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Skin melanoma is one of the most common cancer types in the United States and worldwide, and its incidence continues to grow. Primary skin melanoma can be removed surgically when feasible and if detected at an early stage. Anti-cancer drugs can be applied topically to treat skin cancer lesions and used as an adjunct to surgery to prevent the recurrence of tumor growth. We developed a topical formulation composed of Navitoclax (NAVI), a BCL-2 inhibitor that results in apoptosis, and an ionic liquid of choline octanoate (COA) to treat early-stage melanoma. NAVI is a small hydrophobic molecule that solubilizes at 20% (w/v) when dissolved in 50% COA. Although NAVI is a highly effective chemotherapeutic, it is equally thrombocytopenic. We found that COA-mediated topical delivery of NAVI enhanced its penetration into the skin and held the drug in the deeper skin layers for an extended period. Topical delivery of NAVI produced a higher cancer-cell killing efficacy than orally administrated NAVI. In vivo experiments in a mouse model of human melanoma-induced skin cancer confirmed the formulation's effectiveness via an apoptotic mechanism without any significant skin irritation or systemic absorption of NAVI. Overall, this topical approach may provide a safe and effective option for better managing skin cancer in the clinic.

Bulk Cu compounds such as Cu(OH)2 are extensively used as pesticides in agriculture. Recent investigations suggest that Cu-based nanomaterials can replace bulk materials reducing the environmental impacts of Cu. In this study, stress responses of alfalfa (Medicago sativa L.) seedlings to Cu(OH)2 nanoparticle or compounds were evaluated. Seeds were immersed in suspension/solutions of a Cu(OH)2 nanoform, bulk Cu(OH)2, CuSO4, and Cu(NO3)2 at 25 and 75 mg/L. Six days later, the germination, seedling growth, and the physiological and biochemical responses of sprouts were evaluated. All Cu treatments significantly reduced root elongation (average = 63%). The ionic compounds at 25 and 75 mg/L caused a reduction in all elements analyzed (Ca, K, Mg, P, Zn, and Mn), excepting for S, Fe and Mo. The bulk-Cu(OH)2 treatment reduced K (48%) and P (52%) at 75 mg/L, but increased Zn at 25 (18%) and 75 (21%) mg/L. The nano-Cu(OH)2 reduced K (46%) and P (48%) at 75 mg/L, and also P (37%) at 25 mg/L, compared with control. Confocal microscopy images showed that all Cu compounds, at 75 mg/L, significantly reduced nitric oxide, concurring with the reduction in root growth. Nano Cu(OH)2 at 25 mg/L upregulated the expression of the Cu/Zn superoxide dismutase gene (1.92-fold), while ionic treatments at 75 mg/L upregulated (∼10-fold) metallothionein (MT) transcripts. Results demonstrated that nano and bulk Cu(OH)2 compounds caused less physiological impairments in comparison to the ionic ones in alfalfa seedlings.

Background: In China, burnout, anxiety, depression, and suicidal thoughts among medical staff are common and have been associated with high-intensity work, patient complaints, pressure from public opinion, misunderstanding, and long training and working cycles. However, mental health status of medical personnel has not been well described at a national level. To estimate the mental health status of medical staff, focusing on identifying healthcare providers in the high-risk groups, and executing positive psychological intervention, counseling, treatment initiatives, and moreover, carry out crisis interventions in advance. Methods: This study was using data collected from both the Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) scores, representing the national sample of the medical staff in China, collected from May 2016 to July 2019. The three componentsof mental health, emotional well-being, psychological well-being, and social well-being, were used to evaluate the mental health status of the target population. The survey covered 10 basic information and 40 psychological questions. The main questionnaires were from both the Self-rating Anxiety Scale (SAS) and the Self-rating Depression Scale (SDS), as well as gender, age, marital status, education, professional title, salary, job category, and hospital levels, which were made an electronic questionnaire format by questionnaire star. We sent the message to the healthcare workers’ Wechat group. The responses from 4403 medical physicians (included medical students, refresher doctors, training physicians, and doctors), as well as nursing staff, and medical technicians, were utilized. Findings: The overall pooled prevalence of depression or depressive symptoms among medical personnel in China was 27.8%, and symptoms of anxiety were reported from 22.3% (980 out 4403) physicians. Among these medical staff, the secondary hospital ( P =0.017, P =0.049) and night shift frequency less than 5 days ( P =0.002, P =0.000) and unemotional management-related learning and training ( P =0.000, P =0.000) were significantly associated with SAS and SDS scores. In addition, the study showed that sleep quality (sleep deprivation) were related to gender ( P =0.006) and marital status ( P =0.045), while suicidal ideation were statistically associated with age ( P =0.025), marital status ( P =0.021), occupation ( P =0.028), hospital-level ( P =0.048), professional title ( P =0.037), annual income ( P =0.029), and whether there was emotional management learning ( P =0.001). Interpretation: In this Chinese national study of medical personnel, the findings indicated that the prevalence of depression and anxiety in hospitals at three levels were high. Further research is needed to better understand and identify the high-risk groups of medical staff under high-stress circumstances and to address these issues properly. Trial Registration: Chinese Clinical Trial Registry ChiCTR1800019542 Funding Statement: The National Institute on Minority Health and Health Disparities, a component of the National Institutes of Health (5G12MD007592 and 2U54MD00759226). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The West China Hospital approved this study and waiver of informed consent of the Sichuan University institutional review board.

Since cancer cells have different mitochondrial bioenergetic requirements than non-cancerous cells, therapeutic inhibition of its mitochondrial functionality continues to be an important target for anticancer drug discovery. In this study, a series of acylhydroquinones with different acyl-chain length, and their chlorinated derivatives, in the aromatic ring, synthesized by Fries rearrangement under microwave irradiation, were evaluated for their anticancer activity in two leukemia cell lines. Findings from the primary and secondary screening of the 18 acylhydroquinones, tested at 5 µM on acute promyelocytic leukemia HL-60 and acute lymphoblastic leukemia CEM cells lines, identified an acylchlorohydroquinone (12) with a highly selective anti-proliferative effect toward HL-60 cells. This compound induced S-phase arrest in the cell cycle progression of HL-60 cells with insignificant toxicity on leukemic CEM cells and non-cancerous Hs27 cells. In HL-60 leukemic cells, 12 triggered increased mitochondrial NADH oxidation, increased respiration in presence of oligomycin (state 4o), mitochondrial depolarization, and ROS production, suggesting an uncoupling of OXPHOS. This provoked a metabolic adaptation dependent on AMPK/ACC/autophagy axis, having the mitochondrial β-oxidation a pro-survival role since the combination of 12 and etomoxir, a carnitine palmitoyl-transferase (CPT) inhibitor promoted extensive HL-60 cell death. Finally, 12-induced metabolic stress sensitized to HL-60 cells to cell death by the FDA-approved anti-leukemic drug ABT-199, a BH3 mimetic. Therefore, our results suggest that acylchlorohydroquinone is a promising scaffold in anti-promyelocytic leukemia drug research.

Novel clusters of 3,5-bis(benzylidene)-4-oxo-1-piperidinyl dimers 3–5 were evaluated against human Molt4/C8 and CEM T-lymphocytes and human HeLa cervix adenocarcinoma cells as well as murine L1210 leukemia neoplasms. Several of these compounds demonstrated IC50 values in the submicromolar and low micromolar range and compounds possessing 4-fluoro, 4-chloro and 3,4,5-trimethoxy substituents in the series 3 and 4 were identified as potent molecules. A heat map revealed the very high cytotoxic potencies of representative compounds against a number of additional leukemic and lymphoma cell lines and displayed greater toxicity to these cells than nonmalignant MCF10A and Hs-27 neoplasms. These dienones are more refractory to breast and prostate cancers. The evaluation of representative compounds in series 3–5 against a panel of human cancer cell lines revealed them to be potent cytotoxins with average IC50 values ranging from 0.05 to 8.51 μM. In particular, the most potent compound 4g demonstrated over 382-fold and 590-fold greater average cytotoxic potencies in this screen than the reference drugs, melphalan and 5-fluorouracil, respectively. A mode of action investigation of two representative compounds 3f and 4f indicated that they induce apoptosis which is due, at least in part, to the activation of caspase-3 and depolarization of the mitochondrial membrane potential.

Mitochondrial dysfunction, leading to elevated levels of reactive oxygen species, is associated with the pathogenesis of neurodegenerative disorders. Rotenone, a mitochondrial stressor induces caspase-9 and caspase-3 activation leading proteolytic cleavage of substrate nuclear poly(ADP-ribose) polymerase (PARP). PARP cleavage is directly related to apoptotic cell death. In this study, we have monitored the aggregation of green-fluorescent protein (GFP)-tagged synphilin-1, as a rotenone-induced Parkinsonia-onset biomarker. We report that the innate ketone body, Na- d -β-hydroxybutyrate (NaβHB) reduces markedly the incidence of synphilin-1 aggregation. Furthermore, our data reveal that the metabolic byproduct also prevents rotenone-induced caspase-activated apoptotic cell death in dopaminergic SH-SY5Y cells. Together, these results suggest that NaβHB is neuroprotective; it attenuates effects originating from mitochondrial insult and can serve as a scaffold for the design and development of sporadic neuropathies.

The manufacture and multiple uses of zinc oxide (ZnO) nanoparticles (NPs) will represent a possible source of soil contamination. Little is known about how these NPs transport in soil and plants. In this research, the transport of Zn/ZnO NPs in sandy loam soil and the uptake by corn plants ( Zea mays ) was investigated. Results showed that ZnO NPs exhibit low mobility in a soil column at various ionic strengths. Elution curves suggest that some of the adsorbed ZnO NPs/Zn were released in the presence of chemical perturbations. The breakthrough of released Zn coincided with Fe and Al (indicator of soil colloids) suggesting that soil colloids may act as carriers of strongly adsorbed NPs. By using electron microprobe, Zn/ZnO NPs aggregates were visualized associate with soil clay minerals. The uptake (mg/kg) of Zn by one-month old corn plants varied from 69 to 409 in roots and from 100 to 350 in shoots, respectively, in soils contaminated with different concentrations of ZnO NPs (from 100 to 800 mg NPs/kg soil). Confocal microscope images showed that ZnO NPs aggregates penetrated the root epidermis and cortex through the apoplastic pathway; however, the presence of some NP aggregates in xylem vessels suggests that the aggregates passed the endodermis through the symplastic pathway.

A 96-well fluorescence-based assay has been developed for the rapid screening of potential cytotoxic and bacteriocidal compounds. The assay is based on detection of green fluorescent protein (GFP) in HeLa human carcinoma cells as well as gram negative (Escherichia coli) and gram positive bacteria (Mycobacterium avium). Addition of a toxic compound to the GFP marked cells resulted in the loss of the GFP fluorescence which was readily detected by fluorometry. Thirty-nine distinct naphthoquinone derivatives were screened and several of these compounds were found to be toxic to all cell types. Apart from differences in overall toxicity, two general types of toxic compounds were detected, those that exhibited toxicity to two or all three of the cell types and those that were primarily toxic to the HeLa cells. Our results demonstrate that the parallel screening of both eukaryotic and prokaryotic cells is not only feasible and reproducible but also cost effective.

Reverse transcriptase polymerase chain reaction (RT-PCR) was used to amplify sequences for delayed rectifier potassium (drk) channel transcripts in Xenopus laevis inner ear and brain. We used degenerate primers that spanned a region between the N-terminal cytoplasmic portion and a region located between the S2 and S3 transmembrane domains of the potassium channel protein. When inner ear total RNA or brain mRNA was used as a template for RT-PCR, a unique product of the expected size (approximately 560 bp) was observed as a single band after electrophoresis on agarose gels. The PCR product from reactions using X. laevis genomic DNA as template was similarly sized, indicating a lack of introns in this region. The RT-PCR products from inner ear and brain were isolated, cloned, and sequenced. Sequence analysis showed that the X. laevis inner ear and brain clones were identical. Sequence alignments of the cloned RT-PCR products with posted GenBank sequences established that the drk sequences from X. laevis inner ear and brain share highest identity with larval X. laevis brain, mouse, rat, and human Kv2 sequences. Positive signals were obtained from inner ear and brain mRNA in Northern dot blots hybridized with digoxigenin labeled probes from the inner ear clone. Taken together, results provide evidence for the expression of Kv2 sequences in the X. laevis inner ear and brain.