代谢综合征患者胰岛素抵抗与游离脂肪酸的变化及非诺贝特的干预

目的观察代谢综合征（MS）患者胰岛素抵抗（IR）和游离脂肪酸（FFA）的变化及非诺贝特对其影响。方法入选30例MS患者，给予非诺贝特治疗12周，采用放射免疫法和酶比色法测定治疗前后空腹血清胰岛素和FFA水平及空腹血糖、血脂，计算IR指数。另选30例正常人作为对照。结果MS患者HOMA—IRI和FFA较正常人明显升高（P分别〈0．01和〈0．05）。经非诺贝特干预后，高密度脂蛋白胆固醇明显升高（P〈0．01），甘油三酯、IR指数、FFA均明显下降（P分别〈0．01，〈0．01及〈0．05）。结论非诺贝特能够明显降低MS患者血清甘油三酯水平，升高高密度脂蛋白胆固醇水平，改善IR，其机制可能与降低血清FFA浓度有关。     

心血瘀阻证大鼠血浆代谢网络模型分析

目的：探讨心血瘀阻证大鼠血浆代谢网络模型。方法：代谢通路分析采用KEGG 数据库,代谢产物分子注释、相关的酶或转运蛋白及其相关性质分析采用HMDB 数据库,代谢网络模型可视化采用metPA 网络软件。结果：9 个代谢产物参与了15 条代谢通路,其中泛酸盐和CoA 生物合成、丙酸代谢、不饱和脂肪酸生物合成通路影响值P＜0.05。结论：泛酸盐和CoA 生物合成、丙酸代谢、不饱和脂肪酸生物合成通路参与大鼠心血瘀阻证的病理过程。     

大豆异黄酮对代谢综合征大鼠主动脉内皮细胞功能影响的实验研究

目的：观察大豆异黄酮对膳食诱导代谢综合征大鼠血管内皮功能的影响。方法：采用高脂高糖高盐饲料喂养建立大鼠MS模型。测量体重、血压、空腹血糖、血清胰岛素、血脂、HOMA-IR,筛选MS成模大鼠,予大豆异黄酮高、低剂量灌胃4周,以二甲双胍作为阳性药对照,检测主动脉H染色、血清vWF和eNOSmRNA表达情况。结果：模型组大鼠主动脉组织病理改变明显,SI高剂量组和二甲双胍组主动脉病理改变有不同程度改善。SI高剂量组和二甲双胍组体重、血糖、血清胰岛素和胰岛素抵抗指数较模型组均下降（P〈0.05）;仅SI高剂量组血压下降（P〈0.05）;SI高剂量组大鼠TG、TC和LDL-C水平均显著下降（P〈0.05）;三组大鼠血清vWF水平均降低（P〈0.05）,SI高剂量优于低剂量。在eNOS mRNA表达上SI高剂量组和二甲双胍组均较模型组增高（P〈0.05）。结论：大豆异黄酮能改善MS大鼠主动脉组织结构,降低血清vWF水平,上调主动脉eNOS mRNA表达发挥主动脉内皮保护作用。     

诱导子对丹参有效成分次生代谢的诱导与调控

诱导子被认为是提高药用植物次生代谢产物最有效的方法之一,为当前研究的热点.生物和非生物诱导子对丹参有效成分次生代谢具有诱导和调控作用.作者介绍了诱导子对丹参的诱导、调控机制等方面的研究进展.     

糖尿病性心肌病的发病机理探析

目的：探讨糖尿病性心肌病（DC）的发病机制。方法：查阅研读近年的大量文献，将所获信息整理分类，得出结论。结果：糖尿病性心肌病（DC）是以持续高血糖、RAS的作用、Ca^2＋转运异常等因素共同作用，使存心肌细胞代谢障碍，导致心脏结构和功能障碍，心肌细胞凋亡，心肌间质纤雏化，引起左心室舒张收缩功能不全，心室肥厚重构，功能渐丧而致心力衰竭。结论：从以上各方面探讨了DC的发病机制，希望能为DC早期防治提供理论依据。     

三黄口服液治疗代谢综合征的疗效观察

目的:探讨三黄口服液对代谢综合征肥胖人群的临床疗效。方法:以20名健康志愿者为参照,将100名代谢综合征患者随机分为治疗组(60名)和安慰剂组(40名),分别予三黄口服液和安慰剂治疗12周,观察治疗前后患者心血管危险因素的变化。结果:与安慰剂组相比,治疗组(起效剂量为10 ml/人,黄连素浓度为0.16～0.22 mg/ml)除空腹血糖,甘油三酯在治疗前后无显著差异外,腰围、体质量指数、腰臀围比值、胰岛素抵抗指数,血清C反应蛋白水平、游离脂肪酸明显改善,差异有显著性(P<0.05);随着腰围的增大,男性的糖代谢异常、高血压病、血脂紊乱及代谢综合征的发生率均呈现增高趋势(P<0.01)。结论:三黄口服液可明显降低代谢综合征人群肥胖和胰岛素抵抗程度,并能改善炎症状态,减轻致心血管病的危险性。     

Obesity and Dysmetabolic Factors among Deceased COVID-19 Adults under 65 Years of Age in Italy: A Retrospective Case-Control Study

Background: Italy has witnessed high levels of COVID-19 deaths, mainly at the elderly age. We assessed the comorbidity and the biochemical profiles of consecutive patients ≤65 years of age to identify a potential risk profile for death. Methods: We retrospectively analyzed clinical data from consecutive hospitalized-for-COVID-19 patients ≤65 years, who were died (593 patients) or discharged (912 patients) during February–December 2020. Multivariate logistic regression identified the mortality risk factors. Results: Overweight (adjusted odds ratio (adjOR) 5.53, 95% CI 2.07–14.76), obesity (adjOR 8.58, CI 3.30–22.29), dyslipidemia (adjOR 10.02, 95% CI 1.06–94.22), heart disease (adjOR 17.68, 95% CI 3.80–82.18), cancer (adjOR 13.28, 95% CI 4.25–41.51) and male sex (adjOR 5.24, 95% CI 2.30–11.94) were associated with death risk in the youngest population. In the older population (46-65 years of age), the overweight and obesity were also associated with the death risk, however at a lower extent: the adjORs varyied from 1.49 to 2.36 for overweight patients and from 3.00 to 4.07 for obese patients. Diabetes was independently associated with death only in these older patients. Conclusion: Overweight, obesity and dyslipidemia had a pivotal role in increasing young individuals’ death risk. Their presence should be carefully evaluated for prevention and/or prompt management of SARS-CoV2 infection in such high-risk patients to avoid the worst outcomes.     

Adipose Tissue Dysfunction in Obesity: Role of Mineralocorticoid Receptor

The mineralocorticoid receptor (MR) acts as an essential regulator of blood pressure, volume status, and electrolyte balance. However, in recent decades, a growing body of evidence has suggested that MR may also have a role in mediating pro-inflammatory, pro-oxidative, and pro-fibrotic changes in several target organs, including the adipose tissue. The finding that MR is overexpressed in the adipose tissue of patients with obesity has led to the hypothesis that this receptor can contribute to adipokine dysregulation and low-grade chronic inflammation, alterations that are linked to the development of obesity-related metabolic and cardiovascular complications. Moreover, several studies in animal models have investigated the role of MR antagonists (MRAs) in preventing the metabolic alterations observed in obesity. In the present review we will focus on the potential mechanisms by which MR activation can contribute to adipose tissue dysfunction in obesity and on the possible beneficial effects of MRAs in this setting.     

Conversion of CO2 into organic acids by engineered autotrophic yeast

The increase of CO₂ emissions due to human activity is one of the preeminent reasons for the present climate crisis. In addition, considering the increasing demand for renewable resources, the upcycling of CO₂ as a feedstock gains an extensive importance to establish CO₂-neutral or CO₂-negative industrial processes independent of agricultural resources. Here we assess whether synthetic autotrophic Komagataella phaffii (Pichia pastoris) can be used as a platform for value-added chemicals using CO₂ as a feedstock by integrating the heterologous genes for lactic and itaconic acid synthesis. ¹³C labeling experiments proved that the resulting strains are able to produce organic acids via the assimilation of CO₂ as a sole carbon source. Further engineering attempts to prevent the lactic acid consumption increased the titers to 600 mg L⁻¹, while balancing the expression of key genes and modifying screening conditions led to 2 g L⁻¹ itaconic acid. Bioreactor cultivations suggest that a fine-tuning on CO₂ uptake and oxygen demand of the cells is essential to reach a higher productivity. We believe that through further metabolic and process engineering, the resulting engineered strain can become a promising host for the production of value-added bulk chemicals by microbial assimilation of CO₂, to support sustainability of industrial bioprocesses.

Between 2011 and 2020 the annual average CO₂ emission due to human activity exceeded 38 gigatons, of which around 22 gigatons are removed again from the atmosphere to terrestrial and ocean CO₂ sinks. This imbalance, mostly due to combustion of fossil fuels, causes the steady increase in CO₂ levels in the atmosphere which is one of the primary reasons for the climate crisis our planet is facing today (1).Biologically produced fuels and commodity chemicals bear the potential to counteract this deleterious development, but the most common feedstocks used for bioproduction, such as glucose, sucrose and starch rely on agricultural production and are bearing the risk to threaten food security. Using autotrophic microorganisms as production platforms exploits the potential of CO₂ itself as an alternative carbon source. In nature, autotrophic microorganisms play a major role in CO₂ fixation by fixing 200 gigatons of CO₂ every year (2). However, the rates of most natural microbial CO₂ fixing pathways are low: the photosynthetic efficiency in cyanobacteria is limited to 1 to 2% which makes industrial processes using photoautotrophs economically less feasible (3). Chemoautotrophs may overcome this barrier as their energy harvesting processes are more efficient than light harvesting of photoautotrophs.One well-known autotroph that is being developed for biological production of materials is Cupriavidus necator (formerly known as Ralstonia eutropha). By harvesting energy with a controlled Knallgas reaction these bacteria assimilate CO₂ via the Calvin-Benson-Bessham (CBB) cycle. Besides naturally produced polyhydroxyalkanoates (PHA), metabolic pathway engineering enabled the production of several other chemicals (4–7).Several chemolithotrophic bacteria were demonstrated as production hosts for various chemicals such as ethanol, 2,3-butanediol, butanol, isopropanol, acetone, or isobutyric acid via natural carbon assimilation pathways (8–11). In addition to natural CO₂ fixing microorganisms, implementation of heterologous CO₂ fixing pathways to heterotrophic microorganisms like Myceliophthora thermophila provided a mixotrophic strain that is able to produce malic acid with a higher yield compared to the parent strain in which only the reductive tricarboxylic acid (TCA) cycle is used for the production (12).Natural chemoautotrophs have a large potential to convert CO₂ to chemicals. However, they are often recalcitrant to genetic editing, have complex nutrient demands, or may require complex process technological solutions like the transfer of gaseous substrates and energy sources. To circumvent some of these limitations well established prokaryotic and eukaryotic production hosts have been engineered to assimilate CO₂. The bacterial workhorse Escherichia coli and the yeast Komagataella phaffii (Pichia pastoris) were provided with the CBB cycle, enabling them to assimilate CO₂ by using formate or methanol, respectively, as energy sources. Both engineered microorganisms can grow sustainably with CO₂ as carbon source (13, 14). Conceptually formate and methanol are regarded as sustainable feedstocks for biotechnology when they are derived from CO₂ by hydrogenation or electrochemical reduction (15).To make an impact on the global CO₂ household such autotrophic processes need to convert CO₂ into bulk products. Besides ethanol, short chain organic acids are the second largest group of chemicals manufactured by industrial biotechnology. The market of biologically produced organic acids is expected to reach more than $36 billion by 2026 (16). The annual bioproduction of some of the key organic acids (citric, acetic, lactic, succinic acid) is more than 12 million metric tons (17–20). Recently, itaconic acid has also gained attention as a promising chemical building block with an estimated market increase to 170 kilotons per year and $260 million in 2025 (21). Lactic and itaconic acid are feedstocks for polymer production so that they, and other biobased commodity chemicals compete for the annual polymer production of more than 300 million tons, a volume that denotes a significant impact on the global CO₂ balance.Here, we set out to evaluate if the autotrophic K. phaffii strain can be used as a platform for organic acid production. Synthetic autotrophy was introduced to K. phaffii by converting the native peroxisomal methanol assimilation pathway, the xylulose monophosphate (XuMP) cycle, into the CBB cycle (13). To achieve that, the formaldehyde assimilating enzyme dihydroxyacetone synthase (DAS) was replaced by a bacterial ribulose 1,5-bisphosphate carboxylase/oxygenase (RuBisCO), and phosphoribulose kinase (PRK) from spinach was added to supply ribulose bisphosphate from XuMP precursors. Four yeast glycolytic enzymes were targeted to peroxisomes to close the CBB cycle to glyceraldehyde 3-phosphate (G3P), both as an intermediate and the product of the assimilation cycle (Fig. 1 A and B). In the present work, using modular synthetic biology tools, we implemented the genes for lactic and itaconic acid synthesis plus accessory genes into the K. phaffii genome and demonstrate that the autotrophic K. phaffii strain is capable of producing organic acids solely from CO₂ as carbon source.Open in a separate windowFig. 1.Expression of cadA and ldhL enables organic acid production in synthetic autotrophic K. phaffii. (A–D) Schematic pathways. (A) In wild-type K. phaffii methanol is oxidized to formaldehyde (black arrow) and assimilated in the XuMP cycle (orange arrows) or dissimilated to CO₂, respectively (purple arrow). (B) synthetic autotrophy in K. phaffii: the native assimilatory branch of methanol utilization was interrupted by deleting DAS1 and DAS2 (dashed gray line). AOX1 was knocked out to reduce the rate of formaldehyde formation which could be toxic to the cells. RuBisCO and PRK were integrated to complete a functional CBB cycle (green arrows). Additionally, two bacterial chaperones, groEL and groES, were overexpressed to assist the folding of RuBisCO. TDH3, PGK1, TKL1, TPI1 carrying each a peroxisomal targeting signal were overexpressed to assure the localization of the entire CBB cycle in peroxisomes. More details about the engineering strategy can be found in ref. (13). (C) Itaconic acid (red) and (D) lactic acid production (blue), (E) growth profiles, and (F) organic acid production profiles of the producing strains and the control. Time axis corresponds to the production phase under autotrophic conditions. At least three biological replicates were used in the screening to monitor the producing strains. Shades represent the SDs (±). 3PG: 3-phosphoglycerate, AcCoA: acetyl-coenzyme A, AOX1 and AOX2: alcohol oxidase 1 and 2, cadA: cis-aconitate decarboxylase, CBB cycle: Calvin-Benson-Bassham cycle, CISA_c: cytosolic cis-aconitate, CISA_m: mitochondrial cis-aconitate, DAS1 and DAS2: dihydroxyacetone synthase 1 and 2, DHA: dihydroxyacetone, FAL: formaldehyde, G3P: glyceraldehyde 3-phosphate, ITA: itaconic acid, LA: lactic acid, ldhL: L-lactate dehydrogenase, MeOH: methanol, mttA: mitochondrial tricarboxylic acid transporter, NAD⁺/NADH: nicotinamide adenine dinucleotide, PRK: phosphoribulokinase, PYR: pyruvate, RuBP: ribulose 1,5-bisphosphate, RuBisCO: ribulose 1,5-bisphosphate carboxylase/oxygenase, Xu5P: xylulose 5-phosphate, XuMP cycle: xylulose monophosphate cycle.