Placenta-targeted Treatment Strategies for Preeclampsia and Fetal Growth Restriction: An Opportunity and Major Challenge.

The placenta plays a crucial role in maintaining normal pregnancy. The failure of spiral artery remodeling (SAR) is a key factor leading to placental ischemia and poor perfusion which is strongly associated with obstetric diseases, including preeclampsia (PE) and fetal growth restriction (FGR). Existing interventions for PE and FGR are limited and termination of pregnancy is inevitable when the maternal or fetus condition deteriorates. Considering the safety of the mother and fetus, treatments that may penetrate the placental barrier and harm the fetus are not accepted. Developing targeted treatment strategies for these conditions is urgent and necessary. With the proven efficacy of targeted therapy in treating conditions such as endometrial cancer and trophoblastic tumors, research on placental dysfunction continues to deepen. This article reviews the studies on placenta-targeted treatment and drug delivery strategies, summarizes the characteristics proposes corresponding improvement measures in targeted treatment, provides solutions for existing problems, and makes suggestions for future studies.

Mesenchymal stem cell-derived exosomes: a promising alternative in the therapy of preeclampsia.

Preeclampsia (PE) is a common morbid complication during pregnancy, affecting 2%-8% of pregnancies globally and posing serous risks to the health of both mother and fetus. Currently, the only effective treatment for PE is timely termination of pregnancy, which comes with increased perinatal risks. However, there is no effective way to delay pathological progress and improve maternal and fetal outcomes. In light of this, it is of great significance to seek effective therapeutic strategies for PE. Exosomes which are nanoparticles carrying bioactive substances such as proteins, lipids, and nucleic acids, have emerged as a novel vehicle for intercellular communication. Mesenchymal stem cell-derived exosomes (MSC-Exos) participate in various important physiological processes, including immune regulation, cell proliferation and migration, and angiogenesis, and have shown promising potential in tissue repair and disease treatment. Recently, MSC-Exos therapy has gained popularity in the treatment of ischaemic diseases, immune dysfunction, inflammatory diseases, and other fields due to their minimal immunogenicity, characteristics similar to donor cells, ease of storage, and low risk of tumor formation. This review elaborates on the potential therapeutic mechanism of MSC-Exos in treating preeclampsia, considering the main pathogenic factors of the condition, including placental vascular dysplasia, immunological disorders, and oxidative stress, based on the biological function of MSC-Exos. Additionally, we discuss in depth the advantages and challenges of MSC-Exos as a novel acellular therapeutic agent in preeclampsia treatment.

Design, synthesis, and biological evaluation of novel donepezil-tacrine hybrids as multi-functional agents with low neurotoxicity against Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and deficits in cognitive domains. Low choline levels, oxidative stress, and neuroinflammation are the primary mechanisms implicated in AD progression. Simultaneous inhibition of acetylcholinesterase (AChE) and reactive oxygen species (ROS) production by a single molecule may provide a new breath of hope for AD treatment. Here, we describe donepezil-tacrine hybrids as inhibitors of AChE and ROS. Four series of derivatives with a ß-amino alcohol linker were designed and synthesized. In this study, the target compounds were evaluated for their ability to inhibit AChE and butyrylcholinesterase (BuChE) in vitro, using tacrine (hAChE, IC50 = 305.78 nM; hBuChE, IC50 = 56.72 nM) and donepezil (hAChE, IC50 = 89.32 nM; hBuChE, IC50 = 9137.16 nM) as positive controls. Compound B19 exhibited an excellent and balanced inhibitory potency against AChE (IC50 = 30.68 nM) and BuChE (IC50 = 124.57 nM). The cytotoxicity assays demonstrated that the PC12 cell viability rates of compound B19 (84.37 %) were close to that of tacrine (87.73 %) and donepezil (79.71 %). Potential therapeutic effects in AD were evaluated using the neuroprotective effect of compounds against H2O2-induced toxicity, and compound B19 (68.77 %) exhibited substantially neuroprotective activity at the concentration of 25 µM, compared with the model group (30.34 %). Furthermore, compound B19 protected PC12 cells from H2O2-induced apoptosis and ROS production. These properties of compound B19 suggested that it was a multi-functional agent with AChE inhibition, anti-oxidative, anti-inflammatory activities, and low toxicity and that it deserves further investigation as a promising agent for AD treatment.

Systolic Blood Pressure Time in Target Range and Incident Atrial Fibrillation in Patients With Hypertension: Insights From the SPRINT Trial.

BACKGROUND: Systolic blood pressure (SBP) time in target range (TTR) indicates the mean value, exposure time, and variability in blood pressure over time. The prognostic value of SBP TTR for incident atrial fibrillation (AF) in patients with hypertension is unclear. METHODS: We performed a post hoc analysis of SPRINT (Systolic Blood Pressure Intervention Trial), a randomized controlled trial comparing intensive (<120 mm Hg) and standard (<140 mm Hg) SBP interventions in participants with hypertension. SBP target ranges for intensive and standard arms were defined as 110 to 130 and 120 to 140 mm Hg, respectively. TTR was calculated by linear interpolation method using SBP from months 0 to 3. We used Cox proportional regression models to assess the association of SBP TTR with incident AF. RESULTS: Among 7939 participants included in this analysis, 187 incident AF cases occurred during follow-up. After multivariable adjustment, a 10% increase in SBP TTR was independently associated with a 7% lower risk of incident AF (hazard ratio, 0.93 [95% CI, 0.88-0.97]; P=0.003). The restricted spline curve depicted a linear and inverse relationship between SBP TTR and incident AF. Sensitivity analyses generated consistent results when calculating TTR over a longer period or setting target range as 110 to 140 mm Hg for the whole population. CONCLUSIONS: Higher SBP TTR independently predicts a lower risk of incident AF. Efforts to attain SBP within 110 to 140 mm Hg over time may be an effective strategy to prevent AF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01206062.

Pregnancy feasibility in women with mild pulmonary arterial hypertension: a systematic review and meta-analysis.

BACKGROUND: The aim of this study was to evaluate the pregnancy feasibility of women with mild pulmonary hypertension according to pregnancy outcomes. METHODS: This systematic review and meta-analysis compared the differences in maternal and fetal outcomes between mild and moderate-to-severe pulmonary hypertension. Relevant English and Chinese literature were searched in the PubMed, Embase, Cochrane Central Register of Controlled Trials (COCHRANE), CNKI, WanFang Data, and VIP databases between January 1st, 1990 and April 18th, 2023, and the references of the included articles and relevant systematic reviews were reviewed to determine whether studies were missed. The inclusion criteria were randomized controlled and observational studies (including case-control studies and cohort studies) examining maternal and fetal pregnancy outcomes with pulmonary hypertension. Conference abstracts, case reports, case series reports, non-comparative studies, and review articles were excluded. RESULTS: This meta-analysis included 32 studies. In this study, maternal and fetal outcomes were better in the mild pulmonary hypertension group than in the moderate-to-severe group. Regarding maternal mortality, the mild group was much lower than the moderate to severe group. We found a significant decrease in maternal mortality in the mild group after 2010. However, no significant difference in maternal mortality before and after 2010 was observed in the moderate to severe group. Cardiac complications, ICU admission, neonatal preterm birth, small for gestational age infants, low birth weight infants, neonatal asphyxia, and neonatal mortality were significantly lower in the mild pulmonary hypertension group than in the moderate to severe pulmonary hypertension group. The cesarean section rates of the two groups were similar. However, the vaginal delivery rate in the mild pulmonary hypertension group was significantly higher than that in the moderate to severe pulmonary hypertension group. CONCLUSIONS: This meta-analysis confirmed that pregnancies with mild pulmonary hypertension had significantly better maternal and fetal outcomes than those with moderate to severe pulmonary hypertension. For patients with mild pulmonary hypertension and good cardiac function, continued pregnancy or even delivery should be considered under multidisciplinary monitoring. However, maternal and fetal complications with moderate to severe pulmonary hypertension significantly increase. Hence, it is essential to evaluate pregnancy risk and terminate it in time.

Deeper insight into the role of IL-17 in the relationship beween hypertension and intestinal physiology.

With the incidence of hypertension increasing worldwide, more and more the mechanisms of hypertension from the perspective of immunity have found. Intestinal microbiota as well as its metabolites relationship with hypertension has attracted great attention from both clinicians and investigators. However, the associations of hypertension with lesions of a large number of immune factors including IL-17, MCP-1, IL-6, TGF-ß, IL-10 and others have not been fully characterized. In this review, after introducing the immune factors as the most potent anti/pro-hypertension agents known, we provide detailed descriptions of the IL-17 involved in the pathology of hypertension, pointing out the underlying mechanisms and suggesting the clinical indications.

Restraint Stress in Hypertensive Rats Activates the Intestinal Macrophages and Reduces Intestinal Barrier Accompanied by Intestinal Flora Dysbiosis.

PURPOSE: Hypertension (HTN) is a major risk factor for cardiovascular disease. In recent years, there were numerous studies on the function of stress in HTN. However, the gut dysbiosis linked to hypertension in animal models under stress is still incompletely understood. Purpose of this study is to use multiple determination method to determine the juvenile stage intestinal bacteria, cytokines and changes in hormone levels. METHODS: Four groups of juvenile male spontaneously hypertensive rats (SHRs) and age-matched male Wistar-Kyoto (WKY) rats were randomly selected as control and experimental groups. Rats in the two stress groups were exposed to restraint stress for 3 hours per day for 7 consecutive days. In one day three times in the method of non-invasive type tail-cuff monitoring blood pressure. The detailed mechanism was illuminated based on the intestinal change using immunohistochemical and immunofluorescence staining and the stress-related hormone and inflammation factors were analyzed via ELISA method. The integrity of the epithelial barrier was assessed using FITC/HRP and the expression levels of proteins associated with the tight junction was detected by Western blot. The alteration of stress-related intestinal flora from ileocecal junction and distal colon were also analyzed using its 16S rDNA sequencing. RESULTS: The results indicate that acute stress rapidly increases mean arterial pressure which is positive correlation to hormone concentration, especially in SHR-stress group. Meanwhile, stress promoted the enhancement of epithelial permeability accompanied with a reduced expression of the tight junction-related protein and the macrophages (Mφ) aggregation to the lamina propria. There were remarkable significant increase of stress-related hormones and pro-inflammatory factor interleukin (IL)-6 along with a decrease in the diversity of intestinal flora and an imbalance in the F/B ratio. CONCLUSION: Our results reveal that stress accompanied with HTN could significantly disrupt the domino effect between intestinal flora and homeostasis.

Functions of Dendritic Cells and Its Association with Intestinal Diseases.

Dendritic cells (DCs), including conventional DCs (cDCs) and plasmacytoid DCs (pDCs), serve as the sentinel cells of the immune system and are responsible for presenting antigen information. Moreover, the role of DCs derived from monocytes (moDCs) in the development of inflammation has been emphasized. Several studies have shown that the function of DCs can be influenced by gut microbes including gut bacteria and viruses. Abnormal changes/reactions in intestinal DCs are potentially associated with diseases such as inflammatory bowel disease (IBD) and intestinal tumors, allowing DCs to be a new target for the treatment of these diseases. In this review, we summarized the physiological functions of DCs in the intestinal micro-environment, their regulatory relationship with intestinal microorganisms and their regulatory mechanism in intestinal diseases.

Rhubarb extract relieves constipation by stimulating mucus production in the colon and altering the intestinal flora.

BACKGROUND: Constipation, mainly characterized by the difficulty in defecation, is a clinical symptom caused by a variety of factors. It can be manifested as normal or slow colonic transport abnormalities, which can occur alone or concurrently with defecation disorders. As there is not uniform definition and assessment standard, no clear plan could be used for the treatment of constipation. Although rhubarb, a traditional Chinese medicine, plays a therapeutic role in diseases involving constipation symptoms, the detailed mechanism of it in treating constipation remains unclear. METHODS: A model of constipation-induced by diphenoxylate was prepared. Immunofluorescent staining was used to detect the expression of mucin 2 (MUC2), calnexin and chymase in colon. Western blotting was used to detect changes of tryptase and calnexin in the colon. And real-time polymerase chain reaction (PCR) was utilized to detect the changes of immunoglobulin-binding protein (Bip), X-box binding protein 1 (Xbp1) and C/EBP homologous protein (CHOP) of colonic goblet cells in mRNA levels. ELISA and biochemical kits were utilized to detect the changes of MUC2, Trefoil factor 3 (TFF3), acetylcholine, histamine and C-C motif chemokine ligand 5 (CCL5) in the colon. And the changes of colonic mucosa and intestinal flora of constipation model mice caused by rhubarb extract (RE) were analyzed to identify the mechanism of RE on the treatment of constipation. RESULTS: RE promotes the secretion of colonic mucus by recruiting mast cells and enhancing the content of histamine and Ach in the mice colon. In the process, RE causes up-regulation of Bip and CHOP mRNA expression and down-regulation of Xbp1 and Xbp1s mRNA expression that induces ER stress of colonic epithelium associated with changes in the intestinal flora diversity and short-chain fatty acids content. CONCLUSION: RE could relieve constipation by promoting the secretion of colonic mucus via mast cells activation and improving the intestinal microenvironment.

Biological characteristics of IL-6 and related intestinal diseases.

The intestine serves as an important digestive and the largest immune organ in the body. Interleukin-6(IL-6), an important mediator of various pathways, participates in the interactions between different kinds of cells and closely correlates with intestinal physiological and pathological condition. In this review we summarize the signaling pathways of IL-6 and its functions in maintaining intestinal homeostasis. We also explored its relation with nervous system and highlight its potential role in Parkinson's disease. Based on its specialty of the double-side influences on intestinal tumors and inflammation, we summarize how they are done through distinctive process.