Role of epigenetics in the regulation of skin aging and geroprotective intervention: A new sight.

Multiple epigenetic factors play a regulatory role in maintaining the homeostasis of cutaneous components and are implicated in the aging process of the skin. They have been associated with the activation of the senescence program, which is the primary contributor to age-related decline in the skin. Senescent species drive a series of interconnected processes that impact the immediate surroundings, leading to structural changes, diminished functionality, and heightened vulnerability to infections. Geroprotective medicines that may restore the epigenetic balance represent valid therapeutic alliances against skin aging. Most of them are well-known Western medications such as metformin, nicotinamide adenine dinucleotide (NAD+), rapamycin, and histone deacetylase inhibitors, while others belong to Traditional Chinese Medicine (TCM) remedies for which the scientific literature provides limited information. With the help of the Geroprotectors.org database and a comprehensive analysis of the referenced literature, we have compiled data on compounds and formulae that have shown potential in preventing skin aging and have been identified as epigenetic modulators.

Mechanic evaluation of Wu-Mei-Pill on colitis-associated colorectal cancer: An integrated transcriptomics, metabolomics, and experimental validation study.

BACKGROUND: Chronic intestinal inflammatory diseases play a crucial role in the onset of colorectal cancer (CRC). Effectively impeding the progression of colitis-associated colorectal cancer (CAC) can be instrumental in hindering CRC development. Wu-Mei-Pill (WMP), a formulation comprising various herbal extracts, is clinically employed for CAC treatment, yet the underlying mechanism of WMP's efficacy in CAC remains unclear. Our study firstly demonstrated the effects and mechanisms of WMP on transcriptional and metabolic levels based on integrated transcriptomics and untargeted metabolomics and relative experimental validations. MATERIALS AND METHODS: A CAC mouse model was established through a single injection of azoxymethane (AOM) followed by intermittent dextran sodium sulfate (DSS) intervention, with subsequent WMP administration. Initially, the therapeutic impact of WMP on the CAC model was assessed by observing survival rate, body weight change, colon length, tumor number, tumor load, and pathological changes in the colon tissue of CAC mice post-WMP intervention. Subsequently, differential genes and metabolites in the colorectal tissue of CAC mice following WMP intervention were identified through transcriptomics and non-targeted metabolomics. Finally, the influence of WMP on the peroxisome proliferator activated receptor (PPAR) pathway, Wnt pathway, and CC motif chemokine ligand 3 (CCL3)/ CC motif chemokine receptor 1 (CCR1) axis in CAC mice was verified through western blot, immunofluorescence, and ELISA based on the results of transcriptomics and non-targeted metabolomics. RESULTS: WMP intervention enhanced survival, alleviated body weight loss, shortened colon length, tumor occurrence, and pathological changes in the colorectal tissue of CAC mice, such as glandular damage, tumourigenesis, and inflammatory cell infiltration. Transcriptomic and non-targeted metabolomic results revealed that WMP intervention up-regulated the expression of key regulatory mechanisms of fatty acid oxidation PPAR pathway-related genes (Pparg, Ppara, Cpt1a, and Acadm) and metabolites (L-carnitine and L-palmitoylcarnitine). Additionally, it down-regulated Wnt pathway-related genes (Wnt3, Axin2, Tcf7, Mmp7, Lgr5, Wnt5a, Fzd6, Wnt7b, Lef1, and Fzd10 etc.) and pro-inflammatory related genes (Il1b, Il6, Il17a, Ccl3, and Ccr1 etc.). Experimental validation demonstrated that WMP up-regulated PPAR pathway-related proteins [PPARγ, PPARα, carnitine palmitoyltransferase 1A (CPT1A), and acyl-CoA dehydrogenase medium chain (ACADM)] in the colorectal tissue of CAC mice. It also down-regulated Wnt pathway-related proteins [ß-catenin, T-cell factor (TCF), lymphoid enhancer-binding factor (LEF), and matrix metallopeptidase 7 (MMP7)], inhibited the nuclear translocation of the key transcription factor ß-catenin in the Wnt pathway, and suppressed epithelial-to-mesenchymal transition (EMT) activation induced by the Wnt pathway (up-regulated E-cadherin and down-regulated Vimentin). Furthermore, WMP intervention reduced pro-inflammatory factors [interleukin (IL)-6, IL-1ß, and IL-17A] and decreased CCL3/CCR1 axis factors, including CCL3 protein levels and diminished F4/80+CCR1+ positive expressed cells. CONCLUSION: WMP significantly inhibits CAC tumorigenesis by up-regulating PPARα-mediated fatty acid oxidation, inhibiting the Wnt signaling pathway-mediated EMT, and suppressing CCL3/CCR1-mediated inflammatory responses.

Associations of environmental factors with neurodegeneration: An exposome-wide Mendelian randomization investigation.

Neurodegenerative diseases (NDDs) remain a global health challenge. Previous studies have reported potential links between environmental factors and NDDs, however, findings remain controversial across studies and elusive to be interpreted as evidence of robust causal associations. In this study, we comprehensively explored the causal associations of the common environmental factors with major NDDs including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), based on updated large-scale genome-wide association study data through two-sample Mendelian randomization (MR) approach. Our results indicated that, overall, 28 significant sets of exposure-outcome causal association evidence were detected, 12 of which were previously underestimated and newly identified, including average weekly beer plus cider intake, strenuous sports or other exercises, diastolic blood pressure, and body fat percentage with AD, alcohol intake frequency with PD, apolipoprotein B, systolic blood pressure, and forced expiratory volume in 1 s (FEV1) with ALS, and alcohol intake frequency, hip circumference, forced vital capacity, and FEV1 with MS. Moreover, the causal effects of several environmental factors on NDDs were found to overlap. From a triangulation perspective, our investigation provided insights into understanding the associations of environmental factors with NDDs, providing causality-oriented evidence to establish the risk profile of NDDs.

Toxicity studies of condensed fuzheng extract in mice and rats.

Nutritional supplements have been used to improve immune function. Condensed fuzheng extract (CFE) is a well-known traditional Chinese medicine (TCM) formula that is predominantly made from sheep placenta, Astragalus mongholicus Bunge, and Polygonatum kingianum Collett & Hemsl. However, the toxicological profile of CFE has not been determined. In this study, we investigated the acute (14 days) and sub-chronic (90 days) oral toxicities of CFE in mice and rats and the phytochemical composition of CFE. Materials and methods: For the assessment of acute toxicity, 80 ICR mice of both sexes were randomly divided into four groups. Three groups were treated with 4500, 2250 and 1125 mg/kg/d bw CFE daily (n = 10/group per sex) for 14 days; a separate group was used as control. To test the sub-chronic toxicity, male and female Sprague Dawley rats were orally administered 8150, 4075 or 2037 mg/kg bw of CFE for 90 days; a control group was included. Hematological, biochemical, and histopathological markers were tested at the end of the experiment. The chemical composition of CFE was determined by UPLC-HRMS method. Results: In both acute and sub-chronic toxicity studies, no mortalities, indications of abnormality, or treatment-related adverse effects were observed. The LD50 of CFE was higher than 4500 mg/kg. There were no significant changes in the hematological and biochemical data in the treatment group compared with the control group (p > 0.05). Histopathological analyses of the heart, liver, spleen, lungs, kidneys, thymus, testes (male rats) and ovaries (female rats) revealed no anatomical changes of each organ. Phytochemical analysis of CFE revealed the presence of flavonoids (highest abundance), phenols and alkaloids. In conclusion, our results showed that CFE is a safe and non-toxic formula. We also reported phytochemicals in CFE that may possess important pharmacological effects.

Satellites reveal widespread decline in global lake water storage.

Climate change and human activities increasingly threaten lakes that store 87% of Earth's liquid surface fresh water. Yet, recent trends and drivers of lake volume change remain largely unknown globally. Here, we analyze the 1972 largest global lakes using three decades of satellite observations, climate data, and hydrologic models, finding statistically significant storage declines for 53% of these water bodies over the period 1992-2020. The net volume loss in natural lakes is largely attributable to climate warming, increasing evaporative demand, and human water consumption, whereas sedimentation dominates storage losses in reservoirs. We estimate that roughly one-quarter of the world's population resides in a basin of a drying lake, underscoring the necessity of incorporating climate change and sedimentation impacts into sustainable water resources management.

Satellites reveal hotspots of global river extent change.

Rivers are among the most diverse, dynamic, and productive ecosystems on Earth. River flow regimes are constantly changing, but characterizing and understanding such changes have been challenging from a long-term and global perspective. By analyzing water extent variations observed from four-decade Landsat imagery, we here provide a global attribution of the recent changes in river regime to morphological dynamics (e.g., channel shifting and anabranching), expansion induced by new dams, and hydrological signals of widening and narrowing. Morphological dynamics prevailed in ~20% of the global river area. Booming reservoir constructions, mostly skewed in Asia and South America, contributed to ~32% of the river widening. The remaining hydrological signals were characterized by contrasting hotspots, including prominent river widening in alpine and pan-Arctic regions and narrowing in the arid/semi-arid continental interiors, driven by varying trends in climate forcing, cryospheric response to warming, and human water management. Our findings suggest that the recent river extent dynamics diverge based on hydroclimate and socio-economic conditions, and besides reflecting ongoing morphodynamical processes, river extent changes show close connections with external forcings, including climate change and anthropogenic interference.

Condensed Fuzheng extract increases immune function in mice with cyclophosphamide-induced immunosuppression.

Our general purpose was to examine the effect of condensed Fuzheng extract (CFE) on the alleviation of immunosuppression. A mouse model of immunosuppression was established by intraperitoneal injection of CTX. A healthy control group received no CTX and no CFE; different intragastric doses of CFE were administered to three groups of mice for 28 days (4500, 2250, or 1125 mg/kg/day); a negative control received CTX alone, and a positive control received CTX and levamisole hydrochloride. We evaluated the effects of CFE on the immune system organs, cells, and molecules by comparing the different groups. CFE significantly improved immune system organs (spleen and thymus indices and histology), stimulated immune cell activities (number of white blood cells and lymphocytes, phagocytosis of mononuclear phagocytes, proliferation of splenic lymphocytes, antibody formation, and NK cell activity), and increased the levels of immunoglobulins (IgA, IgG, and IgM) and cytokines (IL-2 and IFN-γ). Thus CFE effectively alleviated CTX-mediated immunosuppression and oxidative stress and enhanced the immunological functions of mice.

Role of MRI in characterizing serous borderline ovarian tumor and its subtypes: Correlation of MRI features with clinicopathological characteristics.

PURPOSE: This study aimed to investigate the diagnostic value of MRI in serous borderline ovarian tumor (SBOT), and to determine the MRI features of SBOT and their correlations with clinicopathological characteristics. MATERIALS AND METHODS: A total of 121 patients suspected of SBOT by preoperative MRI and then underwent surgery at our hospital were retrospectively reviewed. The accuracy of MRI in diagnosing SBOT was assessed. MRI features of the SBOT subtypes were compared and their correlations with clinicopathological characteristics were evaluated. RESULTS: SBOT was confirmed by postoperative pathology in 95 patients, including 77 patients with conventional SBOT (SBOT-C) and 18 patients with micropapillary SBOT (SBOT-MP). The accuracy of MRI in diagnosing SBOT was 87.6%. Three MRI morphological patterns of SBOT were identified: (i) mainly solid, (ii) mainly cystic, and (iii) mixed. Branching papillary architecture and internal branching (PA&IB) structures corresponding to multiple branching papillary projections and internal fibrous stalks in tumors were observed in 69.7% of SBOTs on T2-weighted images. MRI findings were consistent with postoperative pathology. Compared with SBOT-C, patients with SBOT-MP were more likely to display elevated cancer antigen 125, bilateral tumors, peritoneal implantation, lymph node metastasis, and advanced tumor staging. No significant differences were observed in MRI features between SBOT-C and SBOT-MP groups. CONCLUSION: MRI has good performance in diagnosing SBOT. MRI findings of SBOT are consistent with clinicopathological characteristics. The PA&IB structure is the characteristic MRI finding of SBOT. Compared to SBOT-C, SBOT-MP tends to display more aggressive clinical behavior, but their MRI features are similar.

Effect of fecal microbiota transplantation in patients with slow transit constipation and the relative mechanisms based on the protein digestion and absorption pathway.

BACKGROUND: Fecal microbiota transplantation (FMT) is considered an effective treatment for slow transit constipation (STC); nevertheless, the mechanism remains unclear. METHODS: In this study, eight patients with STC were selected according to the inclusion and exclusion criteria; they then received three treatments of FMT. The feces and serum of STC patients were collected after each treatment and analyzed by integrating 16 s rRNA microbiome and metabolomic analyses. RESULTS: The results showed that the percentage of clinical improvement reached 62.5% and the rates of patients' clinical remission achieved 75% after the third treatment. At the same time, FMT improved the Wexner constipation scale (WCS), the Gastrointestinal Quality-of-Life Index (GIQLI) and Hamilton Depression Scale (HAMD). Fecal microbiome alpha diversity and beta diversity altered significantly after FMT. Analysis of the 16 s rRNA microbiome showed that the numbers of Bacteroidetes (Prevotell/Bacteroides) and Firmicute (Roseburia/Blautia) decreased, whereas Actinobacteria (Bifidobacterium), Proteobacteria (Escherichia), and Firmicute (Lactobacillus) increased after FMT. The metabolomics analyses showed that the stool of FMT-treated patients were characterized by relatively high levels of N-Acetyl-L-glutamate, gamma-L-glutamyl-L-glutamic acid, Glycerophosphocholine, et al., after FMT. Compared with baseline, the serum of treated patients was characterized by relatively high levels of L-Arginine, L-Threonine, Ser-Arg, Indoleacrylic acid, Phe-Tyr, 5-L-Glutamyl-L-alanine, and lower levels of Erucamide after the treatment. The correlation analysis between the metabolites and gut microbiota showed a significant correlation. For example, L-Arginine was positively correlated with lactobacillus, et al. L-Threonine was positively correlated with Anaerovibrio, Sediminibacterium but negatively correlated with Phascolarctobacterium. Erucamide had significant negative correlations with Sediminibacterium and Sharpea, while being positively correlated with Phascolarctobacterium. Enriched KEGG pathways analysis demonstrated that the protein digestion and absorption pathways gradually upregulated with the increase of FMT frequency. The L-Arginine and L-Threonine were also involved in the pathway. A large amount of Na + was absorbed in the pathway, so that it might increase mucus secretion and electrical excitability of GI smooth muscle. CONCLUSIONS: Therefore, we speculated that FMT changed the patients' gut microbiota and metabolites involved in the protein digestion and absorption pathways, thereby improving the symptoms of STC. Study on the effectiveness and safety of FMT in the treatment of STC. The study was reviewed and approved by Ethics Committee of Tianjin People's Hospital (ChiCTR2000033227) in 2020.

A Global Assessment of Terrestrial Evapotranspiration Increase Due to Surface Water Area Change.

Surface water, which is changing constantly, is a crucial component in the global water cycle, as it greatly affects the water flux between the land and the atmosphere through evaporation. However, the influences of changing surface water area on the global water budget have largely been neglected. Here we estimate an extra water flux of 30.38 ± 15.51 km3/year omitted in global evaporation calculation caused by a net increase of global surface water area between periods 1984-1999 and 2000-2015. Our estimate is at a similar magnitude to the recent average annual change in global evapotranspiration assuming a stationary surface water area. It is also comparable to the estimated trends in various components of the hydrological cycle such as precipitation, discharge, groundwater depletion, and glacier melting. Our findings suggest that the omission of surface water area changes may cause considerable biases in global evaporation estimation, so an improved understanding of water area dynamics and its atmospheric coupling is crucial to reduce the uncertainty in the estimation of future global water budgets.

Recent Changes in Land Water Storage and its Contribution to Sea Level Variations.

Sea level rise is generally attributed to increased ocean heat content and increased rates glacier and ice melt. However, human transformations of Earth's surface have impacted water exchange between land, atmosphere, and ocean, ultimately affecting global sea level variations. Impoundment of water in reservoirs and artificial lakes has reduced the outflow of water to the sea, while river runoff has increased due to groundwater mining, wetland and endorheic lake storage losses, and deforestation. In addition, climate-driven changes in land water stores can have a large impact on global sea level variations over decadal timescales. Here, we review each component of negative and positive land water contribution separately in order to highlight and understand recent changes in land water contribution to sea level variations.

Little impact of Three Gorges Dam on recent decadal lake decline across China's Yangtze Plain.

The ubiquitous lakes across China's Yangtze Plain (YP) are indispensable freshwater resources sustaining ecosystems and socioeconomics for nearly half a billion people. Our recent survey revealed a widespread net decline in the total YP lake inundation area during 2000-2011 (a cumulative decrease of ~10%), yet its mechanism remains contentious. Here, we uncover the impacts of climate variability and anthropogenic activities including i) Yangtze flow and sediment alterations by the Three Gorges Dam (TGD) and ii) human water consumption in agricultural, industrial, and domestic sectors throughout the downstream Yangtze Basin. Results suggest that climate variability is the dominant driver of this decadal lake decline, whereas studied human activities, despite varying seasonal impacts that peak in fall, contribute marginal fraction (~10-20% or less) to the interannual lake area decrease. Given that the TGD impacts on the total YP lake area and its seasonal variation are both under ~5%, we also dismiss the speculation that the TGD might be responsible for evident downstream climate change by altering lake surface extent and thus open water evaporation. Nevertheless, anthropogenic impacts exhibited a strengthening trend during the past decade. Although the TGD has reached its full-capacity water regulation, the negative impacts of human water consumption and TGD-related net channel erosion are already comparable to that of TGD's flow regulation, and may continue to grow as crucial anthropogenic factors to future YP lake conservation.

Novel C-4'' modified azithromycin analogs with remarkably enhanced activity against erythromycin-resistant Streptococcus pneumoniae: the synthesis and antimicrobial evaluation.

Three novel structural series of C-4'' modified azithromycin analogs with two amide groups, which were connected by different alkyl linkage, were designed, prepared and evaluated for their in vitro antibacterial activity against seven phenotypes of respiratory pathogens. Among them, 7d, 8j and 9j, as representatives of corresponding series, exhibited remarkably improved activity against erythromycin-resistant Streptococcus pneumoniae expressing the erm gene, the mef gene, and the erm and mef genes. In addition, 7a-c, 7f-h, 7j, 8d, 8g, 8i, 9a-b and 9i displayed favorable efficacy against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene.