Nordihydroguaiaretic Acid from Creosote Bush (Larrea tridentata) Mitigates 12-O-Tetradecanoylphorbol-13-Acetate-Induced Inflammatory and Oxidative Stress Responses of Tumor Promotion Cascade in Mouse Skin

Nordihydroguaiaretic acid (NDGA) is a phenolic antioxidant found in the leaves and twigs of the evergreen desert shrub, Larrea tridentata (Sesse and Moc. ex DC) Coville (creosote bush). It has a long history of traditional medicinal use by the Native Americans and Mexicans. The modulatory effects of topically applied NDGA was studied on acute inflammatory and oxidative stress responses in mouse skin induced by stage I tumor promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA). Double TPA treatment adversely altered many of the marker responses of stage I skin tumor promotion cascade. Pretreatment of NDGA in TPA-treated mice mitigated cutaneous lipid peroxidation and inhibited production of hydrogen peroxide. NDGA treatment also restored reduced glutathione level and activities of antioxidant enzymes. Elevated activities of myeloperoxidase, xanthine oxidase and skin edema formation in TPA-treated mice were also lowered by NDGA indicating a restrained inflammatory response. Furthermore, results of histological study demonstrated inhibitory effect of NDGA on cellular inflammatory responses. This study provides a direct evidence of antioxidative and anti-inflammatory properties of NDGA against TPA-induced cutaneous inflammation and oxidative stress corroborating its chemopreventive potential against skin cancer

Small-for-Size Liver Transplantation Increases Pulmonary Injury in Rats: Prevention by NIM811

Pulmonary complications after liver transplantation (LT) often cause mortality. This study investigated whether small-for-size LT increases acute pulmonary injury and whether NIM811 which improves small-for-size liver graft survival attenuates LT-associated lung injury. Rat livers were reduced to 50% of original size, stored in UW-solution with and without NIM811 (5 μM) for 6 h, and implanted into recipients of the same or about twice the donor weight, resulting in half-size (HSG) and quarter-size grafts (QSG), respectively. Liver injury increased and regeneration was suppressed after QSG transplantation as expected. NIM811 blunted these alterations >75%. Pulmonary histological alterations were minimal at 5–18 h after LT. At 38 h, neutrophils and monocytes/macrophage infiltration, alveolar space exudation, alveolar septal thickening, oxidative/nitrosative protein adduct formation, and alveolar epithelial cell/capillary endothelial apoptosis became overt in the lungs of QSG recipients, but these alterations were mild in full-size and HSG recipients. Liver pretreatment with NIM811 markedly decreased pulmonary injury in QSG recipients. Hepatic TNFα and IL-1β mRNAs and pulmonary ICAM-1 expression were markedly higher after QSG transplantation, which were all decreased by NIM811. Together, dysfunctional small-for-size grafts produce toxic cytokines, leading to lung inflammation and injury. NIM811 decreased toxic cytokine formation, thus attenuating pulmonary injury after small-for-size LT

Understanding neuropsychiatric symptoms in Alzheimer’s disease: challenges and advances in diagnosis and treatment

Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) affect up to 97% of AD patients, with an estimated 80% of current AD patients experiencing these symptoms. Common AD-associated NPS include depression, anxiety, agitation, aggression, and apathy. The severity of NPS in AD is typically linked to the disease’s progression and the extent of cognitive decline. Additionally, these symptoms are responsible for a significant increase in morbidity, mortality, caregiver burden, earlier nursing home placement, and greater healthcare expenditure. Despite their high prevalence and significant impact, there is a notable lack of clinical research on NPS in AD. In this article, we explore and analyze the prevalence, symptom manifestations, challenges in diagnosis, and treatment options of NPS associated with AD. Our literature review reveals that distinguishing and accurately diagnosing the NPS associated with AD remains a challenging task in clinical settings. It is often difficult to discern whether NPS are secondary to pathophysiological changes from AD or are comorbid psychiatric conditions. Furthermore, the availability of effective pharmaceutical interventions, as well as non-pharmacotherapies for NPS in AD, remains limited. By highlighting the advance and challenges in diagnosis and treatment of AD-associated NPS, we aspire to offer new insights into the complexity of identifying and treating these symptoms within the context of AD, and contribute to a deeper understanding of the multifaceted nature of NPS in AD

Insecticide susceptibility in larval populations of the West Nile vector Culex pipiens L. (Diptera: Culicidae) in Saudi Arabia

Objective: To investigate the susceptibility to some conventional and non-conventional insecticides in laboratory and field larval populations of the West Nile vector Culex pipiens L. (Cx. pipiens), the dominant species in Jeddah Province, Saudi Arabia. Methods: The tested conventional insecticides were Actikil and Pesgard, while the non-conventional ones were Bacilod, Dudim and Baycidal. Probit analysis and photomicroscopical observations were carried out to shed light on acute toxicity in laboratory and field Cx. pipiens strains. Results: Cx. pipiens were more susceptible to Pesgard (LC50: 0.045 and 0.032 mg/L) than Actikil (0.052 and 0.038 mg/L) and Bacilod (0.129 and 0.104 mg/L), for the field and laboratory strains, respectively. Results showed that treatments with the chitin synthesis inhibitor Dudim and Baycidal evoked morphological effects similar to those induced by other insect growth regulators. According to IC50 values obtained (concentration which to inhibit the emergence of 50% of mosquito adults), the compound Dudim (0.0003 and 0.0001 mg/L) was more effective against Cx. pipiens L. mosquitoes than Baycidal (0.0004 and 0.0003 mg/L) for both the field and laboratory strains, respectively. Conclusions: Our results provide baseline data to enhance control programs and orient public health decisions on the selection of pesticides against mosquito vectors in Saudi Arabia

Green Tea Polyphenols Stimulate Mitochondrial Biogenesis and Improve Renal Function after Chronic Cyclosporin A Treatment in Rats

Our previous studies showed that an extract from Camellia sinenesis (green tea), which contains several polyphenols, attenuates nephrotoxicity caused by cyclosporine A (CsA). Since polyphenols are stimulators of mitochondrial biogenesis (MB), this study investigated whether stimulation of MB plays a role in green tea polyphenol protection against CsA renal toxicity. Rats were fed a powdered diet containing green tea polyphenolic extract (0.1%) starting 3 days prior to CsA treatment (25 mg/kg, i.g. daily for 3 weeks). CsA alone decreased renal nuclear DNA-encoded oxidative phosphorylation (OXPHOS) protein ATP synthase-β (AS-β) by 42%, mitochondrial DNA (mtDNA)-encoded OXPHOS protein NADH dehydrogenase-3 (ND3) by 87% and their associated mRNAs. Mitochondrial DNA copy number was also decreased by 78% by CsA. Immunohistochemical analysis showed decreased cytochrome c oxidase subunit IV (COX-IV), an OXPHOS protein, in tubular cells. Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, the master regulator of MB, and mitochondrial transcription factor-A (Tfam), the transcription factor that regulates mtDNA replication and transcription, were 42% and 90% lower, respectively, in the kidneys of CsA-treated than in untreated rats. These results indicate suppression of MB by chronic CsA treatment. Green tea polyphenols alone and following CsA increased AS-β, ND3, COX-IV, mtDNA copy number, PGC-1α mRNA and protein, decreased acetylated PGC-1α, and increased Tfam mRNA and protein. In association with suppressed MB, CsA increased serum creatinine, caused loss of brush border and dilatation of proximal tubules, tubular atrophy, vacuolization, apoptosis, calcification, and increased neutrophil gelatinase-associated lipocalin expression, leukocyte infiltration, and renal fibrosis. Green tea polyphenols markedly attenuated CsA-induced renal injury and improved renal function. Together, these results demonstrate that green tea polyphenols attenuate CsA-induced kidney injury, at least in part, through the stimulation of MB

NIM811 Prevents Mitochondrial Dysfunction, Attenuates Liver Injury, and Stimulates Liver Regeneration After Massive Hepatectomy

Massive hepatectomy (MHX) leads to failure of remnant livers. Excessive metabolic burden in remnant livers may cause mitochondrial dysfunction. This study investigated whether blockade of the mitochondrial permeability transition (MPT) with N-methyl-4-isoleucine cyclosporin (NIM811) improves the outcome of MHX

Suaeda maritima-based herbal coils and green nanoparticles as potential biopesticides against the dengue vector Aedes aegypti and the tobacco cutworm Spodoptera litura

The overuse of synthetic pesticides to control insect pests leads to physiological resistance and adverse environmental effects, in addition to high operational cost. Insecticides of botanical origin have been reported as useful for control of agricultural and public health insect pests. This research proposed a novel method of mangrove-mediated synthesis of insecticidal silver nanoparticles (AgNP) using Suaeda maritima, acting as a reducing and stabilizing agent. AgNP were characterized by UV–vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and X-ray diffraction (XRD) analysis. S. maritima aqueous extract and mangrove-synthesized AgNP showed larvicidal and pupicidal toxicity against the dengue vector Aedes aegypti and the tobacco cutworm Spodoptera litura. In particular, LC50 of AgNP ranged from 8.668 (larva I) to 17.975 ppm (pupa) for A. aegypti, and from 20.937 (larva I) to 46.896 ppm (pupa) for S. litura. In the field, the application of S. maritima extract and AgNP (10 × LC50) led to 100% mosquito larval reduction after 72 h. Smoke toxicity experiments conducted on A. aegypti adults showed that S. maritima leaf-, stem- and root-based coils evoked mortality rates comparable or higher if compared to permethrin-based positive control (62%, 52%, 42%, and 50.2 respectively). In ovicidal experiments, egg hatchability was reduced by 100% after treatment with 20 ppm of AgNP and 250 ppm of S. maritima extract. Furthermore, low doses of the AgNP inhibited the growth of Bacillus subtilis, Klebsiella pneumoniae and Salmonella typhi. Overall, our results highlighted the potential of S. maritima-based herbal coils and green nanoparticles as biopesticides in the fight against the dengue vector A. aegypti and the tobacco cutworm S. litura

Inhibition of transforming growth factor-β/Smad signaling improves regeneration of small-for-size rat liver grafts

Transforming growth factor-β (TGF-β) is a potent inhibitor of cell proliferation. This study investigated whether overexpression of Smad7, which blocks TGF-β–induced activation of Smad2/3, could prevent the suppression of regeneration of small-for-size liver grafts. Rats were intravenously given adenoviruses (2 × 109 pfu/rat) carrying the LacZ gene or the Smad7 gene (Ad-Smad7) 3 days prior to liver harvesting. Half-size livers were implanted into recipients of the same weight or twice the donor weight, and this resulted in half-size or quarter-size liver grafts. Cell proliferation, detected by 5-bromo-2′-deoxyuridine (BrdU) incorporation, increased to 23% in half-size grafts at 38 hours after implantation but was only 4% in quarter-size grafts. Graft weight did not increase after 38 hours in full-size and quarter-size grafts but increased 28% in half-size grafts. Ad-Smad7 restored BrdU labeling to 32%, and the graft weight increased to 43% in quarter-size grafts. Serum total bilirubin increased approximately 30-fold after the implantation of quarter-size grafts. Ad-Smad7 blunted hyperbilirubinemia by 80%. The basal hepatic TGF-β1 level was 7 ng/g of liver wet weight, and this increased to 30 ng/g at 1.5 hours after the transplantation of full-size grafts but decreased rapidly afterwards. After the transplantation of quarter-size grafts, however, TGF-β1 progressively increased to 159 ng/g in 38 hours. Nuclear phosphorylated Smad2/3 was barely detectable, and p21Cip1 expression was negligible in full-size grafts but increased markedly in quarter-size grafts. Ad-Smad7 blocked Smad2/3 activation and expression of p21Cip1. Together, these data show that TGF-β is responsible, at least in part, for the defective liver regeneration in small-for-size grafts by activating the Smad signaling pathway

Early prediction of neonatal hyperbilirubinemia

The study aim was to predict, using serum bilirubin, level measured 18 to 24 hours (SB, 18-24) after birth, the occurrence of peak serum bilirubin level >15 mg/dL (hyperbilirubinemia) or the requirement of phototherapy, any time from the second to fifth postnatal day. The study was conducted on a prospective cohort of 274 neonates born in north India. The main outcome measures were (a) hyperbilirubinemia and (b) phototherapy. Serum bilirubin level was estimated at 18-24 hours of age and then daily from second to fifth postnatal day. Exclusion criteria were Rh incompatibility, asphyxia and life threatening congenital malformations; and neonates of women with gestational diabetes or history intake of drugs affecting the fetal liver. Hyperbilirubinemia was found in 12.8%; and 19.3% neonates received phototherapy. Dichotomous SB 18-24, using a cut-off of >3.99 mg/dL, as the "prediction test" had the following sensitivity and specificity for predicting (a) hyperbilirubinemia: 67% and 67%, respectively, and (b) the treatment with phototherapy: 64% and 68%, respectively. We concluded that by using SB 18-24 as the "prediction test", approximately two-thirds of neonates were test negative and had about one in ten chances of re-admission for treatment of hyperbilirubinemia, if discharged. After further validation, our results will be of benefit to neonates delivered in developing countries