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Amyloid beta peptide （Aβ） is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein （APP）, by β- and y-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer＇s disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer＇s disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer＇s disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer＇s disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ inhibitors or modulators of β- and y-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

Alcoholic liver disease (ALD) is a global public health challenge due to the high incidence and lack of effective therapeutics. Evidence from animal studies and ALD patients has demonstrated that iron overload is a hallmark of ALD. Ethanol exposure can promote iron absorption by downregulating the hepcidin expression, which is probably mediated by inducing oxidative stress and promoting erythropoietin (EPO) production. In addition, ethanol may enhance iron uptake in hepatocytes by upregulating the expression of transferrin receptor (TfR). Iron overload in the liver can aggravate ethanol-elicited liver damage by potentiating oxidative stress via Fenton reaction, promoting activation of Kupffer cells (KCs) and hepatic stellate cells (HSCs), and inducing a recently discovered programmed iron-dependent cell death, ferroptosis. This article reviews the current knowledge of iron metabolism, regulators of iron homeostasis, the mechanism of ethanol-induced iron overload, detrimental effects of iron overload in the liver, and potential therapeutic targets.

Curcumin is an anticancer agent, but adverse effects and low bioavailability are its main drawbacks, which drives efforts in chemical modifications of curcumin. This study evaluated antiproliferative activity and cancer cell selectivity of a curcumin derivative, curcumin nicotinate (CN), in which two niacin molecules were introduced. Our data showed that CN effectively inhibited proliferation and clonogenic growth of colon (HCT116), breast (MCF-7) and nasopharyngeal (CNE2, 5-8F and 6-10B) cancer cells with IC50 at 27.7 μM, 73.4 μM, 64.7 μM, 46.3 μM, and 31.2 μM, respectively. In cancer cells, CN induced apoptosis and cell cycle arrest at G2/M phase through a p53-mediated mechanism, where p53 was activated, p21 and pro-apoptotic proteins Bid and Bak were upregulated, and PARP was cleaved. In non-transformed human mammary epithelial cells MCF10A, CN at 50 µM had no cytotoxicity and p53 was not activated, but curcumin at 12.5 µM activated p53 and p21 and inhibited MCF10A cell growth. These data suggest that CN inhibits cell growth and proliferation through p53-mediated apoptosis and cell cycle arrest with cancer cell selectivity.

A better understanding of the mechanisms underlying PD‐L1 aberrant expression in head and neck squamous cell carcinoma (HNSCC) will help reveal predictive biomarkers and overcome resistance to treatment. In this study, the prognostic significance of PD‐L1 in forty‐five HNSCC archival samples was determined by qRT‐PCR. The biological function associated with malignant behaviour was assessed by PD‐L1 depletion, miR‐382‐3p re‐expression and regulation of circ_0000052. The interactions of PD‐L1‐miRNA and miRNA‐circRNA were determined by qRT‐PCR, Western blot analysis, dual‐luciferase reporter assays and RNA immunoprecipitation assays. PD‐L1 was highly expressed in patient samples and cancer cell lines. Higher levels of PD‐L1 were associated with patient recurrences and play a pivotal role in regulating cell proliferation, migration, invasion, clonogenicity and apoptosis. In addition to demonstrating that the IFN‐γ/JAK2/STAT1 signalling pathway can induce PD‐L1 overexpression in HNSCC, a novel mechanism by which upregulated circ_0000052 mediates PD‐L1 overexpression was also demonstrated. To do this, circ_0000052 competitively binds to miR‐382‐3p and alleviates its repression of PD‐L1. This leads to overexpression of PD‐L1, causing the aggressiveness of the cells. Our data demonstrate that circ_0000052 is oncogenic, and the circ_0000052/miR‐382‐3p/PD‐L1 axis is critical in HNSCC progression. The manipulation of circRNAs/miRNAs in combination with anti‐PD‐L1 therapy may improve personalized disease management.

Alcoholic liver disease (ALD) remains to be a worldwide health problem. It is generally accepted that oxidative stress plays critical roles in the pathogenesis of ALD, and antioxidant therapy represents a logical strategy for the prevention and treatment of ALD. Nuclear factor erythroid-derived 2-like 2 (NFE2L2 or Nrf-2) is essential for the antioxidant responsive element (ARE)-mediated induction of endogenous antioxidant enzymes such as heme oxygenase 1 (HO-1) and glutamate–cysteine ligase [GCL, the rate-limiting enzyme in the synthesis of glutathione (GSH)]. Activation of Nrf-2 pathway by genetic manipulation or pharmacological agents has been demonstrated to provide protection against ALD, which suggests that targeting Nrf-2 may be a promising approach for the prevention and treatment of ALD. Herein, we review the relevant literature about the potential hepatoprotective roles of Nrf-2 activation against ALD.

Increases in ambient temperatures have been a severe threat to crop production in many countries around the world under climate change. Chloroplasts serve as metabolic centers and play a key role in physiological adaptive processes to heat stress. In addition to expressing heat shock proteins that protect proteins from heat-induced damage, metabolic reprogramming occurs during adaptive physiological processes in chloroplasts. Heat stress leads to inhibition of plant photosynthetic activity by damaging key components functioning in a variety of metabolic processes, with concomitant reductions in biomass production and crop yield. In this review article, we will focus on events through extensive and transient metabolic reprogramming in response to heat stress, which included chlorophyll breakdown, generation of reactive oxygen species (ROS), antioxidant defense, protein turnover, and metabolic alterations with carbon assimilation. Such diverse metabolic reprogramming in chloroplasts is required for systemic acquired acclimation to heat stress in plants.

An implementable algorithm for solving nonsmooth nonconvex constrained optimization is proposed by combining bundle ideas, proximity control, and the exact penalty function. We construct two kinds of approximations to nonconvex objective function; these two approximations correspond to the convex and concave behaviors of the objective function at the current point, which captures precisely the characteristic of the objective function. The penalty coefficients are increased only a finite number of times under the conditions of Slater constraint qualification and the boundedness of the constrained set, which limit the unnecessary penalty growth. The given algorithm converges to an approximate stationary point of the exact penalty function for constrained nonconvex optimization with weakly semismooth objective function. We also provide the results of some preliminary numerical testing to show the validity and efficiency of the proposed method.

Nitric oxide (NO) has been known to preserve the level of chlorophyll (Chl) during leaf senescence. However, the mechanism by which NO regulates Chl breakdown remains unknown. Here we report that NO negatively regulates the activities of Chl catabolic enzymes during dark-induced leaf senescence. The transcriptional levels of the major enzyme genes involving Chl breakdown pathway except for RED CHL CATABOLITE REDUCTASE (RCCR) were dramatically up-regulated during dark-induced Chl degradation in the leaves of Arabidopsis NO-deficient mutant nos1/noa1 that exhibited an early-senescence phenotype. The activity of pheide a oxygenase (PAO) was higher in the dark-induced senescent leaves of nos1/noa1 compared with wild type. Furthermore, the knockout of PAO in nos1/noa1 background led to pheide a accumulation in the double mutant pao1 nos1/noa1, which retained the level of Chl during dark-induced leaf senescence. The accumulated pheide a in darkened leaves of pao1 nos1/noa1 was likely to inhibit the senescence-activated transcriptional levels of Chl catabolic genes as a feed-back inhibitory effect. We also found that NO deficiency led to decrease in the stability of photosynthetic complexes in thylakoid membranes. Importantly, the accumulation of pheide a caused by PAO mutations in combination with NO deficiency had a synergistic effect on the stability loss of thylakoid membrane complexes in the double mutant pao1 nos1/noa1 during dark-induced leaf senescence. Taken together, our findings have demonstrated that NO is a novel negative regulator of Chl catabolic pathway and positively functions in maintaining the stability of thylakoid membranes during leaf senescence.

Changes in functional properties of biological denitrification in the long-term use of methanol were explored in both pre- and post-denitrification processes. The two systems employed were sequencing batch reactor (SBR) using post-denitrification in temporal sequence, and Carrousel oxidation ditch, which was equipped with a separate pre-denitrification zone. In the SBR, stable nitrate reduction rates reached after 37 days elapsed with addition of methanol (TOC/N = 1.4–1.8) at the start of anoxic phase, and specific denitrification rate increased from 0.378 mgNOx-N·(gVSS·h)−1 to 2.406 mgNOx-N·(gVSS·h)−1. Besides, by means of nitrogen uptake rate (NUR) batch tests based on methanol-adapted sludge, the appropriate range of TOC/N ratios for complete denitrification was estimated to be 1.10–2.68. By comparison, the Carrousel oxidation ditch that was fed with methanol in the anaerobic zone took fewer days (29 days) to obtain a constant effluent nitrate. Moreover, the denitrification yield in ditch was elevated from an initial value of 0.082 mgTN/mgCOD to 0.123 mgTN/mgCOD, and the nitrogen removal efficiency reached up to a level of 68%. The focus on denitrification potential with external methanol is valuable to provide information for developing carbon dosage control, as well as predict the nitrate effluent quality of the plant.

Regarding the issue of intense mining pressure appearing in the underlying gateway below the remaining coal pillar in the close‐distance coal seam (the remaining coal pillar is perpendicular to the underlying section coal pillar), 401 working face is used as the engineering background. Field measurements, laboratory experiments, numerical simulations, and engineering verification techniques are used to study the abutment pressure's evolution properties and the plastic zone's propagation laws before and after the underlying coal seam roadway experienced the mining impact. The conclusions are as follows: ① The maximum plastic area on the two sides and the roof of the roadway underlying the gob are up to 2 and 1.5 m, whereas the maximum plastic area on the two sides and the roof of the roadway underlying the remaining coal pillar are up to 5 and 4.5 m, respectively. Moreover, the plastic area extends along the two sides, and the section coal pillar is completely broken when the working face is mined below the remaining coal pillar. ② The stress increase coefficient K in the overlap area of the remaining coal pillar and the underlying section coal pillar reaches 3.4 when the mining face penetrates the underlying remaining coal pillar and the advance abutment pressure is overlaid with the concentrated stress of the coal pillar. ③ When the underlying working face is mined to 4, −2, −8, and −14 m away from the remaining coal pillar, the damage range of the roadway 5–10 m ahead increases in turn. At the same time, the maximum plastic area of the roof passes through the plastic area of the upper coal seam floor. Therefore, the underlying and transition areas on both sides of the remaining coal pillar are divided into Area I (15 m) → Area II (the most complicated area to control under the remaining coal pillar, 20 m) → Area III (25 m) according to the width. Furthermore, the divisional differentiated combined control technology of channel steel truss anchor cable with joint double‐way locking control function of roof and coal pillar in Areas I and III, while channel steel truss anchor cable with joint double‐way locking control function of roof and side + high resistance integral door‐type support is proposed in Area II. Field engineering practice shows that the deformation of the roadway surrounding rock can be controlled within 210 mm after adopting the above divisional combined control technology. Finally, the mining operation can safely and efficiently pass through the remaining coal pillar. The research results have important reference values for surrounding rock control of mining roadways in the overlapping area of similar “+”‐type cross‐working face. Regarding the issue of intense mining pressure appearing in the underlying gateway below the remaining coal pillar in the close‐distance coal seam (the remaining coal pillar is perpendicular to the underlying section coal pillar), 4#–401 working face is used as the engineering background. The evolution characteristics of the abutment pressure and the expansion regulation of the plastic zone before and after the underlying coal seam roadway experienced the mining impact are analyzed using field measurements, laboratory tests, numerical simulations, and engineering verification methods.