Capsular warning syndrome and its clinical awareness and therapeutic approach: two case reports and a systematic review of the literature.

Introduction: Capsular warning syndrome (CWS) is characterized by recurrent stereotyped episodes of unilateral transient motor and/or sensory symptoms affecting the face and upper and lower limbs, without cortical signs in 24 h and with a high risk of developing stroke. Among the possible underlying mechanisms, small perforating artery disease is the most common. The aim was to assess the most common risk factors, the therapeutic alternatives, and the different outcomes in patients with CWS, along with the presentation of two cases treated in our Emergency Department. Methods: Stroke Code, launched at our institution in January 2017, was triggered 400 times, and by December 2022, 312 patients were admitted as having an acute ischemic stroke. Among them, two of them fulfilled the criteria of CWS. A systematic search was carried out in PubMed, Scopus, and Web of Science databases to seek demography and therapeutic approaches in CWS. Results: Of 312 cases, two with acute ischemic stroke exhibited CWS. The first patient had six events of right hemiparesis with recovery in 10-30 min; after MRI and digital subtraction angiography (DSA), he received apixaban and clopidogrel; however, a day after admission, he developed ischemic infarction with partial recovery. The second patient presented five transient events of right hemiparesis. After MRI and DSA with an intra-arterial infusion of nimodipine, oral aspirin, and ticagrelor, he presented another event-developing stroke and was discharged with partial recovery. A systematic review found 190 cases of CWS in 39 articles from 1993 to 2022. Most were male subjects (66.4%), and hypertension (60%), smoking (36%), diabetes (18%), and dyslipidemia (55%) were the most common risk factors. Over 50% of the cases were secondary to small perforating artery disease. The most commonly used treatments were dual antiplatelet therapy (DAT), recombinant tissue plasminogen activator, and anticoagulant therapy (ACT), where the combination of DAT plus ACT was linked to the most positive functional outcomes (82.6%). Conclusion: Our cases fit with the description of patients with partial recovery and risk factors (hypertension, diabetes, and smoking) in male patients. There is a lack of evidence regarding the best treatment option; dual antiplatelet therapy and anticoagulation therapy are strong contenders for a favorable result.

Hyperoside Suppresses Renal Inflammation by Regulating Macrophage Polarization in Mice With Type 2 Diabetes Mellitus.

Accumulating evidence reveals that both inflammation and lymphocyte dysfunction play a vital role in the development of diabetic nephropathy (DN). Hyperoside (HPS) or quercetin-3-O-galactoside is an active flavonoid glycoside mainly found in the Chinese herbal medicine Tu-Si-Zi. Although HPS has a variety of pharmacological effects, including anti-oxidative and anti-apoptotic activities as well as podocyte-protective effects, its underlying anti-inflammatory mechanisms remain unclear. Herein, we investigated the therapeutic effects of HPS on murine DN and the potential mechanisms responsible for its efficacy. We used C57BLKS/6J Lepdb/db mice and a high glucose (HG)-induced bone marrow-derived macrophage (BMDM) polarization system to investigate the potentially protective effects of HPS on DN. Our results showed that HPS markedly reduced diabetes-induced albuminuria and glomerular mesangial matrix expansion, accompanied with a significant improvement of fasting blood glucose level, hyperlipidaemia and body weight. Mechanistically, pretreatment with HPS effectively regulated macrophage polarization by shifting proinflammatory M1 macrophages (F4/80+CD11b+CD86+) to anti-inflammatory M2 ones (F4/80+CD11b+CD206+) in vivo and in bone marrow-derived macrophages (BMDMs) in vitro, resulting in the inhibition of renal proinflammatory macrophage infiltration and the reduction in expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) while increasing expression of anti-inflammatory cytokine Arg-1 and CD163/CD206 surface molecules. Unexpectedly, pretreatment with HPS suppressed CD4+ T cell proliferation in a coculture model of IL-4-induced M2 macrophages and splenic CD4+ T cells while promoting their differentiation into CD4+IL-4+ Th2 and CD4+Foxp3+ Treg cells. Taken together, we demonstrate that HPS ameliorates murine DN via promoting macrophage polarization from an M1 to M2 phenotype and CD4+ T cell differentiation into Th2 and Treg populations. Our findings may be implicated for the treatment of DN in clinic.

Therapeutic silencing of SMOC2 prevents kidney function loss in mouse model of chronic kidney disease.

Chronic kidney disease (CKD) is associated with substantial morbidity and mortality. We developed a mouse model that mimics human CKD with inflammation, extracellular matrix deposition, tubulointerstitial fibrosis, increased proteinuria, and associated reduction in glomerular filtration rate over time. Using this model, we show that genetic deficiency of SMOC2 or therapeutic silencing of SMOC2 with small interfering RNAs (siRNAs) after disease onset significantly ameliorates inflammation, fibrosis, and kidney function loss. Mechanistically, we found that SMOC2 promotes fibroblast to myofibroblast differentiation by activation of diverse cellular signaling pathways including MAPKs, Smad, and Akt. Thus, targeting SMOC2 therapeutically offers an approach to prevent fibrosis progression and CKD after injury.

Seed- and Soil-Dependent Differences in Murine Breast Tumor Microenvironments Dictate Anti-PD-L1 IgG Delivery and Therapeutic Efficacy.

We sought to determine if Stephen Paget's "seed and soil" hypothesis of organ-preference patterns of cancer metastasis can explain the development of heterogeneity in a tumor microenvironment (TME) as well as immunotherapeutic delivery and efficacy. We established single-cell-derived clones (clones 1 and 16) from parental 4T1 murine breast cancer cells to create orthotopic primary and liver metastasis models to deconvolute polyclonal complexity cancer cells and the difference in TME-derived heterogeneities. Tumor-bearing mice were treated with anti-PD-L1 IgG or a control antibody, and immunofluorescent imaging and quantification were then performed to evaluate the therapeutic efficacy on tumor growth, the delivery of therapy to tumors, the development of blood vessels, the expression of PD-L1, the accumulation of immune cells, and the amount of coagulation inside tumors. The quantification showed an inverse correlation between the amount of delivered therapy and therapeutic efficacy in parental-cell-derived tumors. In contrast, tumors originating from clone 16 cells accumulated a significantly greater amount of therapy and responded better than clone-1-derived tumors. This difference was greater when tumors grew in the liver than the primary site. A similar trend was found in PD-L1 expression and immune cell accumulation. However, the change in the number of blood vessels was not significant. In addition, the amount of coagulation was more abundant in clone-1-derived tumors when compared to others. Thus, our findings reconfirmed the seed- and soil-dependent differences in PD-L1 expression, therapeutic delivery, immune cell accumulation, and tumor coagulation, which can constitute a heterogeneous delivery and response of immunotherapy in polyclonal tumors growing in different organs.