The Role of Chitinase-3-like Protein-1 (YKL40) in the Therapy of Cancer and Other Chronic-Inflammation-Related Diseases.

Chitinase-3-like protein-1 (CHI3L1), also known as YKL40, is a glycoprotein that belongs to the chitinase protein family. It is involved in various biological functions, including cell proliferation and tissue remodeling, with inflammatory and immunomodulatory capabilities. Several studies have shown that CHI3L1(YKL40) is upregulated in various diseases, such as cancer, asthma, and inflammatory bowel disease, among others. Although the expression level of CHI3L1(YKL40) is associated with disease activity, severity, and prognosis, its potential as a therapeutic target is still under investigation. In this review, we summarize the biological functions, pathological roles, and potential clinical applications of specific inhibitors and targeted therapies related to CHI3L1(YKL40).

Accelerated 3D MR neurography of the brachial plexus using deep learning-constrained compressed sensing.

OBJECTIVES: To explore the use of deep learning-constrained compressed sensing (DLCS) in improving image quality and acquisition time for 3D MRI of the brachial plexus. METHODS: Fifty-four participants who underwent contrast-enhanced imaging and forty-one participants who underwent unenhanced imaging were included. Sensitivity encoding with an acceleration of 2 × 2 (SENSE4x), CS with an acceleration of 4 (CS4x), and DLCS with acceleration of 4 (DLCS4x) and 8 (DLCS8x) were used for MRI of the brachial plexus. Apparent signal-to-noise ratios (aSNRs), apparent contrast-to-noise ratios (aCNRs), and qualitative scores on a 4-point scale were evaluated and compared by ANOVA and the Friedman test. Interobserver agreement was evaluated by calculating the intraclass correlation coefficients. RESULTS: DLCS4x achieved higher aSNR and aCNR than SENSE4x, CS4x, and DLCS8x (all p < 0.05). For the root segment of the brachial plexus, no statistically significant differences in the qualitative scores were found among the four sequences. For the trunk segment, DLCS4x had higher scores than SENSE4x (p = 0.04) in the contrast-enhanced group and had higher scores than SENSE4x and DLCS8x in the unenhanced group (all p < 0.05). For the divisions, cords, and branches, DLCS4x had higher scores than SENSE4x, CS4x, and DLCS8x (all p ≤ 0.01). No overt difference was found among SENSE4x, CS4x, and DLCS8x in any segment of the brachial plexus (all p > 0.05). CONCLUSIONS: In three-dimensional MRI for the brachial plexus, DLCS4x can improve image quality compared with SENSE4x and CS4x, and DLCS8x can maintain the image quality compared to SENSE4x and CS4x. CLINICAL RELEVANCE STATEMENT: Deep learning-constrained compressed sensing can improve the image quality or accelerate acquisition of 3D MRI of the brachial plexus, which should be benefit in evaluating the brachial plexus and its branches in clinical practice. KEY POINTS: •Deep learning-constrained compressed sensing showed higher aSNR, aCNR, and qualitative scores for the brachial plexus than SENSE and CS at the same acceleration factor with similar scanning time. •Deep learning-constrained compressed sensing at acceleration factor of 8 had comparable aSNR, aCNR, and qualitative scores to SENSE4x and CS4x with approximately half the examination time. •Deep learning-constrained compressed sensing may be helpful in clinical practice for improving image quality and acquisition time in three-dimensional MRI of the brachial plexus.

3D hippocampal segmentation based on spatial and frequency domain features adaptive fusion and inter⁃class boundary region enhancement / 解剖学报

Objective Hippocampal atrophy is a clinically important marker for the diagnosis of many psychiatric disorders such as Alzheimer’s disease‚ so accurate segmentation of the hippocampus is an important scientific issue. With the development of deep learning‚ a large number of advanced automatic segmentation method have been proposed. However‚ 3D hippocampal segmentation is still challenging due to the effects of various noises in MRI and unclear boundaries between various classes of the hippocampus. Therefore‚ the aim of this paper is to propose new method to segment the hippocampal head‚ body‚ and tail more accurately. Methods To overcome these challenges‚ this paper proposed two strategies. One was the spatial and frequency domain features adaptive fusion strategy‚ which reduced the influence of noise on feature extraction by automatically selecting the appropriate frequency combination through fast Fourier transform and convolution. The other was an inter-class boundary region enhancement strategy‚ which allowed the network to focus on learning the boundary regions by weighting the loss function of the boundary regions between each class to achieve the goal of pinpointing the boundaries and regulating the size of the hippocampal head‚ body and tail. Results Experiments performed on a 50-case teenager brain MRI dataset show that our method achieves state-of-the-art hippocampal segmentation. Hippocampal head‚ body and tail had been improved compared to the existing method. Ablation experiments demonstrated the effectiveness of our two proposed strategies‚ and we also validated that the network had a strong generalization ability on a 260-case Task04_Hippocampus dataset. It was shown that the method proposed in this paper could be used in more hippocampal segmentation scenarios. Conclusion The method proposed in this paper can help clinicians to observe hippocampal atrophy more clearly and accomplish more accurate diagnosis and follow-up of the condition.

Palladium-Catalyzed Cascade Endo-dig Cycloisomerization and Olefination with Alkenes to Access Fused Oxatricyclic Compounds.

A novel cascade Pd(II)-catalyzed endo-dig cycloisomerization and olefination reaction of 2-benzyl-3-alkynyl chromones with activated/unactivated alkenes has been developed for the synthesis of fused oxatricyclic compounds. This concise one-pot synthetic approach was applied to the difunctionalization of unbiased alkynes based on 2-benzyl-3-(alkynyl)-4H-chromen-4-one via O-attack endo-dig cycloisomerization, followed by olefination with both activated and unactivated alkenes.

NRICM101 ameliorates SARS-CoV-2-S1-induced pulmonary injury in K18-hACE2 mice model.

The coronavirus disease 2019 (COVID-19) pandemic continues to represent a challenge for public health globally since transmission of different variants of the virus does not seem to be effectively affected by the current treatments and vaccines. During COVID-19 the outbreak in Taiwan, the patients with mild symptoms were improved after the treatment with NRICM101, a traditional Chinese medicine formula developed by our institute. Here, we investigated the effect and mechanism of action of NRICM101 on improval of COVID-19-induced pulmonary injury using S1 subunit of the SARS-CoV-2 spike protein-induced diffuse alveolar damage (DAD) of hACE2 transgenic mice. The S1 protein induced significant pulmonary injury with the hallmarks of DAD (strong exudation, interstitial and intra-alveolar edema, hyaline membranes, abnormal pneumocyte apoptosis, strong leukocyte infiltration, and cytokine production). NRICM101 effectively reduced all of these hallmarks. We then used next-generation sequencing assays to identify 193 genes that were differentially expressed in the S1+NRICM101 group. Of these, three (Ddit4, Ikbke, Tnfaip3) were significantly represented in the top 30 enriched downregulated gene ontology (GO) terms in the S1+NRICM101 group versus the S1+saline group. These terms included the innate immune response, pattern recognition receptor (PRR), and Toll-like receptor signaling pathways. We found that NRICM101 disrupted the interaction of the spike protein of various SARS-CoV-2 variants with the human ACE2 receptor. It also suppressed the expression of cytokines IL-1ß, IL-6, TNF-α, MIP-1ß, IP-10, and MIP-1α in alveolar macrophages activated by lipopolysaccharide. We conclude that NRICM101 effectively protects against SARS-CoV-2-S1-induced pulmonary injury via modulation of the innate immune response, pattern recognition receptor, and Toll-like receptor signaling pathways to ameliorate DAD.

Isolation of Anti-SARS-CoV-2 Natural Products Extracted from Mentha canadensis and the Semi-synthesis of Antiviral Derivatives.

Traditional herbal medicine offers opportunities to discover novel therapeutics against SARS-CoV-2 mutation. The dried aerial part of mint (Mentha canadensis L.) was chosen for bioactivity-guided extraction. Seven constituents were isolated and characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). Syringic acid and methyl rosmarinate were evaluated in drug combination treatment. Ten amide derivatives of methyl rosmarinate were synthesized, and the dodecyl (13) and 3-ethylphenyl (19) derivatives demonstrated significant improvement in the anti-SARS-CoV-2 plaque reduction assay, achieving IC50 of 0.77 and 2.70 µM, respectively, against Omicron BA.1 as compared to methyl rosmarinate's IC50 of 57.0 µM. Spike protein binding and 3CLpro inhibition assays were performed to explore the viral inhibition mechanism. Molecular docking of compounds 13 and 19 to 3CLpro was performed to reveal potential interaction. In summary, natural products with anti-Omicron BA.1 activity were isolated from Mentha canadensis and derivatives of methyl rosmarinate were synthesized, showing 21- to 74-fold improvement in antiviral activity against Omicron BA.1.

The Moderated Mediating Effects of Nutrition and Physical Activity Between Fatigue and Quality of Life in Childhood Cancer Survivors

Purpose@#The aim of this study was to investigate the associations between nutrition, physical activity, fatigue, and quality of life (QoL) among childhood cancer survivors. The specific purpose was to examine whether nutrition mediated and physical activity moderated the relationship between fatigue and QoL in this population. @*Methods@#A pooled sample of 120 childhood cancer survivors was recruited at pediatric oncology wards and ambulatory settings between August 2020 and May 2021. We collected data on participants’ demographic characteristics, fatigue, nutritional status, physical activity, and QoL. We then adapted Hayes Process Macro to examine the mediating and moderating effects of nutrition and physical activity on the relationship between fatigue and QoL. @*Results@#In models adjusted for age and sex, (1) the simple mediation analysis identified the mediating effect of nutrition on the relationship between fatigue and QoL; and (2) the mediation and moderation analysis identified that the direct effect of nutrition between fatigue and QoL was significant when adding (a) physical activity and (b) fatigue × physical activity. There were significantly decreasing trends in physical activity at 1 standard deviation below the mean and at the mean, but not at 1 standard deviation above the mean. @*Conclusions@#Our findings demonstrate that nutrition mediated and physical activity moderated the relationship between fatigue and QoL. This highlights an opportunity to enhance QoL among childhood cancer survivors through healthy lifestyle interventions. To ensure that future interventions address children's needs and promote the greatest impact, such interventions should include nutrition and physical activity components that involve nurses, pediatric oncology physicians, nutritionists, and physical therapists.Keyword

Changes of plasma METTL3, WTAP and FTO levels in patients with systemic lupus erythematosus and their correlation with clinical indicators / 中国医师杂志

Objective:To explore the clinical significance of N6-methyladenine (m6A) in systemic lupus erythematosus (SLE) by comparing the changes in plasma levels of m6A modification related proteins [methyltransferase 3 (METTL3), methyltransferase 14 (METTL14), Wilms tumor 1 associated protein (WTAP), AlkB homologous protein 5 (ALKBH5), and fat mass and obesity-associated protein (FTO)] and m6A between patients with systemic lupus erythematosus (SLE) and healthy controls.Methods:A total of 64 SLE patients admitted to the Seventh Affiliated Hospital of Sun Yat-Sen University from May 2020 to June 2022 and 24 healthy volunteers during the same period were selected to compare and analyze the plasma levels of METTL3, METTL14, WTAP, ALKBH5, FTO and m6A between the two groups. The correlation between METTL3, WTAP, FTO levels and clinical indicators was analyzed.Results:The plasma METTL3 level of SLE patients was significantly higher than that of control group ( P<0.05), and the plasma WTAP and FTO levels were significantly lower than those of control group (all P<0.05). In SLE patients, plasma METTL3 level was negatively correlated with hemoglobin level ( r=-0.344, P<0.05), plasma FTO level was positively correlated with plasma IgM level ( r=0.337, P<0.05), and plasma IgA level was negatively correlated with SLE patients ( r=-0.286, P<0.05). The incidence of renal involvement and positive rate of plasma anti-histone antibody were higher in SLE patients with high METTL3 level (all P<0.05). The positive rates of plasma anti-dsDNA antibody, anti-SM antibody and AuaA antibody were higher in SLE patients with low FTO level (all P<0.05). Conclusions:The plasma METTL3 level in SLE patients are significantly increased, while the plasma WTAP and FTO levels are significantly reduced, which are related to various clinical indicators and may be related to the onset of SLE.

SRT1720 as an SIRT1 activator for alleviating paraquat-induced models of Parkinson's disease.

Epidemiological studies have linked herbicides and Parkinson's disease (PD), with the strongest associations resulting from long exposure durations. Paraquat (PQ), an herbicide, induces PD-like syndromes and has widely been accepted as a PD mimetic. Currently, there is still no cure to prevent the progression of PD, and the search for effective therapeutic ways is urgent. Recently, the impairing activity of sirtuins (SIRTs), such as SIRT1, may correlate with PD etiology. However, the nonspecificity of SIRT1 agonists has made the protective mechanisms against PD unclear and hampered the therapeutic application of SIRT1. Thus, this study investigated the protective mechanism and therapeutic potential of SRT1720, a more specific agonist for SIRT1 synthesized by Sirtris, in alleviating the toxicity of PQ-induced cellular and animal models of PD. Here we show that SRT1720 alleviates PQ-induced toxicity in cell and animal models. Genetic silencing and pharmacological inhibition of SIRT1 attenuated SRT1720's protection against PQ-induced toxicity. Moreover, SRT1720 not only attenuated PQ-induced increased oxidative stress and mitochondrial free radical formations but also decreased mitochondrial membrane potential. Furthermore, SRT1720 reversed PQ-induced decreased PGC-1α levels and mitochondrial biogenesis. Although PQ and SRT1720 elevated NRF2 and antioxidative enzyme levels, only PQ decreased antioxidative enzyme activity but not SRT1720. NRF2 and PGC-1α silencing attenuated SRT1720 protection against PQ-induced toxicity. SRT1720 targeted SIRT1 and activated downstream PGC-1α and NRF2 signalings to prevent PQ-induced toxicity involving oxidative stress and mitochondrial dysfunction. Thus, SRT1720 might have therapeutic potential in preventing PD.

Targeting spike protein-induced TLR/NET axis by COVID-19 therapeutic NRICM102 ameliorates pulmonary embolism and fibrosis.

The global COVID-19 pandemic remains a critical public health threat, as existing vaccines and drugs appear insufficient to halt the rapid transmission. During an outbreak from May to August 2021 in Taiwan, patients with severe COVID-19 were administered NRICM102, which was a traditional Chinese medicine (TCM) formula developed based on its predecessor NRICM101 approved for treating mild cases. This study aimed to explore the mechanism of NRICM102 in ameliorating severe COVID-19-related embolic and fibrotic pulmonary injury. NRICM102 was found to disrupt spike protein/ACE2 interaction, 3CL protease activity, reduce activation of neutrophils, monocytes and expression of cytokines (TNF-α, IL-1ß, IL-6, IL-8), chemokines (MCP-1, MIP-1, RANTES) and proinflammatory receptor (TLR4). NRICM102 also inhibited the spread of virus and progression to embolic and fibrotic pulmonary injury through reducing prothrombotic (vWF, PAI-1, NET) and fibrotic (c-Kit, SCF) factors, and reducing alveolar type I (AT1) and type II (AT2) cell apoptosis. NRICM102 may exhibit its protective capability via regulation of TLRs, JAK/STAT, PI3K/AKT, and NET signaling pathways. The study demonstrates the ability of NRICM102 to ameliorate severe COVID-19-related embolic and fibrotic pulmonary injury in vitro and in vivo and elucidates the underlying mechanisms.

Bromelain Ameliorates Atherosclerosis by Activating the TFEB-Mediated Autophagy and Antioxidant Pathways.

Bromelain, a cysteine protease found in pineapple, has beneficial effects in the treatment of inflammatory diseases; however, its effects in cardiovascular pathophysiology are not fully understood. We investigated the effect of bromelain on atherosclerosis and its regulatory mechanisms in hyperlipidemia and atheroprone apolipoprotein E-null (apoe-/-) mice. Bromelain was orally administered to 16-week-old male apoe-/- mice for four weeks. Daily bromelain administration decreased hyperlipidemia and aortic inflammation, leading to atherosclerosis retardation in apoe-/- mice. Moreover, hepatic lipid accumulation was decreased by the promotion of cholesteryl ester hydrolysis and autophagy through the AMP-activated protein kinase (AMPK)/transcription factor EB (TFEB)-mediated upregulation of autophagy- and antioxidant-related proteins. Moreover, bromelain decreased oxidative stress by increasing the antioxidant capacity and protein expression of antioxidant proteins while downregulating the protein expression of NADPH oxidases and decreasing the production of reactive oxygen species. Therefore, AMPK/TFEB signaling may be crucial in bromelain-mediated anti-hyperlipidemia, antioxidant, and anti-inflammatory effects, effecting the amelioration of atherosclerosis.

Multifunctional Cyanine-Based Theranostic Probe for Cancer Imaging and Therapy.

Cancer is one of the leading causes of death in the world. A cancer-targeted multifunctional probe labeled with the radionuclide has been developed to provide multi-modalities for NIR fluorescence and nuclear imaging (PET, SPECT), for photothermal therapy (PTT), and targeted radionuclide therapy of cancer. In this study, synthesis, characterization, in vitro, and in vivo biological evaluation of the cyanine-based probe (DOTA-NIR790) were demonstrated. The use of cyanine dyes for the selective accumulation of cancer cells were used to achieve the characteristics of tumor markers. Therefore, all kinds of organ tumors can be targeted for diagnosis and treatment. The DOTA-NIR790 labeled with lutetium-111 could detect original or metastatic tumors by using SPECT imaging and quantify tumor accumulation. The ß-emission of 177Lu-DOTA-NIR790 can be used for targeted radionuclide therapy of tumors. The DOTA-NIR790 enabled imaging by NIR fluorescence and by nuclear imaging (SPECT) to monitor in real-time the tumor accumulation and the situation of cancer therapy, and to guide the surgery or the photothermal therapy of the tumor. The radionuclide-labeled heptamethine cyanine based probe (DOTA-NIR790) offers multifunctional modalities for imaging and therapies of cancer.

New Diterpenoids from Mesona procumbens with Antiproliferative Activities Modulate Cell Cycle Arrest and Apoptosis in Human Leukemia Cancer Cells.

Mesona procumbens is a popular material used in foods and herbal medicines in Asia for clearing heat and resolving toxins. However, phytochemical research on this plant is very rare. In this study, eleven new diterpenoids, mesonols A-K (1-11), comprising seven ent-kauranes, three ent-atisanes, and one sarcopetalane, were isolated from its methanolic extract. Structural elucidation of compounds 1-11 was performed by spectroscopic methods, especially 2D NMR, HRESIMS, and X-ray crystallographic analysis. All isolates were assessed for their antiproliferative activity, and compounds 1-4 showed potential antiproliferative activities against A549, Hep-3B, PC-3, HT29, and U937 cancer cells, with IC50 values ranging from 1.97 to 19.86 µM. The most active compounds, 1 and 2, were selected for further investigation of their effects on cell cycle progression, apoptosis, and ROS generation in U937 human leukemia cancer cells. Interestingly, it was found that compounds 1 and 2 induced antiproliferative effects in U937 cells through different mechanisms. Compound 1 caused cell cycle arrest at the G2/M phase and subsequent cell death in a dose- and time-dependent manner. However, 2-mediated antiproliferation of U937 cells triggered ROS-mediated mitochondrial-dependent apoptosis. These results provide insight into the molecular mechanism involved in the antiproliferative activities of compounds 1 and 2 in U937 cells. Altogether, the study showed that new diterpenoid compounds 1 and 2 from M. procumbens are potent and promising anticancer agents.

Depilatory creams increase the number of hair follicles, and dermal fibroblasts expressing interleukin-6, tumor necrosis factor-α, and tumor necrosis factor-ß in mouse skin.

Besides using for hair removal, depilatory agents have been considered to be used as a penetration enhancer for transepidermal drug delivery. To examine the effect in hair follicles (HFs), two commercially available depilatory creams were tested on the dorsal skin of mice to monitor the effect deep into the skin structure. Fifteen male BALB/c mice were used in this study. Depilatory creams were applied to the dorsal skin of the same animal using shaved and untouched treatments as controls to minimize individual differences. Skin samples were collected at three days, one week and two weeks (n = 5 for each) after the treatment, and subjected for hematoxylin-eosin staining, and immunohistochemical analysis for proinflammatory cytokines. The morphological examination showed an increase in the thickness of epidermal layer of the depilatory cream-treated skin at early time points and in the subcutis at two weeks. Depilatory cream promoted entry of anagen phase and increased the number of hair follicles in the subcutis at one and two weeks. Immunohistochemistry showed elevated percentages of dermal fibroblasts expressing interleukin-6, tumor necrosis factor-α, and tumor necrosis factor-ß. Shaving process increased the thickness of epidermis and dermis as depilatory creams did, but did neither induce the expression of proinflammatory cytokines in the dermal fibroblasts nor the number of HFs. The results suggested that the commercially available depilatory creams caused a transient minor inflammatory response of the skin and increased the levels of cytokines that might subsequently affect hair growth.

Perspiration promotes the effect of sulphite on the shielding response of rodent skin.

Perspiration and environmental chemicals, such as air pollutants, are two of the complicating factors of skin disease. It has not been studied how perspiration affect the skin responding to air pollutants. We applied topically artificial eccrine perspiration, sulphite or both to the mouse skin for one and two weeks to examine the influence of both factors on the shielding ability of healthy skin. Morphological examination showed apparent thickening of the epidermal layer in the skin samples with combined treatment at 1 week, and in the sections applied with sulphite and combined treatment at 2 weeks without significant difference in the extent of epidermal hyperplasia between two groups. The outcomes of immunohistochemical (IHC) analysis showed elevated percentages of dermal fibroblasts expressing interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), tumor necrosis factor ß (TNF-ß) and cyclooxygenase-2 (Cox-2). Results of two-way repeated measured analysis of variance (two-way RMANOVA) showed that both perspiration and sulphite, but not the interaction between them, were significant factors affecting the expression of proinflammatory cytokines. The evidences indicated that perspiration induced cytokines expressions in the dermal fibroblasts and promoted the effect of sulphite on the shielding response of the skin by inducing epidermis hyperplasia.

A novel 111indium-labeled dual carbonic anhydrase 9-targeted probe as a potential SPECT imaging radiotracer for detection of hypoxic colorectal cancer cells.

Tumor hypoxia is a common feature in colorectal cancer (CRC), and is associated with resistance to radiotherapy and chemotherapy. Thus, a specifically targeted probe for the detection of hypoxic CRC cells is urgently needed. Carbonic anhydrase 9 (CA9) is considered to be a specific marker for hypoxic CRC diagnosis. Here, a nuclear imaging Indium-111 (111In)-labeled dual CA9-targeted probe was synthesized and evaluated for CA9 detection in in vitro, in vivo, and in human samples. The CA9-targeted peptide (CA9tp) and CA9 inhibitor acetazolamide (AAZ) were combined to form a dual CA9-targeted probe (AAZ-CA9tp) using an automatic microwave peptide synthesizer, which then was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for radioisotope (111In) labeling (111In-DOTA-AAZ-CA9tp). The assays for cell binding, stability, and toxicity were conducted in hypoxic CRC HCT15 cells. The analyses for imaging and biodistribution were performed in an HCT15 xenograft mouse model. The binding and distribution of 111In-DOTA-AAZ-CA9tp were detected in human CRC samples using microautoradiography. AAZ-CA9tp possessed good CA9-targeting ability in hypoxic HCT15 cells. The dual CA9-targeted radiotracer showed high serum stability, high surface binding, and high affinity in vitro. After exposure of 111In-DOTA-AAZ-CA9tp to the HCT15-bearing xenograft mice, the levels of 111In-DOTA-AAZ-CA9tp were markedly and specifically increased in the hypoxic tumor tissues compared to control mice. 111In-DOTA-AAZ-CA9tp also targeted the areas of CA9 overexpression in human colorectal tumor tissue sections. The results of this study suggest that the novel 111In-DOTA-AAZ-CA9tp nuclear imaging agent may be a useful tool for the detection of hypoxic CRC cells in clinical practice.

Triterpene Acids from Mesona procumbens Exert Anti-inflammatory Effects on LPS-Stimulated Murine Macrophages by Regulating the MAPK Signaling Pathway.

Five new triterpene acids, mesonaic acids A-C (1-3), 2α,3α,19α-trihydroxy-24-nor-4(23),12-oleanadien-28-oic acid (4), and 3α,19α,22α-trihydroxy-2-oxo-12-ursen-28-oic acid (5), and 10 known triterpene acid compounds (6-15) were isolated from a methanolic extract of Mesona procumbens. Triterpenes 1-3 possess unusual hexacyclic skeletons with a 13α,27-cyclopropane ring. Regarding their anti-inflammatory activity, compounds 1-3, 6, and 7 inhibited NO production with EC50 values lower than 15 µM, which were better than that of the positive control quercetin. Compounds 1-3, 6, and 7 markedly decreased levels of the inducible iNOS and COX-2 proteins in macrophages by inhibiting the activation of NF-κB through interference with the MAPK signaling pathway. Based on these data, compounds 1-3, 6, and 7 have great potential as NO inhibitors.

A Universal Bacteriophage T4 Nanoparticle Platform to Design Multiplex SARS-CoV-2 Vaccine Candidates by CRISPR Engineering

A "universal" vaccine design platform that can rapidly generate multiplex vaccine candidates is critically needed to control future pandemics. Here, using SARS-CoV-2 pandemic virus as a model, we have developed such a platform by CRISPR engineering of bacteriophage T4. A pipeline of vaccine candidates were engineered by incorporating various viral components into appropriate compartments of phage nanoparticle structure. These include: expressible spike genes in genome, spike and envelope epitopes as surface decorations, and nucleocapsid proteins in packaged core. Phage decorated with spike trimers is found to be the most potent vaccine candidate in mouse and rabbit models. Without any adjuvant, this vaccine stimulated robust immune responses, both TH1 and TH2 IgG subclasses, blocked virus-receptor interactions, neutralized viral infection, and conferred complete protection against viral challenge. This new type of nanovaccine design framework might allow rapid deployment of effective phage-based vaccines against any emerging pathogen in the future.

Mesonosides A-H, primeverose derivatives from Mesona procumbens suppress adipogenesis by downregulating PPARγ and C/EBPα in 3T3-L1 cells.

Obesity is becoming a worldwide epidemic, especially in industrialized countries. We hereby report a methanolic extract of Mesona procumbens (known as Hsian-tsao in Taiwan) significantly inhibits lipid accumulation in 3T3-L1 adipocytes, and eight new primeverose derivatives, mesonosides A-H (1-8), were isolated from the methanolic extract of M. procumbens. Structural elucidation of 1-8 was established by spectroscopic methods, especially 2D NMR techniques (1H-1H COSY, HSQC, HMBC, and NOESY) and HRESIMS. Anti-obesity evaluation revealed that isolates 1-5, 7, and 8 showed inhibitory effects on lipid accumulation and protein levels of adipogenic transcription factor, PPARγ and C/EBPα in 3T3-L1 cells. Our study suggests that M. procumbens extract including new primeverose isolates may be potentially used as a natural source to ameliorate fat accumulation and even obesity.

Huang Lian Jie Du Tang attenuates paraquat-induced mitophagy in human SH-SY5Y cells: A traditional decoction with a novel therapeutic potential in treating Parkinson's disease.

Huang Lian Jie Du Tang (HLJDT) is a traditional Chinese medical decoction for heat-fire clearing and detoxication. Theoretically, the cause of Parkinson's disease (PD) has been attributed to the dysregulations of internal wind, phlegm, fire, and stasis. Thus, HLJDT has been used to treat PD. However, the molecular mechanism is unknown. Besides, paraquat (PQ) as an herbicide has been known to impair midbrain dopaminergic neurons, resemblance to the pathology of PD. Thus, the molecular mechanism of HLJDT in treating PD and PQ-induced in vitro PD model was investigated in this study. Primarily, the dose-response of PQ (0.1∼1 mM)-induced neurotoxicity for 24 h was performed in the human neuroblastoma SH-SY5Y cells. The LD50 of PQ is around 0.3 mM and was applied throughout the following experiments. The neutral red assay was used to estimate cell viability. Co-transfection of the mitochondrial marker and proapoptotic factor genes were applied to measure the release of mitochondrial proapoptotic factors during PQ intoxication and HLJDT protection. The fluorescent dyes were used to detect mitochondrial membrane potential and free radical formation. Western blot and dot-blot analysis and immunocytochemistry were used to estimate the level of proteins related to apoptosis and mitophagy. PINK1 gene silencing was used to determine the significance of mitophagy during PQ intoxication. In this study, HLJDT attenuated PQ-induced apoptosis in SH-SY5Y cells. HLJDT reversed PQ-induced decreased mitochondrial membrane potential and suppressed PQ-induced increased cytosolic and mitochondrial free radical formations and mitochondrial proapoptotic factor releases. Furthermore, HLJDT mitigated PQ-induced increases in full-length PINK1, phosphorylations of Parkin and ubiquitin, mitochondrial translocation of phosphorylated Parkin, and mitophagy. PINK1 gene silencing attenuated PQ-induced neurotoxicity. Therefore, HLJDT attenuated PQ-induced cell death by regulating mitophagy.