Animal Studies Research Articles

Role of steatosis in preventing post-hepatectomy liver failure after major resection: findings from an animal study

Role of steatosis in preventing post-hepatectomy liver failure after major resection: findings from an animal study

Delivery of JAL-TA9 to the brain by nasal application

We have reported on two Catalytides (Catalytic peptides), JAL-TA9 (YKGSGFRMI) and ANA-TA9 (SKGQAYRMI). Both peptides belong to the Tob/BTG family proteins and cleave Aβ42. Although Catalytides must be delivered to the brain parenchyma to treat Alzheimer's disease, the blood-brain barrier (BBB) limits their entry into the brain from the systemic circulation. Thus, we evaluated the direct route of ANA-TA9 from the nasal cavity to the brain to bypass the BBB. In this study, we present our findings on JAL-TA9. Animal studies using rats and mice clarified that the plasma clearance of JAL-TA9 was more rapid than its in vitro degradation in plasma, whole blood, and cerebrospinal fluid (CSF). After nasal administration of JAL-TA9, brain concentrations were significantly higher than after intraperitoneal administration, despite much lower plasma concentration. This observation strongly suggests direct delivery of JAL-TA9 to the brain from the nasal cavity. Similar findings were observed for its transport to CSF after nasal and intravenous administration. The concentration of JAL-TA9 in the olfactory bulb peaked at 5 ‍min, while those in the frontal brain peaked at 30 ‍min and in the occipital brain at 60 ‍min. In conclusion, JAL-TA9 was efficiently delivered to the brain by nasal application compared to other routes.

Exercise improves muscle mitochondrial dysfunction-associated lipid profile under circadian rhythm disturbance.

We investigated whether endurance exercise training (EXT) ameliorates circadian rhythm (CR)-induced risk factors by improving skeletal muscle (SKM) mitochondrial biogenesis, reducing oxidative stress, and modulating apoptotic protein expression. We distinguished between regular and shift workers using the National Health and Nutrition Examination Survey (NHANES) and investigated the health problems caused by shift work (CR disturbance) and the potential therapeutic effects of exercise. In our animal study, 36 rats underwent 12 weeks of CR disturbance, divided into regular and irregular CR groups. These groups were further split into EXT (n = 12) and sedentary (n = 12) for an additional 8 weeks. We analyzed SKM tissue to understand the molecular changes induced by CR and EXT. NHANES data were analyzed using SAS 9.4 and Prism 8 software, while experimental animal data were analyzed using Prism 8 software. The statistical procedures used in each experiment are indicated in the figure legends. Our studies showed that CR disturbance increases dyslipidemia, alters circadian clock proteins (BMAL1, PER2), raises apoptotic protein levels, and reduces mitochondrial biogenesis in SKM. EXT improved LDL-C and HDLC levels without affecting muscle BMAL1 expression. It also enhanced mitochondrial biogenesis (AMPK, PGC-1α, Tfam, NADH-UO, COX-I), antioxidant levels (Catalase, SOD1, SOD2), and apoptotic protein (p53, Bax/Bcl2) expression or activity in SKM. We demonstrated that shift work-induced CR disturbance leads to dyslipidemia, diminished mitochondrial biogenesis, and reduced antioxidant capacity in SKM. However, EXT can counteract dyslipidemia under CR disturbance, potentially lowering the risk of cardiovascular disorders.

Clinical Relevance of Oxidative Stress Biomarkers in Human Flavivirus Infections as Predictors of Disease Progression and Severity.

Several Flaviviridae constitute an emerging threat to global health because of their continuing spread and the expansion of vector habitats, largely driven by climate change and intensified global travel. Infections can result in severe neurological or visceral pathologies. The relationship between oxidative stress (OS), an imbalance between generated reactive oxygen species and the antioxidant defences of the host, and flavivirus infection has been repeatedly demonstrated in in vitro and animal studies, but measuring biomarkers of oxidative stress in vivo could prove useful in clinical patient management. We summarise the knowledge and prospects of measuring peripheral OS biomarker levels for clinical case management and correlation with disease severity in six important human flavivirus infections (dengue virus (DENV), Japanese encephalitis virus, West Nile virus (WNV), tick-borne encephalitis virus (TBEV), yellow fever virus and zika virus). We searched the Medline and Web of Science databases for 'Oxidative Stress' AND 'Biomarkers' AND 'Flavivirus', combined with 'clinical', 'in vivo/in vivo', 'patient' and/or 'disease' and included 43 peer-reviewed publications. Correlation between OS and infection has been studied in all six Flaviviridae, but most clinically relevant data are available for DENV, TBEV and WNV. Plasma protein carbonyls, glutathione peroxidase activity and nitrogen monoxide are promising prognostic markers, but their measurement would benefit from methodological harmonisation. Future studies should investigate a broad range of OS biomarkers as predictors of clinically relevant outcomes. We advocate the validation and use of universal or disease-specific oxidative stress indexes that incorporate the most significant outcomes into one, easy-to-use clinical determinant.

Association between thyroid function and osteoarthritis: a population-based cohort study

ObjectivesPrevious genetic and animal studies indicated a causal role of thyroid hormones in osteoarthritis (OA), which has not been observed in the general population. We aimed to investigate whether thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were associated with hand, hip, or knee OA. MethodsParticipants from the Rotterdam Study with baseline TSH, FT4, and joint radiographs were included. We used multivariable regression models to investigate the association of thyroid function with the prevalence, severity, incidence, and progression of OA. We conducted stratified analyses by sex, age, body mass index (BMI) and weight-bearing physical activity. ResultsAmong 9054 participants included (mean age 65 years, 56.3% women), higher FT4 concentrations were associated with an increased risk of prevalent knee OA (OR 1.04 per pmol/L, 95% CI 1.01-1.06, corresponding to an OR of 1.62 across the reference range [i.e., 14pmol/L changes] of FT4) and more severe knee OA. There was a positive association between FT4 and overall progression of knee OA (OR 1.03 per pmol/L, 1.00-1.07). No association of TSH with hand, hip, or knee OA was identified. Stratified analysis revealed an association between FT4 and prevalent knee OA among individuals with BMI≥30 kg/m2 (OR 1.05 per pmol/L, 1.01-1.08) and those with high levels of weight-bearing physical activity (OR 1.05 per pmol/L, 1.01-1.10). ConclusionsOur study indicated that higher FT4 concentrations may increase the risk of knee OA. This association might be greater in individuals with extra joint loading, such as those with obesity.

Investigation of the Efficacy of Nowarta110 in the Treatment of HPV-16 and HPV-18 Oncogenically-transformed Human Cells and Cancer-implanted Animal Models.

Cervical cancer is the third leading cause of cancer-related death in women worldwide. Nearly all cases of cervical cancer are due to infection with human papillomavirus (HPV). Nowata110 has shown breakthrough therapeutic efficacy in phase II clinical study against plantar warts, with no reported side effects. This study evaluated the effectiveness of Nowarta110 in killing cultured HPV-transformed cancer cells and its anti-cancer effects in mice, using both vaginally engrafted and subcutaneously implanted animal cancer models. Nowata110 is a novel compound composed of colloidal silver and fig extract. The cytotoxic properties of Nowarta110 were evaluated on HPV-16 and HPV-18-transformed human cancer cells (ARPE-19/HPV-16 and HeLa cells, respectively). The therapeutic potential of Nowarta110 in vivo was evaluated following the engraftment of ME-180 epidermoid carcinoma cells in the mouse vagina or their subcutaneous implantation. Nowarta110 treatment was initiated when the tumor reached an approximate volume of 65 mm3 Results: Our data showed that HPV16-expressing human retinal pigmented epithelial cells are susceptible to Nowarta110-induced cell death, with a reduction in cell viability observed at 1% Nowarta110 and a complete absence of viable cells at 5% Nowarta110. In HPV18-expressing HeLa cells, Nowarta110 caused significant and rapid cell death at a dose of 5%, whereas lower doses of 1% did not produce the same effects. The results from animal studies indicated that Nowarta110 effectively induced tumor regression in both the intravaginal and subcutaneous tumor models. Nowarta110 effectively induced cell death in HPV-16 and HPV-18-transformed human cancer cells. It also effectively induced tumor regression in mouse models with intravaginally engrafted or subcutaneously implanted cancer cells. Considering the high prevalence of HPV-induced cervical dysplasia and cancer and the lack of treatment, clinical studies to promote the implementation of Nowarta110 are warranted.

Re‐evaluation of saccharin and its sodium, potassium and calcium salts (E 954) as food additives

Abstract This opinion deals with the re‐evaluation of saccharin and its sodium, potassium and calcium salts (E 954) as food additives. Saccharin is the chemically manufactured compound 1,2‐benzisothiazol‐3(2H)‐one‐1,1‐dioxide. Along with its sodium (Na), potassium (K) and calcium (Ca) salts, they are authorised as sweeteners (E 954). E 954 can be produced by two manufacturing methods i.e. Remsen‐Fahlberg and Maumee. No analytical data on potential impurities were provided for products manufactured with the Maumee process; therefore, the Panel could only evaluate saccharins (E 954) manufactured with the Remsen‐Fahlberg process. The Panel concluded that the newly available studies do not raise a concern for genotoxicity of E 954 and the saccharins impurities associated with the Remsen‐Fahlberg manufacturing process. For the potential impurities associated with the Maumee process, a concern for genotoxicity was identified. The data set evaluated consisted of animals and human studies. The Panel considered appropriate to set a numerical acceptable daily intake (ADI) and considered the decrease in body weight in animal studies as the relevant endpoint for the derivation of a reference point. An ADI of 9 mg/kg body weight (bw) per day, expressed as free imide, was derived for saccharins (E 954). This ADI replaces the ADI of 5 mg /kg bw per day (expressed as sodium saccharin, corresponding to 3.8 mg /kg bw per day saccharin as free imide) established by the Scientific Committee on Food. The Panel considered the refined brand‐loyal exposure assessment scenario the most appropriate exposure scenario for the risk assessment. The Panel noted that the P95 exposure estimates for chronic exposure to saccharins (E 954) were below the ADI. The Panel recommended the European Commission to consider the revision of the EU specifications of saccharin and its sodium, potassium and calcium salts (E 954).

Osteoclast indices in osteogenesis imperfecta: systematic review and meta-analysis.

Osteogenesis imperfecta (OI) is a rare bone fragility disorder caused by mutations in genes encoding collagen type I or that affect its processing. Alterations in osteoclasts were suggested to contribute to OI pathophysiology. We aimed to systematically identify studies reporting measures of osteoclast formation and function in patients and mouse models of OI, to quantify OI-induced changes. The systematic search of Medline, Ovid, and Web of Science identified 798 unique studies. After screening, we included 23 studies for meta-analysis, reporting osteoclast parameters in 310 patients with OI of 9 different types and 16 studies reporting osteoclast parameters in 406 animals of 11 different OI mouse models. The standardized mean difference with 95% confidence interval (CI) was used as the effect size, and random-effects meta-analysis was performed. In patients with OI, collagen degradation markers were significantly higher compared with age-matched controls, with an effect size of 1.23 (CI: 0.36, 2.10]. Collagen degradation markers were the most elevated in the 3- to 7-year-old age group and in patients with more severe forms of OI. Bone histomorphometry demonstrated the trends for higher osteoclast numbers (1.16; CI: -0.22, 2.55) and osteoclast surface (0.43; CI: -0.63, 1.49), and significantly higher eroded surface (3.24; CI: 0.51, 5.96) compared with age-matched controls. In OI mice, meta-analysis demonstrated significant increases in collagen degradation markers (1.59; CI: 1.07, 2.11), in osteoclast numbers (0.94; CI: 0.50, 1.39), osteoclast surface (0.73; CI: 0.22, 1.23), and eroded surface (1.31; CI: 0.54, 2.08). The largest differences were in OI mice with the mutations in Col1a1 and Col1a2 genes. There were no differences between males and females in clinical or animal studies. Quantitative estimates of changes in osteoclast indices and their variance for patients with OI are important for planning future studies. We confirmed that similar changes are observed in mice with OI, supporting their translational utility.

Psychopharmacological Treatment of Depression and Anxiety and their Different Drug Delivery Targets

Abstract: General practitioners observe a high prevalence of anxiety and depression symptoms. Depressed or anxious patients frequently develop both conditions. The symptoms of both diseases may be present at the same time. There has been numerous studies on higher levels of depression, bipolar disorder II, and mixed depression. So, we ended up reviewing different drug delivery targets. Even at low dosages, antidepressants were better absorbed and were more effective when given by the nose. In this review, we focused on cutting-edge methods for intranasal antidepressant delivery vehicles. Consequently, it seems that drugs that are sufficiently effective, have fewer side effects, and are less expensive. The researchers in this metaanalysis set out to determine whether or not they have been used successfully in traditional medicine to treat depression in human or animal studies.

Synthesis and evaluation of a novel BODIPY fluorescent probe targeting integrin αvβ3 for cancer diagnosis.

A series of integrin αvβ3 targeting BODIPY-RGD conjugate were designed and synthesized. Their in vitro and in vivo fluorescence imaging behaviors were investigated. The small molecule compound was designed as an optical imaging near-infrared fluorescent dye which was combined RGD peptide with the meso-amide BODIPYs using succinic moiety as a spacer. The construction alleviated the traditional BODIPY problems including poor water solubility, aggregate caused quench (ACQ) effect, low biocompatibility, etc. In cellular research, BDP-RGD-2 showed rapid, selective uptake in 3 highly expressing integrin αvβ3 cell lines MDA-MB-231, A549, U87MG at different extent rather than an integrin αvβ3 low level expression cell MCF-7. In animal study, fluorescence imaging of U87MG model targeted by BDP-RGD-2 displayed a highest tumor uptake level and T/N ratio up to 6h after tail-intravenous injection, which demonstrated BDP-RGD-2 was a promising probe for tracing integrin αvβ3 overexpressing tumors.

Thymol as adjuvant in oncology: molecular mechanisms, therapeutic potentials, and prospects for integration in cancer management.

Cancer remains a global health challenge, prompting a search for effective treatments with fewer side effects. Thymol, a natural monoterpenoid phenol derived primarily from thyme (Thymus vulgaris) and other plants in the Lamiaceae family, is known for its diverse biological activities. It emerges as a promising candidate in cancer prevention and therapy. This study aims to consolidate current research on thymol's anticancer effects, elucidating its mechanisms and potential to enhance standard chemotherapy, and to identify gaps for future research. A comprehensive review was conducted using databases like PubMed/MedLine, Google Scholar, and ScienceDirect, focusing on studies from the last 6years. All cancer types were included, assessing thymol's impact in both cell-based (in vitro) and animal (in vivo) studies. Thymol has been shown to induce programmed cell death (apoptosis), halt the cell division cycle (cell cycle arrest), and inhibit cancer spread (metastasis) through modulation of critical signaling pathways, including phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), extracellular signal-regulated kinase (ERK), mechanistic target of rapamycin (mTOR), and Wnt/β-catenin. It also enhances the efficacy of 5-fluorouracil (5-FU) in colorectal cancer treatments. Thymol's broad-spectrum anticancer activities and non-toxic profile to normal cells underscore its potential as an adjunct in cancer therapy. Further clinical trials are essential to fully understand its therapeutic benefits and integration into existing treatment protocols.

Vagus Nerve Stimulation for Neurologic Recovery

Neural plasticity, a potential mode of managing various neurologic diseases, can be modulated via bursts of neurotransmitter release, including norepinephrine and acetylcholine. One method to do so is by electrically stimulating the vagus nerve while performing a specific task. Vagus nerve stimulation (VNS) has proven to be a viable intervention for conditions, including treatment-resistant epilepsy, depression, and, more recently, motor recovery after ischemic stroke. This article aims to explain the neurobiologic mechanism of VNS-induced cortical plasticity. It highlights both animal and human studies of VNS therapy, with a primary focus on recovery after stroke, traumatic brain injury, and spinal cord injury recovery. Furthermore, we discuss the long-term effects of VNS therapy, suggest potential solutions to overcome challenges encountered in previous studies, and elaborate on future directions in the field.

Self-healing hydrogels loaded with Spatholobi Caulis alleviate disc degeneration by promoting autophagy in nucelus pulposus

Intervertebral disc degeneration (IDD) is a common degenerative disease of the spine that has a significant impact on both society and human health. Many studies have confirmed that there is a close relationship between IDD and senescence and apoptosis, and autophagy can combat apoptosis and senescence. Spatholobi caulis (SC) is an herb that contains various active compounds that are effective in tissue repair and regeneration, but it has not been explored in field of IDD. In this study, it was first found that SC can boost autophagy and reduce the apoptosis and senescence of Nucleus pulposus cell (NPCs). However, our animal studies revealed limited absorption of SC. To improve the bioavailability and efficacy of SC, we developed a hydrogel incorporating quaternary ammonium chitosan (QCS) and oxidized starch (OST) as carriers for SC. The QCS-OST/SC hydrogel exhibits excellent compatibility with cells, can be easily injected, and can release SC durably. At the cellular level, the QCS-OST/SC hydrogel enhances cell viability, initiates autophagy and release of the extracellular matrix (ECM), and inhibits cellular senescence and apoptosis. The injection of the QCS-OST/SC hydrogel via microneedles (MNs) into discs had successfully diminished disc degeneration in rats, which shows that this hydrogel has broad potential in the treatment of IDD.

TissueGene-C induces anti-inflammatory activity and M2 macrophage polarization via activation of prostaglandin E2 signaling

Osteoarthritis (OA) is the most common form of degenerative joint disease that commonly affects the knees, hips, and hands. OA is a mechano-inflammatory disease characterized by low-grade inflammation, which results in the breakdown of the cartilage extracellular matrix (ECM) within joints, leading to pain, stiffness, and inflammation. TissueGene-C (TG-C) is a cell and gene therapy investigational drug for treating knee OA that comprises human allogenic chondrocytes and an irradiated modified cell line stably expressing transforming growth factor-β1 (TGF-β1). Previous preclinical animal studies have shown that TG-C provides pain relief via its anti-inflammatory effects and cartilage structural improvement in rat OA model. The goal of this study was to investigate the mechanism of action of TG-C, explore its anti-inflammatory activity, and identify the TG-C-derived active factor(s) responsible for its efficacy. Our results showed that TG-C induces the polarization of M2 macrophages and the upregulation of interleukin-10 (IL-10) and interleukin-1 receptor antagonist (IL-1ra) while inhibiting tumor necrosis factor alpha (TNF-α) expression. Additionally, this study identified prostaglandin E2 (PGE2) as the main bioactive factor responsible for the anti-inflammatory activity of TG-C. Our results demonstrated that PGE2 is expressed by the TG-C chondrocyte component and modulated by TGF-β1 derived from the second component of TG-C. Finally, the present study provides insight into the mechanism of action of TG-C in the treatment of OA.

Radish red protects against early diabetic kidney disease through inhibiting inflammation, pyroptosis and insulin resistance via IRAK1 signaling suppression

Diabetic kidney disease (DKD) is a major diabetic complication and a leading cause of end-stage renal disease (ESRD), but the therapeutic strategies for DKD are still limited. Red radishes (Raphanus sativus L.) are a rich source of natural anthocyanins that have antioxidant, anti-apoptotic and anti-inflammatory activities. In this study, we attempted to explore the effects of natural pigment anthocyanin called radish red (RR) extracted from red radishes on DKD progression and the underlying molecular mechanisms. RR dose-dependently reduced the tubular cell injury, indicated by the decreased expression of kidney injury molecule 1 (KIM1). Furthermore, releases of pro-inflammatory cytokines including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) stimulated by HF were strongly relieved by RR. Inflammatory response and pyroptosis were also identified to be induced by HF stimulation but were mitigated by RR in HK2 cells through repressing nuclear factor-κB (NF-κB) activation and NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. IR and lipogenesis due to HF exposure were also significantly ameliorated by RR in HK2 cells. Mechanistically, RNA-Seq analysis showed that RR strongly depressed interleukin-1 receptor-associated kinase-1 (IRAK1)-mediated NLRP3 inflammasome, pyroptosis, IR and lipid deposition. Importantly, IRAK1 overexpression almost diminished the beneficial effects of RR, while being rescued upon NLRP3 knockdown in HF-treated HK2 cells, revealing that RR performed its nephroprotective functions in diabetic kidney via inactivating the IRAK1-NLRP3 signaling pathway. Similarly, animal studies confirmed that RR supplementation efficiently ameliorated HFF-caused metabolic disturbance, IR, renal dysfunctions in mice and improved structural kidney damage. Consistently, RR consumption dramatically reduced lipid accumulation, inflammatory response and pyroptosis in kidney tissues of HFF-challenged mice mainly through repressing IRAK1-NLRP3 axis. Our results demonstrated that dietary supplementation with RR may serve as an IRAK1-NLRP3 inhibitor for preventing and treating diabetic nephropathy.

Hair follicle-targeted delivery for hair recoloration using scalp-curvature-conforming microneedles based on sodium alginate and polyvinylpyrrolidone

Hair-related disorders are currently widely concerned issues for not only the scientific society but also the public attentions. Microneedle-based drug delivery system has been regarded as a promise hair follicle-targeted drug delivery approach, largely because they can effectively penetrate the stratum corneum barrier and deliver drugs to hair follicles within dermis. However, the currently reported microneedles for treating hair-related disorders usually rely on rigid backings, showing poor adaptability to the curved scalp and thereby restricting their usability for hair follicles targeted drug delivery. To this end, this study utilized sodium alginate and polyvinylpyrrolidone to construct a scalp-curvature-conforming microneedle with flexible backing. Subsequently, Psoralea corylifolia extract (PE) was loaded into the microneedles to investigate its capability in delivering PE to the hair follicle site for treating leukotrichia associated with vitiligo. These PE-loaded microneedles can effectively conform to the curvature of skin, enhancing the efficiency of microneedle insertion and ensuring stable drug delivery. Moreover, animal studies demonstrate that the PE loaded microneedles can effectively penetrate the stratum corneum, benefiting the drug delivery to hair follicles located site, and consequently showing a successful inhibition of hair graying. In summary, the present study reports a design and preparation of scalp-curvature-conforming microneedle. This design may offer a potential solution for efficient drug delivery using microneedles to the curved skin.

Autologous neurosensory retinal flap transplantation in a porcine model of retinal hole

PurposeAutologous retinal transplantation (ART) has been successfully employed in the treatment of large and myopic macular holes that are refractory to standard surgical treatments. Patients transplanted with a peripheral neurosensory retinal graft have shown unexpected improvements in visual acuity. The study aims to investigate if neural integration of the graft takes place in a porcine model of retinal hole. DesignExperimental animal study. SubjectsLeft eyes of ten Danish landrace pigs. MethodsThe pigs underwent vitrectomy under general anesthesia, and a subretinal bleb was created within the visual streak on both sites of the optic disc. A retinal hole, approximately 1900-4000 microns in size, was cut temporally using a vitrector. A graft of matching size was harvested from the nasal retina. The graft was gently moved toward the retinal hole under perfluoro-n-octane and placed within it. Endolaser was applied around the donor site, and either air or oil tamponade was used. Optical Coherence Tomography (OCT) and Color Fundus Photography were performed two and six weeks after surgery. At the end of follow-up, the eyes were enucleated for histological examination, including immunohistochemical analysis with antibodies against retinal glial cells, photoreceptors, and inner retinal neurons. ResultsRetinal hole closure was achieved in 9 out of 10 cases, with the graft remaining in situ in 6 cases. In 4 cases, OCT scans indicated preservation of the outer retinal layers, and in 2 of these cases, there was apparent integration with the adjacent host retina. Corresponding histology confirmed the preservation of the photoreceptor layer in 3 cases, but there was no evidence of graft integration with degeneration of the inner retina in all cases. The distance between the margins of the retinal hole decreased during follow-up, suggesting that the graft contracts and drags the surrounding retina towards the center. ConclusionThe outer retina of a retinal graft can be preserved, while the inner retina degenerates. No evidence of neuroretinal integration of the graft was observed. The retinal graft serves as a scaffold, promoting the centripetal migration of the edges of the hole, resulting in closure of large retinal holes.

Term infant brain MRI after ROP treatment by anti-VEGF injection versus laser therapy.

Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents is used to treat posterior type 1 retinopathy of prematurity (ROP). Recent reports indicate that anti-VEGF therapy may be associated with white matter brain injury, according to animal studies, and neurodevelopmental impairments in children born preterm. We investigated whether type 1 ROP treated with bevacizumab is associated with structural brain injury on infant term magnetic resonance images (MRIs) in very low birth weight infants compared with those treated with laser ablation. We retrospectively reviewed the medical records of very low birth weight infants from 2006 to 2021 with type 1 ROP who had been treated with laser or anti-VEGF therapy. Intravitreal bevacizumab injection was used for type 1 ROP in zone 1 or very posterior zone 2 or when laser treatment was not feasible. A pediatric neuroradiologist reviewed brain MRIs at term equivalent age (36-46 weeks' postmenstrual age) and classified infants for severity (no/mild vs moderate/severe) of overall brain and white matter injury using the validated Kidokoro scoring system. Fifty-two infants met inclusion criteria: 35 (67%) treated with laser and 17 (33%) with bevacizumab. Moderate-to-severe brain injury scores were not statistically different between bevacizumab and laser treatment groups in either continuous or binary adjusted analyses, for either the overall score or the white matter subscore. Severity of structural injury on term brain MRI (total and white matter) did not differ between infants with type 1 ROP treated with anti-VEGF agent (bevacizumab) and those treated with laser ablation.

Limited uptake of [14C]Gardenia Blue administered orally in male and female rats and mice.

Gardenia blue (GB), a widely used plant-derived food color is prepared by reaction of genipin, the aglycone of geniposide, with protein hydrolysate. Recent animal studies investigating GB toxicity have indicated blue coloration in the gastrointestinal tract, kidneys and mesenteric lymph nodes in rodents following dietary administration. This study investigated the uptake and disposition of [14C]GB in male and female rats and mice administered 100 or 1000 mg/kg by gavage. [14C]GB was prepared by reaction of [2-14C]genipin with soy protein hydrolysate. Following administration in rats, 14C was eliminated primarily in feces (89-97% of administered dose), exhaled volatile organic chemical (VOC) and CO2 traps contained no radioactivity, and urine contained 0.2-0.4 %. In bile-duct-cannulated rats (100 mg/kg [14C]GB), 0.25% of dose was recovered in bile, and in urine, 0.5%. The percent of the dose absorbed was 0.9%, based on radioactivity in urine, bile, and carcass minus digestive tract contents. The highest level of radioactivity in tissues was in kidney; however renal recovery was low, with only 0.02-0.04% of the dose recovered in kidney. Repeated dosing indicated that 14C accumulated in kidney, and was slowly removed following cessation of dosing, consistent with previous studies, in the absence of any functional or histopathological changes.

Cariprazine and Cognition in Patients with Schizophrenia and Bipolar Disorder: A Systematic Review.

Cariprazine (CAR), an antipsychotic with partial agonism at the D3 receptor and higher affinity than dopamine, has shown significant procognitive effects in preclinical animal studies. This study systematically reviews CAR's effects on cognitive measures in patients with schizophrenia and bipolar disorder. Two independent reviewers systematically searched PubMed, Web of Science, Scopus, and the Cochrane Library up to May 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Additional studies were found by hand searching the references of included studies. Eligible studies were randomized controlled trials (RCTs) in English that assessed CAR's effects on cognition in patients with schizophrenia or bipolar disorder. Quality was assessed using the Jadad scale. Out of 139 reports, 5 studies (involving 6,104 patients with schizophrenia or bipolar disorder) were included. In schizophrenia, CAR showed better cognitive outcomes (mainly indirect measures) than placebo (PBO) in both early and late stages. It also outperformed risperidone and aripiprazole in attention-related cognitive tests. In bipolar disorder, CAR improved cognition compared to PBO (also using indirect measures). Most studies found the greatest cognitive benefits with low doses of CAR (1.5-3 mg/d). CAR improved cognitive measures compared to PBO and other D2 antagonists or partial agonists in RCTs, especially in patients with greater baseline impairment. Thus, CAR may be a promising option for enhancing cognition in schizophrenic and bipolar patients; though, more trials using specific cognitive assessment tools are needed. PROSPERO CRD42023485028.