Dual drug-loaded PLGA fibrous scaffolds for effective treatment of breast cancer in situ.

Advanced metastatic breast cancer remains nearly an incurable disease. In situ therapy may help patients with worse prognoses have better clinical outcomes by significantly reducing systematic toxicity. Dural-drug fibrous scaffold was created and assessed using an in-situ therapeutic strategy, simulating the preferred regimens advised by the National Comprehensive Cancer Network. DOX, a once-used chemotherapy drug is embedded into scaffolds and produces a fast release for two cycles to kill tumor cells. PTX, a hydrophobic drug is continuously injected and produces a gradual release for up to two cycles to treat long cycles. Chosen drug loading system and the designated fabrication parameter controlled the releasing profile. Drug carrier system complied with the clinical regimen. It demonstrated both in vitro and in vivo anti-proliferative effects on the breast cancer model. The dosage of an intratumoral injection to drug capsules, the local tissue toxicity could be significantly reduced. To optimized intravenous injection with dual drugs, fewer side effects and a higher survival rate were seen even in the large tumor model (450-550 mm3). Drug delivery system makes the precise accumulation of the topical drug concentration possible, simulating clinically successful therapy and possibly offering better clinical treatment options for solid tumors.

Pre-Induced ICD Membrane-Coated Carrier-Free Nanoparticles for the Personalized Lung Cancer Immunotherapy.

Immunotherapy is a required adjuvant method in lung cancer therapy clinically. The single immune adjuvant failed to show the expected clinical therapeutic efficacy due to its rapid drug metabolism and inability to accumulate in the tumor site efficiently. Immunogenic cell death (ICD) is a new anti-tumor strategy combined with immune adjuvants. It can provide tumor-associated antigens, activate dendritic cells, and attract lymphoid T cells into the tumor microenvironment. Here doxorubicin-induced tumor membrane-coated iron (II)-cytosine-phosphate-guanine nanoparticles (DM@NPs) are shown for efficient co-delivery of tumor-associated antigens and adjuvant. Higher expression of ICD-related membrane proteins on the surface of the DM@NPs leads to the enhanced uptake of DM@NPs by dendritic cells (DCs), thereby promoting the DCs maturation and pro-inflammatory cytokines release. DM@NPs can remarkably increase the T cell infiltrations, remodel the tumor immune microenvironment and inhibit tumor progression in vivo. These findings reveal that pre-induced ICD tumor cell membrane-encapsulated nanoparticles can enhance immunotherapy responses and provide an effective biomimetic nanomaterial-based therapeutic strategy for lung cancer.

Mechanisms of Panax Ginseng on Treating Sepsis by RNA-Seq Technology.

Purpose: To explore the potential active targets and mechanisms of Panax Ginseng in the treatment of sepsis using network pharmacology and RNA-seq technology. Patients and Methods: Patients with sepsis and healthy volunteers were collected according to SEPSIS 3.0, and their peripheral blood was used for RNA-seq analysis. The active ingredients and targets of Panax Ginseng were obtained using the TCMSP database, PPI and GO analysis were performed for disease-drug intersection targets. Then, we used Meta-analysis to screen core genes. Finally, single-cell RNA-seq was used to perform cell localization analysis on core genes. Results: RNA-seq analysis collected 4521 sepsis-related genes, TCMSP database obtained 86 Panax Ginseng active ingredients and their 294 active targets. PPI and GO analysis showed intersection targets were closely linked, and mainly involved in cellular response to chemical stress, response to drug and molecule of bacterial origin, etc. Then, core targets, IL1B, ALOX5, BCL2 and IL4R, were sorted by Meta-analysis, and all four genes have high expression in the sepsis survivor group compared to the sepsis non-survivor group; single-cell RNA-seq revealed that IL1B was mainly localized in macrophages, ALOX5 was mainly localized in macrophages and B cells, BCL2 was mainly localized in natural killer cells, T cells and B cells, IL4R was widely distributed in immune cells. Finally, according to the correspondence between the active ingredients and targets of Panax Ginseng in TCMSP database, we found that Ginsenoside rh2 regulates the expression of IL1B, Ginsenoside rf regulates the expression of IL1B and IL4R, Kaempferol regulates the expression of ALOX5 and BCL2, and ß-sitosterol regulates the expression of BCL2. Conclusion: Ginsenoside rh2, Ginsenoside rf, Kaempferol and ß-sitosterol may produce anti-sepsis effects by regulating the expression of IL1B, ALOX5, BCL2 and IL4R, thus improving the survival rate of sepsis patients.

The Role of Vitamin D in Combination Treatment for Patients With Rheumatoid Arthritis.

Background: The aim of this study is to evaluate the clinical efficacy of vitamin D (VitD) supplementation in terms of response to treatment and improvement of disease activity in rheumatoid arthritis (RA). Methods: This study analyzed 1180 RA patients' records treated at Mianyang Central Hospital from February 2015 to July 2019. The patients were allocated into VitD group and control group based on their medical regimens. The outcome measures were primary efficacy, defined as treatment response-based EULAR response criteria in RA, and secondary efficacy, defined as improvement in disease activity indicators. Safety was evaluated according to the incidence of all-cause infections. Results: At month 6, the primary efficacy revealed that there were 22.8% good responders and 19.0% moderate responders in the VitD group, and 22.3% good responders and 22.3% moderate responders in the control group; there were no differences between the two groups (p = 0.754). The similar primary efficacy outcomes were observed at months 3, 12, and >12. The secondary efficacy indicated that there were no differences in most indexes between the two groups at months 1, 3, 6, 12, and >12. The subgroups (based on baseline DAS28 (CRP), glucocorticoids use and disease duration) analysis results suggested that VitD group didn't have the advantage for treating RA. The incidence of infections was similar in the two groups. Conclusion: VitD supplementation did not provide additional benefit for anti-rheumatic treatment. These data supported the need for prospective, randomized, controlled trials to evaluate the role of VitD supplementation in treating RA.

Differential distribution of characteristic constituents in root, stem and leaf tissues of Salvia miltiorrhiza using MALDI mass spectrometry imaging.

Segmentation-quantification is the most commonly used method for studying the tissue distribution of bioactive constituents in plant, but this method would bring uncontrollable pollution, compound migration and denaturation. Mass spectrometry imaging (MSI), as a new method developed in the past 20 years, has high sensitivity, high spatial resolution, high degree of visualization, and low risk of contamination and degeneration when studying tissue distribution of compounds. For the first time we applied matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to tissue distribution of characteristic constituents of the medicinal plant Salvia miltiorrhiza. From the collected data, we found the regional differences in root, stem, and leaf tissues, and the ion information with differential distribution characteristics. We also identified 18 bioactive constituents in S. miltiorrhiza with their spatial distribution information. In addition, the plant was divided into five parts, and the identified compounds were analyzed for differences between tissues using LC-MS, which results verified those found from the MSI. It is figured out that MALDI-MSI can be reliably applied to the differential distribution of salvianolic acids and tanshinones.

Anti-apoptotic potential of several antidiabetic medicinal plants of the eastern James Bay Cree pharmacopeia in cultured kidney cells.

BACKGROUND: Our team has identified 17 Boreal forest species from the traditional pharmacopeia of the Eastern James Bay Cree that presented promising in vitro and in vivo biological activities in the context of type 2 diabetes (T2D). We now screened the 17 plants extracts for potential anti-apoptotic activity in cultured kidney cells and investigated the underlying mechanisms. METHODS: MDCK (Madin-Darnby Canine Kidney) cell damage was induced by hypertonic medium (700 mOsm/L) in the presence or absence of maximal nontoxic concentrations of each of the 17 plant extracts. After 18 h' treatment, cells were stained with Annexin V (AnnV) and Propidium iodide (PI) and subjected to flow cytometry to assess the cytoprotective (AnnV-/PI-) and anti-apoptotic (AnnV+/PI-) potential of the 17 plant extracts. We then selected a representative subset of species (most cytoprotective, moderately so or neutral) to measure the activity of caspases 3, 8 and 9. RESULTS: Gaultheria hispidula and Abies balsamea are amongst the most powerful cytoprotective and anti-apoptotic plants and appear to exert their modulatory effect primarily by inhibiting caspase 9 in the mitochondrial apoptotic signaling pathway. CONCLUSION: We conclude that several Cree antidiabetic plants exert anti-apoptotic activity that may be relevant in the context of diabetic nephropathy (DN) that affects a significant proportion of Cree diabetics.

Differentiated demographic histories and local adaptations between Sherpas and Tibetans.

BACKGROUND: The genetic relationships reported by recent studies between Sherpas and Tibetans are controversial. To gain insights into the population history and the genetic basis of high-altitude adaptation of the two groups, we analyzed genome-wide data in 111 Sherpas (Tibet and Nepal) and 177 Tibetans (Tibet and Qinghai), together with available data from present-day human populations. RESULTS: Sherpas and Tibetans show considerable genetic differences and can be distinguished as two distinct groups, even though the divergence between them (~3200-11,300 years ago) is much later than that between Han Chinese and either of the two groups (~6200-16,000 years ago). Sub-population structures exist in both Sherpas and Tibetans, corresponding to geographical or linguistic groups. Differentiation of genetic variants between Sherpas and Tibetans associated with adaptation to either high-altitude or ultraviolet radiation were identified and validated by genotyping additional Sherpa and Tibetan samples. CONCLUSIONS: Our analyses indicate that both Sherpas and Tibetans are admixed populations, but the findings do not support the previous hypothesis that Tibetans derive their ancestry from Sherpas and Han Chinese. Compared to Tibetans, Sherpas show higher levels of South Asian ancestry, while Tibetans show higher levels of East Asian and Central Asian/Siberian ancestry. We propose a new model to elucidate the differentiated demographic histories and local adaptations of Sherpas and Tibetans.

Rhododendron groenlandicum (Labrador tea), an antidiabetic plant from the traditional pharmacopoeia of the Canadian Eastern James Bay Cree, improves renal integrity in the diet-induced obese mouse model.

Content Our team has identified Labrador tea [Rhododendron groenlandicum L. (Ericaceae)] as a potential antidiabetic plant from the traditional pharmacopoeia of the Eastern James Bay Cree. In a previous in vivo study, the plant extract was tested in a high-fat diet (HFD)-induced obese model using C57BL/6 mice and it improved glycaemia, insulinaemia and glucose tolerance. Objective In the present study, we assessed the plant's potential renoprotective effects. Materials and methods Rhododendron groenlandicum was administered at 250 mg/kg/d to mice fed HFD for 8 weeks to induce obesity and mild diabetes. Histological (periodic acid-Schiff (PAS), Masson and Oil Red O staining), immunohistochemical (IHC) and biochemical parameters were assessed to evaluate the renoprotective potential of R. groenlandicum treatment for an additional 8 weeks. Results Microalbuminuria and renal fibrosis were developed in HFD-fed mice. Meanwhile, there was a tendency for R. groenlandicum to improve microalbuminuria, with the values of albumin-creatinine ratio (ACR) reducing from 0.69 to 0.53. Renal fibrosis value was originally 4.85 arbitrary units (AU) in HFD-fed mice, dropped to 3.27 AU after receiving R. groenlandicum treatment. Rhododendron groenlandicum reduced renal steatosis by nearly one-half, whereas the expression of Bcl-2-modifying factor (BMF) diminished from 13.96 AU to 9.43 AU. Discussion and conclusions Taken altogether, the results suggest that R. groenlandicum treatment can improve renal function impaired by HFD.

Labrador tea (Rhododendron groenlandicum) attenuates insulin resistance in a diet-induced obesity mouse model.

PURPOSE: Using a diet-induced obesity (DIO) mouse model, we investigated the antidiabetic effect of Labrador tea [Rhododendron groenlandicum (Oeder) Kron and Judd], a beverage and medicinal tea used by the Cree Nations of northern Quebec. METHODS: C57BL6 mice were divided into five groups and given standard chow (~4 % of lipids) or high-fat diet (~35 % of lipids) for 8 weeks until they became obese and insulin resistant. Treatment began by adding the plant extract at three doses (125, 250 and 500 mg/kg) to the high-fat diet for another 8 weeks. At the end of the study, insulin-sensitive tissues (liver, skeletal muscle, adipose tissue) were collected to investigate the plant's molecular mechanisms. RESULTS: Labrador tea significantly reduced blood glucose (13 %), the response to an oral glucose tolerance test (18.2 %) and plasma insulin (65 %) while preventing hepatic steatosis (42 % reduction in hepatic triglyceride levels) in DIO mice. It stimulated insulin-dependent Akt pathway (55 %) and increased the expression of GLUT4 (53 %) in skeletal muscle. In the liver, Labrador tea stimulated the insulin-dependent Akt and the insulin-independent AMP-activated protein kinase pathways. The improvement in hepatic steatosis observed in DIO-treated mice was associated with a reduction in inflammation (through the IKK α/ß) and a decrease in the hepatic content of SREBP-1 (39 %). CONCLUSIONS: Labrador tea exerts potential antidiabetic action by improving insulin sensitivity and mitigating high-fat diet-induced obesity and hyperglycemia. They validate the safety and efficacy of this plant, a promising candidate for culturally relevant complementary treatment in Cree diabetics.

A mitochondrial revelation of early human migrations to the Tibetan Plateau before and after the last glacial maximum.

As the highest plateau surrounded by towering mountain ranges, the Tibetan Plateau was once considered to be one of the last populated areas of modern humans. However, this view has been tremendously changed by archeological, linguistic, and genetic findings in the past 60 years. Nevertheless, the timing and routes of entry of modern humans into the Tibetan Plateau is still unclear. To make these problems clear, we carried out high-resolution mitochondrial-DNA (mtDNA) analyses on 562 Tibeto-Burman inhabitants from nine different regions across the plateau. By examining the mtDNA haplogroup distributions and their principal components, we demonstrated that maternal diversity on the plateau reflects mostly a northern East Asian ancestry. Furthermore, phylogeographic analysis of plateau-specific sublineages based on 31 complete mtDNA sequences revealed two primary components: pre-last glacial maximum (LGM) inhabitants and post-LGM immigrants. Also, the analysis of one major pre-LGM sublineage A10 showed a strong signal of post-LGM population expansion (about 15,000 years ago) and greater diversity in the southern part of the Tibetan Plateau, indicating the southern plateau as a refuge place when climate dramatically changed during LGM.

Prehistorical East-West admixture of maternal lineages in a 2,500-year-old population in Xinjiang.

As an area of contact between Asia and Europe, Central Asia witnessed a scenario of complex cultural developments, extensive migratory movements, and biological admixture between West and East Eurasians. However, the detanglement of this complexity of diversity requires an understanding of prehistoric contacts of the people from the West and the East on the Eurasia continent. We demonstrated the presence of genetic admixture of West and East in a population of 35 inhabitants excavated in Gavaerk in southern Xinjiang and dated 2,800-2,100 years before present by analyzing their mitochondrial DNA variations. This result indicates that the initial contact of the East and the West Eurasians occurred further east than Central Asia as early as 2,500 years ago.

Mitochondrial DNA evidence for a diversified origin of workers building First Emperor of China.

Variant studies on ancient DNA have attempted to reveal individual origin. Here, based on cloning sequencing and polymerase chain reaction-restriction fragment length polymorphisms, we analyzed polymorphisms in the first hypervariable region and coding regions of mitochondrial DNA of 19 human bone remains which were excavated from a tomb near the Terra Cotta Warriors and dated some 2,200 years before present. With the aim of shedding light on origins of these samples who were supposed to be workers building the mausoleum for the First Emperor of China, we compared them with 2,164 mtDNA profiles from 32 contemporary Chinese populations at both population and individual levels. Our results showed that mausoleum-building workers may be derived from very diverse sources of origin.