidectomy and radiotherapy, often lead to significant side effects, including impaired thyroid function. Therefore, there is an urgent need for non-invasive therapeutic approaches. This study aims to explore the potential of photobiomodulation therapy (PBMT), a non-invasive treatment using specific wavelengths of light, in the management of PTC.MethodsWe investigated the effects of blue light PBMT on PTC cells, focusing on the Retinal-OPSIN 3 (OPN3) complex’s role in mediating cellular responses. Blue light exposure was applied to PTC cells, and subsequent changes in cellular proliferation, cell cycle progression, and protein expression were analyzed. Statistical tests, including one-way ANOVA and t-tests, were used to evaluate the significance of the findings.ResultsBlue light exposure led to the dissociation of 11-cis-retinal from OPN3, resulting in the accumulation of all-trans retinal. This accumulation disrupted cellular proliferation pathways and induced G0/G1 cell cycle arrest in PTC cells. The Retinal-OPN3 complex was found to be a key mediator in these processes, demonstrating that thyroid cells can respond to specific light wavelengths and utilize their photoreceptive potential for therapeutic purposes.ConclusionsOur findings suggest that PBMT, through the modulation of the Retinal-OPN3 complex, offers a promising non-invasive approach for treating PTC. This study highlights the therapeutic potential of light signal transduction in non-ocular tissues and opens new avenues for non-invasive cancer therapies.

Exploring the pharmacological mechanism of fermented Eucommia ulmoides leaf extract in the treatment of cisplatin-induced kidney injury in mice: Integrated traditional pharmacology, metabolomics and network pharmacology

Cisplatin (CP) is a widely utilized anticancer drug, which also produces significant side effects, notably acute kidney injury (AKI). Fermented Eucommia ulmoides leaf (FEUL), a medicinal and edible Chinese herbal remedy, is known for its renoprotective properties. However, the effect and underlying mechanism of FEUL in AKI therapy have remained largely unexplored. This research aimed to elucidate the protective roles of FEUL in an AKI mouse model through biochemical assays, histopathological examinations, and investigating the underlying mechanisms based on metabolomics and network pharmacology. The findings demonstrated that pretreatment with orally administered FEUL significantly reduced blood urea nitrogen (BUN), and serum creatinine (SCr) levels, and ameliorated CP-induced kidney histopathological injuries. Moreover, FEUL attenuated CP-induced endoplasmic reticulum (ER) stress by reducing the protein expressions of PERK, IRE 1α, GRP78, ATF6, ATF4, and CHOP. The metabolomics results indicated that a total of 31 metabolites, involved in taurine and hypotaurine metabolism, lysine degradation, and steroid hormone biosynthesis, were altered after FEUL administration. Furthermore, metabolomics integrated with network pharmacology revealed that 8 targets, 4 metabolites, and 3 key pathways including steroid hormone biosynthesis, purine metabolism, and tryptophan metabolism were the main mechanisms of FEUL in treating CP-induced AKI. These findings suggested that FEUL could offer valuable insights for potential CP-induced AKI treatment strategies.

The Pivotal Role of One-Carbon Metabolism in Neoplastic Progression During the Aging Process

One-carbon (1C) metabolism is a complex network of metabolic reactions closely related to producing 1C units (as methyl groups) and utilizing them for different anabolic processes, including nucleotide synthesis, methylation, protein synthesis, and reductive metabolism. These pathways support the high proliferative rate of cancer cells. While drugs that target 1C metabolism (like methotrexate) have been used for cancer treatment, they often have significant side effects. Therefore, developing new drugs with minimal side effects is necessary for effective cancer treatment. Methionine, glycine, and serine are the main three precursors of 1C metabolism. One-carbon metabolism is vital not only for proliferative cells but also for non-proliferative cells in regulating energy homeostasis and the aging process. Understanding the potential role of 1C metabolism in aging is crucial for advancing our knowledge of neoplastic progression. This review provides a comprehensive understanding of the molecular complexities of 1C metabolism in the context of cancer and aging, paving the way for researchers to explore new avenues for developing advanced therapeutic interventions for cancer.

Effects of Ketamine 0.5 mg/kgBW administration as preemptive analgesia on analgesia duration and the need for Fentanyl following hysterectomy surgery: a randomized controlled trial

INTRODUCTION: Hysterectomy is a surgical procedure with a high number of moderate to severe postoperative pain complications. Preemptive analgesia prevents central sensitization before surgery, hampering postoperative hyperesthesia. Ketamine is one of several preemptive analgesia available. This study aims to study the effects of ketamine 0.5 mg/kgBW administration as preemptive analgesia on analgesia duration and the need for fentanyl following hysterectomy surgery. MATHERIALS AND METHODS: This study is a double-blind randomized controlled trial experiment on two groups: the treatment group (n = 20) was given ketamine 0.5 mg/kgBW and the control group (n = 20). The duration was measured starting from surgery completion up to the need for additional fentanyl 25 µg analgesia through Patient Controlled Analgesia (PCA) within 24-hour periods following surgery. Numerical data statistical analysis was done using unpaired T-test and Mann—Whitney for normally distributed data and non-normally distributed data respectively. Categorical data statistical analysis was done using the Exact Fisher test. RESULTS: The mean time recorded until additional analgesia was needed in the treatment group was 246.00 ± 33.150 minutes and in the control group was 121.50 ± 23.792 minutes. The mean total 24-hour post-surgery additional analgesia was 82.50 ± 11.75 µg and 118.75 ± 11.10 µg for the treatment group and control group respectively. There were statistically significant differences in the duration of analgesia and the need for additional analgesia between the two subject groups (p < 0.05). CONCLUSIONS: Administration of ketamine preemptive analgesia at a dose of 0.5 mg/kgBW resulted in longer analgesia duration and reduced the need for fentanyl as an additional analgesic in postoperative patients compared with no preemptive analgesia and showed no significant side effects.

The Effects of Systemic Tranexamic Acid Administration on Drainage Volume, Duration of Drain Placement, and Length of Hospital Stay in Skin- and Nipple-Sparing Mastectomies with Immediate Expander-Based Breast Reconstruction

Background: Skin- (SSM) and nipple-sparing (NSM) mastectomies are frequently performed surgeries with a considerable risk for post-operative hematoma or seroma. Tranexamic acid (TXA) is a potent antifibrinolytic drug commonly used in many surgical fields but rather novel in plastic and, specifically, breast surgery. This study investigates the influence of TXA in patients undergoing SSM or NSM with expander-based reconstruction (EbR) on post-operative outcomes. Methodology: A retrospective study was conducted on 132 patients undergoing uni- or bilateral SSM or NSM with EbR between May 2015 and March 2022. Patients receiving systemic TXA treatment for 48 h following a standardized protocol were compared to those who received no treatment. Multivariable linear regression was performed to identify influencing factors and quantify their effect on drainage volume, duration of drain placement, length of hospital stay, post-operative bleeding, and seroma formation. Results: The 132 patients underwent a total of 155 mastectomies (72 in the TXA group, 83 in the control group). TXA significantly reduced drainage volume (−22.3 mL, p = 0.011). Duration of drain placement and length of hospital stay were significantly shorter in the TXA group (p < 0.001 and p = 0.001). No significant side effects were reported. Conclusion: TXA is a safe drug if administered respecting the well-defined contraindications. Systemic TXA administration significantly reduces drainage volume in patients undergoing SSM or NSM and should encourage surgeons to reconsider using drains in post-operative protocols. Duration of drain placement and length of hospital stay were significantly reduced in the TXA group but other factors like resection weight might have a more substantial impact.

Isotretinoin-associated chronic diarrhea as a complication of systemic isotretinoin therapy

Objective: Isotretinoin is a synthetic derivative of vitamin A that is highly effective in treating acne vulgaris. Although its common side effects include skin dryness, photosensitivity, epistaxis, and depressive disorders, gastrointestinal side effects should also be considered, though they are less frequently highlighted. Case: We aim to present a 28-year-old female patient who developed chronic diarrhea and associated hypokalemic paralysis during isotretinoin treatment, prescribed for acne management. This case underlines the importance of recognizing gastrointestinal side effects, alongside the more commonly known adverse effects of isotretinoin. Conclusion: Chronic diarrhea is a rare but significant side effect of isotretinoin that may lead to serious complications such as hypokalemic paralysis. In this case, we demonstrated how isotretinoin can cause metabolic imbalances, even in relatively healthy young adults, by inducing diarrhea. While the association between isotretinoin and inflammatory bowel disease remains inconclusive, clinicians should remain vigilant regarding the gastrointestinal side effects of isotretinoin. Early recognition and discontinuation of the drug, combined with appropriate supportive treatments, are essential in preventing further complications. Dermatologists and gastroenterologists should collaborate in identifying patients at higher risk, such as those with pre-existing gastrointestinal conditions, and closely monitor for any adverse effects during isotretinoin treatment. Future studies, particularly large-scale randomized controlled trials, are needed to better understand the relationship between isotretinoin and gastrointestinal side effects.

The Therapeutic Effects of Lactic Acid Bacteria Isolated from Spotted Hyena on Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice

Background: Inflammatory bowel disease (IBD) is a chronic condition characterized by recurrent episodes and an unclear etiology. Given the limitations of current therapeutic options, which include suboptimal efficacy and significant side effects, there is a pressing need to explore novel treatments. Probiotics derived from diverse species have been identified as a promising approach for managing IBD, owing to their anti-inflammatory properties and their ability to regulate gut flora, among other beneficial effects. Methods: In this study, three strains of lactic acid bacteria (LAB) were isolated from the feces of the scavenger spotted hyena (Crocuta crocuta), a scavenging mammal. Based on their capability to survive within and adhere to the gastrointestinal tract, along with their profile of antibiotic resistance, a high-quality strain of Lactobacillus acidophilus (LA) was selected and demonstrated to be safe for mice. Subsequently, the therapeutic efficacy of LA was evaluated using a dextran sulfate sodium (DSS)-induced model of ulcerative colitis in mice. Results: The results indicated that LA restored the disease activity index and improved histopathological lesions in the model group. It also reduced inflammation and oxidative stress and significantly restored the expression of mucins and intestinal tight junction (TJ) proteins (ZO-1, Occludin). Furthermore, LA corrected the DSS-induced disruption of the intestinal flora, leading to a significant decrease in the prevalence of potentially harmful bacterial genera, such as Bacteroides, and an increase in beneficial bacterial genera, including Lactobacillus. In conclusion, Lactobacillus acidophilus LA1, isolated from spotted hyena feces, has potential as a functional supplement for alleviating symptoms of IBD and regulating intestinal flora.

A-β Related Pathogenesis of AD Progress of Its Targeted Therapy

Alzheimer’s disease is a common type of dementia in people 65 years of age and older. Tens of millions of people worldwide are living with AD, and the number continues to grow. To date, there are several hypotheses about the pathogenesis of AD, the most widely studied of which is related to the accumulation of Aβ. Currently, there are five drugs in clinical treatment, most of which are inhibitors, as well as monoclonal antibody drugs such as Aducanumab that target Aβ. These drugs can effectively reduce the accumulation of Aβ. However, these drugs have significant side effects and are generally significantly reduced by the end of AD symptoms. This review will summarize the pathogenesis of AD related to Aβ, such as APP and neuroinflammation. This article will also discuss the progress and problems of existing Aβ-based therapies. In addition, this paper will also compare Aβ and Tau proteins to explore better AD treatment methods. These are the basis for further study of the pathogenesis of AD related to Aβ and the development of drugs based on it. Future studies could focus on the direction of immunotherapy targeting Aβ, and apply these drugs to therapies targeting Tau protein.

Osteonecrosis of the jaw in patients with clear cell renal cell carcinoma treated with targeted agents: a case series and large-scale pharmacovigilance analysis

ObjectiveTo optimize the use of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) for cancer patients, we characterized and evaluated ONJ related to TKIs and ICIs by analyzing a public database and reviewing the relevant literature. TKIs and ICIs are limited to drugs that treat renal cancer recommended by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Kidney Cancer.MethodsWe described a case series of patients experiencing ONJ while on TKIs or ICIs. We also analyzed spontaneous reports submitted to the FAERS in an observational and retrospective manner between January 2004 and December 2022. Selecting ONJ’ adverse events to TKIs and ICIs. Associations between TKIs, ICIs and ONJ were assessed using reporting odds ratios (ROR), drug interaction signals based on the Ω shrinkage measure.Results29 patients with ONJ events while on TKIs and ICIs were included in our case series. 240 were related to ONJ AEs. Specifically, 32.1% ICSRs were linked to sunitinib, 16.7% to lenvatinib, 12.9% to pazopanib, 12.5% to nivolumab, 10.0% to axitinib, 5.4% to sorafenib, 5.0% to pembrolizumab, 4.2% to cabozantinib, and 1.3% to ipilimumab. More ICSRs were generally seen in male and reported in Europe. The median age was 63 years. Renal cancer and lung cancer was the most common indication for TKIs and ICIs, respectively. Excluding missing data, the prevalence of mortality was highest for sunitinib-related ONJ ICSRs (18.5%), followed by sorafenib-related ONJ ICSRs (15.4%). With the criteria of ROR, sunitinib and lenvatinib were significantly associated with ONJ AEs. With the criteria of Ω, nivolumab + cabozantinib was significantly associated with ONJ AEs.ConclusionTKIs and ICIs have been reported to have significant ONJ side effects. Patients and physicians need to recognize and monitor these potentially fatal adverse events.

Pimecrolimus Efficacy and Safety in Management of Children with Atopic Dermatitis

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. Early management of AD is crucial for preventing the development of atopic disease such as asthma, allergic rhinitis, etc. Topical glucocorticoids (TGCs) are used as first-line therapy, however, their long-term use poses the risk for patient's health. Despite the rapid clinical response at skin process aggravation, long-term use of TGCs in first-line therapy is associated with various adverse events, including: skin atrophy, hypothalamic-pituitaryadrenal axis suppression, telangiectasis, etc. All together it limits the long-term TGCs use, especially in management of pediatric patients and using such drugs in sensitive regions such as face and intertriginous areas. Due to these limitations TGCs should only be used for a short period of time. Thus, limitations in both treatment duration and number of drugs make TGCs non-optimal for long-term AD treatment. Pimecrolimus (1% cream) is a topical calcineurin inhibitor that is indicated for the treatment of mild to moderate AD. Pimecrolimus does not cause any significant side effects compared to TGCs and it is well tolerated for long-term administration.

Biogenically synthesized gold nanocarrier ameliorated antiproliferative and apoptotic efficacy of doxorubicin against lung cancer

IntroductionConventional chemotherapy treatment is commonly linked to significant side effects due to high therapeutic doses. In this regard, nanoformulations with chemotherapeutic medications hold promise in enhancing drug effectiveness through the reduction of therapeutic dosages, thereby mitigating the potential for adverse side effects. Because of numerous applications in the biomedical arena, there has been a rising interest in developing an environmentally acceptable, long-lasting, and affordable technique for the production of gold nanoparticles. In this particular context, the incorporation of plant extracts in the production of metallic nanoparticles has garnered the interest of numerous scholars. Here, we report the synthesis of gold particles by the green method using Cannabis sativa L. leaf extract and their conjugation with doxorubicin.MethodsThe gold nanoparticles were synthesized by using Cannabis sativa extract and were characterized with various biophysical techniques. Subsequently, gold nanoparticles were conjugated with doxorubicin and their efficacy was tested on A549 cells.Results and DiscussionThe biogenic synthesis of gold nanoparticles was ascertained through an absorption peak at a wavelength of 524 nm, and it was shifted to 527 nm when conjugated with doxorubicin. Nanoparticles were found to be stable exhibiting a zeta potential value of −20.1 mV, and it changed to −12.7 mV when loaded with doxorubicin. The hydrodynamic diameter of nanoparticles was determined to be 45.64 nm and it was increased to 58.95 nm when conjugated with the drug. The average size of nanoparticles analyzed by TEM was found to be approximately 17.2 nm, while it was 23.5 nm in the case of drug-nanoconjugate. Moreover, there was a significant amelioration in the antiproliferative potential of doxorubicin against lung cancer A549 cells when delivered with gold nanocarrier, which was evident by the lower IC50 and IC75 values of drug-nanoconjugates in comparison to drug alone. Furthermore, the inhibitory effect of drug-nanoconjugates and drug alone was characterized by alteration in the cell morphology, nuclear condensation, increased production of reactive oxygen species, abrogation of mitochondrial membrane potential, and enhanced caspase activities in A549 cells. In sum, our results suggested enhanced efficacy of doxorubicin-gold nanoconjugates, indicating effective delivery of doxorubicin inside the cell by gold nanoparticles.

Up-titration of Guideline Directed Medical Therapy (GDMT) and the occurrence of side effects in Heart Failure with reduced Ejection Fraction (HFrEF)

Abstract Background The ESC Guidelines recommend early, full-dose use of heart failure (HF) medications to enhance survival, but real-world application often faces delays and inconsistencies. Clinicians often fear side effects during up-titration to the recommended target dose (TD), i.e. hypotension, bradycardia, renal impairment, and hyperkalemia (HK). The dependency of side effects during dose escalation from the severity of HF remains unclear. Purpose This study aimed to evaluate the relationship between the occurrence of side effects during up-titration of HF medication and HF severity reflected by N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods 425 patients with HFrEF and a complete data set of patient characteristics, medications and laboratory values at baseline (BL), 2 months (2M), and 6 months (6M) were included from our outpatient HF unit's prospective registry. Significant side effects were defined as: systolic blood pressure (SBP) <90mmHg, heart rate (HR) <50 beats per minute (bpm), potassium (K) >5.0mmol/l or K >5,5mmol/l and estimated glomerular filtration rate (eGFR) <30ml/min/1.73m2. Patients were categorized into three risk groups based on their NT-proBNP levels, i.e. low-risk with NT-proBNP <1000pg/ml, medium-risk with NT-proBNP 1000-2000pg/ml or high-risk with NT-proBNP >2000pg/ml. The occurrence of side effects was recorded and the development compared among the HF risk groups. Results Figure 1 shows up-titration of HF medication. Mean daily dosages of betablockers (BB), mineralocorticoid receptor antagonists (MRA) and renin-angiotensin-system inhibitors (RASi) increased significantly during follow-up (BL vs 2M and BL vs 6M, p<0.001 for all). The majority of patients received ≥50% of the recommended TDs at 6M (89% for BB, 83% for MRA, 88% for RASi and 91% for total mean TDs ≥50%), and the achieved daily dosages at 6M were largely comparable across the HF risk groups at 6M, except for RASi (p=0.030). Figure 2 depicts the side effects. Side effects developed almost exclusively at short-term within 2M except for lower SBP (Figure 2A). Newly developed side effects occurring after up-titration (2B) were even more rare and predominantly occurred within the highest NT-proBNP group. The occurrence of hypotension and bradycardia was infrequent and comparable within the HF risk groups. Renal dysfunction (at 6M p=0,041) and HK occurred predominantly in higher risk patients (HK at 2M p=0,001 and at 6M p<0,001). Conclusions Up-titration of HF medications is highly feasible, particularly in low- and medium-risk patients. Despite rare side effects such as hyperkalemia and renal impairment, up-titration remains unimpeded, especially in patients with NT-proBNP levels below 2000pg/ml. These findings emphasize the safety of up-titration in HF.

Macrophages overexpressing interleukin-10 target and prevent atherosclerosis: regression of plaque formation and reduction in necrotic core

Abstract Background Atherosclerosis, a slowly progressing inflammatory disease, is characterized by the presence of monocyte-derived macrophages. Interventions targeting the inflammatory characteristics of atherosclerosis hold promising potential. Although interleukin (IL)-10 is widely acknowledged for its anti-inflammatory effects, systemic administration of IL-10 has limitations due to its short half-life and significant systemic side effects. Purpose We aimed to investigate the effectiveness of an approach designed to overexpress IL-10 in macrophages and subsequently introduce these genetically modified cells into ApoE-/- mice to promote atherosclerosis regression. Methods We engineered RAW264.7 cells to overexpress IL-10 (referred to as IL-10M) using lentivirusvectors. The ApoE-/- mice were divided into two groups based on the timing of the intervention. The early intervention group (n = 45) received intravenous tail injections from the beginning of Western diet (WD) at six weeks old. The late intervention group (n = 45) started receiving injections at 16 weeks old, 2 months after being fed the WD. Both the early and late intervention group stopped receiving injections after 5 months of being fed the WD. Results The IL-10M exhibited robust IL-10 secretion, maintained phagocytic function, improved mitochondrial membrane potentials, reduced superoxide production and showed a tendency toward the M2 phenotype when exposed to inflammatory stimuli. IL-10M can selectively target plaques in ApoE-/- mice, and oil red staining of the entire aorta unequivocally demonstrated that intervention with IL-10M elicited a substantial reduction in plaque area. H&E staining revealed that mice treated with IL-10M in the early intervention group showed a significant reduction in the ratio of plaque area to lumen area. However, the late intervention group did not exhibit statistically significant differences. Notably, mice treated with IL-10M exhibited significantly smaller necrotic cores and reduction in matrix metalloproteinase 9 within the aortic plaques in both the early and late intervention groups. Additionally, the administration of IL-10M showed no obvious side effects. Conclusion We developed an anti-inflammatory protein delivery system based on engineered macrophages that can target atherosclerotic plaques and reduce the plaque area and necrotic core. This approach has a promising safety profile and has the potential to be a therapeutic strategy for the intervention of atherosclerosis.

The Impact of Reduced Immunosuppression on Alloimmunity: A Retrospective Study of Pediatric Kidney Transplant Recipients.

Kidney transplantation is the best treatment for end-stage kidney disease but requires immunosuppressive medications, which have significant side effects. Many pediatric recipients experience these side effects, leading to dosage reductions, which potentially increase the risk of alloimmunity. We aimed to describe the alteration in immunosuppressive medication, explore the reasons for the reductions, and assess the potential impact on alloimmunity. Data from 49 pediatric kidney transplant recipients receiving an allograft from 2009 to 2020 were retrospectively studied. The recipients were screened for HLA antibodies after the transplantation. The median age of recipients was 11 years (IQR 8), with a median follow-up of 5 years (IQR 5). Eighty percent of the transplantations were corticosteroid-free. During follow-up, 11% developed de novo donor-specific antibodies (dnDSA), and 60% had detectable HLA antibodies. The 1-year rejection rate was 4%. Immunosuppressive medication was altered substantially in most recipients, resulting in 72% being on mono- or dual therapy with a reduced mycophenolate mofetil (MMF) dosage by the end of the first posttransplant year. The median MMF dose was nearly half of the intended. Tacrolimus levels were maintained close to the target of 5 ng/mL. No association was found between reduced immunosuppression and dnDSA or rejections. Reductions were primarily due to MMF-related side effects: leukopenia in 77%, gastrointestinal issues in 34%, and infections with Epstein-Barr virus, cytomegalovirus, and BK polyomavirus in 49%. Reduced MMF with a sufficient trough tacrolimus level in a population of mainly corticosteroid-free pediatric kidney transplant recipients did not lead to unacceptable alloimmunity.

Design, Synthesis, and Evaluation of Doxifluridine Derivatives as Nitroreductase-Responsive Anticancer Prodrugs

Antimetabolite antitumor drugs interfere with nucleic acid and DNA synthesis, causing cancer cell death. However, they also affect rapidly dividing normal cells and cause serious side effects. Doxifluridine (5′-deoxy-5-fluorouridine [5′-DFUR]), a 5-fluorouracil (5-FU) prodrug converted to 5-FU by thymidine phosphorylase (TP), exerts antitumor effects. Since TP is distributed in tumor and normal tissues, 5′-DFUR features side effects. Here we designed a series of novel 5′-DFUR derivatives based on high nitroreductase (NTR) levels in the hypoxic microenvironment of tumor tissues by introducing nitro-containing moieties into the 5′-DFUR structure. These derivatives exert their antitumor effects by producing 5-FU under the dual action of TP and NTR in the tumor microenvironment. The derivatives were synthesized and their stability, release, and cytotoxicity evaluated in vitro and antitumor activity evaluated in vivo. Compound 2c, featuring nitrofuran fragments, was stable in phosphate-buffered saline and plasma at different pH values and reduced rapidly in the presence of NTR. The in vitro cytotoxicity evaluation indicated that compound 2c showed excellent selectivity in the MCF-7 and HT29 cell lines. Moreover, it exhibited antitumor effects comparable to those of 5′-DFUR in vivo without significant toxic side effects. These results suggest that compound 2c is a promising antitumor prodrug.

Exercise as a therapeutic approach to alleviate diabetic kidney disease: mechanisms, clinical evidence and potential exercise prescriptions

Diabetic kidney disease (DKD) is a global and severe complication that imposes a significant burden on individual health, families, and society. Currently, the main treatment approaches for DKD include medication, blood glucose control, protein-restricted diet, and blood pressure management, all of which have certain limitations. Exercise, as a non-pharmacological intervention, has attracted increasing attention. This review introduces the mechanisms and clinical evidence of exercise on DKD, and proposes potential exercise prescriptions. Exercise can improve blood glucose stability related to DKD and the renin-angiotensin-aldosterone system (RAAS), reduce renal oxidative stress and inflammation, enhance the crosstalk between muscle and kidneys, and improve endothelial cell function. These mechanisms contribute to the comprehensive improvement of DKD. Compared to traditional treatment methods, exercise has several advantages, including safety, effectiveness, and no significant side effects. It can be used as an adjunct therapy to medication, blood glucose control, protein-restricted diet, and blood pressure management. Despite the evident benefits of exercise in DKD management, there is still a lack of large-scale, long-term randomized controlled trials to provide more evidence and develop exercise guidelines for DKD. Healthcare professionals should actively encourage exercise in DKD patients and develop personalized exercise plans based on individual circumstances.

Recent Developments in Luteolin-Loaded Nanoformulations for Enhanced Anti-Carcinogenic Activities: Insights from In Vitro and In Vivo Studies

With approximately 18 million people affected by cancer in 2020 globally, scientists are exploring innovative approaches to develop effective treatments for various types of cancer. Traditional chemotherapy drugs, although effective against cancer cells, often lead to significant side effects on healthy tissues, such as hair loss, anemia, and nausea. To discover safer alternatives, researchers are investigating natural bioactive compounds found abundantly in plants. Luteolin, a flavonoid found in celery and artichokes, stands out due to its diverse anti-carcinogenic properties, including inhibiting proliferation, inducing apoptosis, activating autophagy, and inhibiting angiogenesis and metastasis. However, the therapeutic potential of luteolin is hindered by challenges related to its bioavailability and solubility. This critical review explores the specific anti-carcinogenic properties of luteolin while analyzing the impact of its limited bioavailability and solubility on effectiveness. Additionally, it investigates the outcomes of encapsulating luteolin in nanoformulations, providing insights into potential strategies for enhancing its anti-carcinogenic effects. Finally, the review compares the efficacy of luteolin with and without nanoformulations. This review provides valuable insights into the potential of utilizing luteolin-loaded nanoformulations as a safer and more effective method for treating cancer, contributing to the ongoing efforts in improving cancer care and outcomes worldwide.

Why hematopoietic stem cells fail in Fanconi anemia: Mechanisms and models.

Fanconi anemia (FA) is generally classified as a DNA repair disorder, conferring a genetic predisposition to cancer and prominent bone marrow failure (BMF) in early childhood. Corroborative human and murine studies point to a fetal origin of hematopoietic stem cell (HSC) attrition under replicative stress. Along with intriguing recent insights into non-canonical roles and domain-specific functions of FA proteins, these studies have raised the possibility of a DNA repair-independent BMF etiology. However, deeper mechanistic insight is critical as current curative options of allogeneic stem cell transplantation and emerging gene therapyhave limited eligibility, carry significant side effects, and involve complex procedures restricted to resource-rich environments. To develop rational and broadly accessible therapies for FA patients, the field will need more faithful disease models that overcome the scarcity of patient samples, leverage technological advances, and adopt investigational clinical trial designs tailored for rare diseases.

Effect of fermentation on the constituents in the branches and leaves of Taxus media and non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a prominent lung cancer disease worldwide. Currently, commonly used methods, such as surgery and radiotherapy, have significant side effects. Traditional Chinese medicine (TCM) has become a research hotspot because of its safe and effective characteristics. The branches and leaves of Taxus media are abundant in antitumor active compounds, and there has been no research conducted as yet regarding its anti-lung cancer molecular mechanism. The aim of this study is to investigate the antitumor activity of two samples before and after fermentation of T. media, and to research the molecular mechanism of its inhibitory effect on NSCLC. The chemical composition of pre-fermentation T. media (TM) and post-fermentation T. media qu (TMQ) were investigated using UHPLC-Q-Qrbitrap HRMS and high-performance liquid chromatography (HPLC). The anti-lung cancer activities of TM and TMQ were compared using an A549-induced tumor mouse model. An enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (H&E) staining, immunohistochemistry, and immunofluorescence were used to determine the of TMQ mechanism of action. The results indicated that TM and TMQ contained 83 compounds, consisting primarily of flavonoids, organic acids, and taxanes. Both taxanes and flavonoids in TMQ were higher than that in TM. Both TM and TMQ effectively inhibited the tumor growth in non-small cell lung cancer (NSCLC), and the inhibition rate was greater in TMQ (57.24%) than in TM (49.62%). TMQ administration downregulated the tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and the glutathione (GSH) level and upregulated interferon-γ (IFN-γ), reactive oxygen species (ROS), and malondialdehyde (MDA) levels in the serum of tumor mice. TMQ treatment also increased the protein expression of Bax, Caspase-3, and Beclin-1 in tumor tissues. In contrast, the bcl-2, PI3K, Ki67, ULK1, and mTOR protein levels were suppressed by TMQ. Protein assay analyses reemphasized the superior antitumor effect of TMQ over TM. These cumulative findings demonstrated that the mechanism of action of TMQ was closely related to the activation of transcriptional misregulation in the cancer pathway that inhibited the cholinergic synaptic, AMPK, and PI3K/Akt/mTOR signaling pathways. This study demonstrated that fermentation increased the active ingredient contents and antitumor effects of T. media. In addition, post-fermentation TMQ was superior to TM as a herbal medicine for NSCLC treatment.