Cl Treatment Research Articles

Chronic β3-AR stimulation activates distinct thermogenic mechanisms in brown and white adipose tissue and improves systemic metabolism in aged mice.

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic β3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Considering that people lose BAT with aging, activation of futile lipid cycling in WAT presents a novel strategy for improving age-related metabolic dysfunction.

Chronic β3 adrenergic agonist treatment improves brain microvascular endothelial function and cognition in aged mice.

Microvascular endothelial dysfunction, characterized by impaired neurovascular coupling, reduced glucose uptake, blood-brain barrier disruption, and microvascular rarefaction, plays a critical role in the pathogenesis of age-related vascular cognitive impairment (VCI). Emerging evidence points to non-cell autonomous mechanisms mediated by adverse circulating milieu (an increased ratio of pro-geronic to anti-geronic circulating factors) in the pathogenesis of endothelial dysfunction leading to impaired cerebral blood flow and cognitive decline in the aging population. In particular, age-related adipose dysfunction contributes, at least in part, to an unfavorable systemic milieu characterized by chronic hyperglycemia, hyperinsulinemia, dyslipidemia, and altered adipokine profile, which together contribute to microvascular endothelial dysfunction. Hence, in the present study, we aimed to test whether thermogenic stimulation, an intervention known to improve adipose and systemic metabolism by increasing cellular energy expenditure, could mitigate brain endothelial dysfunction and improve cognition in the aging population. Eighteen-month-old old C57BL/6J mice were treated with saline or CL (β3-adrenergic agonist) for 6 weeks followed by functional analysis to assess endothelial function and cognition. CL treatment improved neurovascular coupling responses and rescued brain glucose uptake in aged animals. In addition, CL treatment also attenuated blood-brain barrier leakage and associated neuroinflammation in the cortex of aged animals. More importantly, these beneficial changes in microvascular function translated to improved cognitive performance in radial arm water maze and Y-maze tests. Our results suggest that β3-adrenergic agonist treatment improves multiple aspects of brain microvascular endothelial function and can be potentially repurposed for treating age-associated cognitive decline.

The metabolic benefits of thermogenic stimulation are preserved in aging.

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the US (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic β3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Our study provides foundational evidence for targeting adipose thermogenesis to improve age-related metabolic dysfunction.

Review of Leishmaniasis Treatment: Can We See the Forest through the Trees?

There are three known clinical syndromes of leishmaniasis: cutaneous (CL), mucocutaneous (MCL), and visceral disease (VL). In MCL and VL, treatment must be systemic (either oral or intravenous), while CL treatment options vary and include observation-only localized/topical treatment, oral medications, or parenteral drugs. Leishmaniasis treatment is difficult, with several factors to be considered. First, the efficacy of treatments varies among different species of parasites prevalent in different areas on the globe, with each species having a unique clinical presentation and resistance profile. Furthermore, leishmaniasis is a neglected tropical disease (NTD), resulting in a lack of evidence-based knowledge regarding treatment. Therefore, physicians often rely on case reports or case series studies, in the absence of randomized controlled trials (RCT), to assess treatment efficacy. Second, defining cure, especially in CL and MCL, may be difficult, as death of the parasite can be achieved in most cases, while the aesthetic result (e.g., scars) is hard to predict. This is a result of the biological nature of the disease, often diagnosed late in the course of disease (with possible keloid formation, etc.). Third, physicians must consider treatment ease of use and the safety profile of possible treatments. Thus, topical or oral treatments (for CL) are desirable and promote adherence. Fourth, the cost of the treatment is an important consideration. In this review, we aim to describe the diverse treatment options for different clinical manifestations of leishmaniasis. For each currently available treatment, we will discuss the various considerations mentioned above (efficacy, ease of use, safety, and cost).

Fungal sinusitis of the maxillary sinus

The retrospective study included a group of 36 patients, 20 women and 16 men with an average age of 40 years in the period 2016— 2021, in which the diagnosis of fungal sinusitis was established and confirmed postoperatively with the postoperative surveillance period not less than 5 years. The patients were divided into two research groups. The first group consisted of 16 patients, aged between 24 and 58 years, who underwent the radical Caldwell–Luc maxillary sinus cure. The second group consisted of 20 patients, aged between 25 and 58 years, of which 5 men and 15 women operated by means of functional endoscopic surgery of the maxillary sinus. The comparative analysis of MSM treatment methods proved that both FESS and CL treatment methods show equal efficiency, they can be used in certain clinical situations at the discretion of specialists.

Efficacy of Peracetic Acid and Chlorine on the Reduction of Shiga Toxin-producing Escherichia coli and a Nonpathogenic E. coli Strain in Preharvest Agricultural Water

Produce-borne outbreaks of Shiga toxin-producing Escherichia coli (STEC) linked to preharvest water emphasize the need for efficacious water treatment options. This study quantified reductions of STEC and generic E. coli in preharvest agricultural water using commercially available sanitizers. Water was collected from two sources in Virginia (pond, river) and inoculated with either a seven-strain STEC panel or environmental generic E. coli strain TVS 353 (∼9 log10 CFU/100 mL). Triplicate inoculated water samples were equilibrated to 12 or 32°C and treated with peracetic acid (PAA) or chlorine (Cl) [low (PAA:6ppm, Cl:2–4 ppm) or high (PAA:10 ppm, Cl:10–12 ppm) residual concentrations] for an allotted contact time (1, 5, or 10 min). Strains were enumerated, and a log-linear model was used to characterize how treatment combinations influenced reductions. All Cl treatment combinations achieved a ≥3 log10 CFU/100 mL reduction, regardless of strain (3.43 ± 0.25 to 7.05 ± 0.00 log10 CFU/100 mL). Approximately 80% (19/24) and 67% (16/24) of PAA treatment combinations achieved a ≥3 log10 CFU/100 mL for STEC and E. coli TVS 353, respectively. The log-linear model showed contact time (10 > 5 > 1 min) and sanitizer type (Cl > PAA) had the greatest impact on STEC and E. coli TVS 353 reductions (p < 0.001). E. coli TVS 353 in water samples was more resistant to sanitizer treatment (p < 0.001) indicating applicability as a good surrogate. Results demonstrated Cl and PAA can be effective agricultural water treatment strategies when sanitizer chemistry is managed. These data will assist with the development of in-field validation studies and may identify suitable candidates for the registration of antimicrobial pesticide products for use against foodborne pathogens in preharvest agricultural water treatment.

Limited role for hyperammonemia in the progression of diet-induced nonalcoholic steatohepatitis.

To determine whether hyperammonemia has a direct impact on steatohepatitis in mice fed with a high-fat diet (HFD). Male C57BL/6 mice were divided into two groups receiving either chow diet or HFD. After 12-week NASH modeling, hyperammonemia was induced by intragastric administration of ammonium chloride solution (NH4 Cl) or liver-specific carbamoyl phosphate synthetase 1 (Cps1) knockdown. In vitro experiments were performed in HepG2 cells induced by free fatty acid (FFA) and NH4 Cl. NH4 Cl administration led to increased levels of plasma and hepatic ammonia in NASH mice. NH4 Cl-induced hyperammonemia did not influence liver histological changes in mice fed with HFD; however, elevated plasma cholesterol level, and an increasing trend of liver lipid content were observed. No significant effect of hyperammonemia on hepatic inflammation and fibrosis in NASH mice was found. In vitro cell experiments showed that NH4 Cl treatment failed to increase the lipid droplet content and the expressions of de novo lipogenesis genes in HepG2 cells induced by FFA. The knockdown of Cps1 in HFD-fed mice resulted in elevated plasma ammonia levels but did not cause histological change in the liver. Our study revealed a limited role of ammonia in aggravating the progression of NASH. Further studies are needed to clarify the role and mechanism of ammonia in NASH development.

Comparative single-cell profiling reveals distinct cardiac resident macrophages essential for zebrafish heart regeneration.

Zebrafish exhibit a robust ability to regenerate their hearts following injury, and the immune system plays a key role in this process. We previously showed that delaying macrophage recruitment by clodronate liposome (-1d_CL, macrophage-delayed model) impairs neutrophil resolution and heart regeneration, even when the infiltrating macrophage number was restored within the first week post injury (Lai et al., 2017). It is thus intriguing to learn the regenerative macrophage property by comparing these late macrophages vs. control macrophages during cardiac repair. Here, we further investigate the mechanistic insights of heart regeneration by comparing the non-regenerative macrophage-delayed model with regenerative controls. Temporal RNAseq analyses revealed that -1d_CL treatment led to disrupted inflammatory resolution, reactive oxygen species homeostasis, and energy metabolism during cardiac repair. Comparative single-cell RNAseq profiling of inflammatory cells from regenerative vs. non-regenerative hearts further identified heterogeneous macrophages and neutrophils, showing alternative activation and cellular crosstalk leading to neutrophil retention and chronic inflammation. Among macrophages, two residential subpopulations (hbaa+ Mac and timp4.3+ Mac 3) were enriched only in regenerative hearts and barely recovered after +1d_CL treatment. To deplete the resident macrophage without delaying the circulating macrophage recruitment, we established the resident macrophage-deficient model by administrating CL earlier at 8 d (-8d_CL) before cryoinjury. Strikingly, resident macrophage-deficient zebrafish still exhibited defects in revascularization, cardiomyocyte survival, debris clearance, and extracellular matrix remodeling/scar resolution without functional compensation from the circulating/monocyte-derived macrophages. Our results characterized the diverse function and interaction between inflammatory cells and identified unique resident macrophages prerequisite for zebrafish heart regeneration.

Cutaneous leishmaniasis in Kutaber District, Ethiopia: Prevalence, sand fly fauna and community knowledge, attitude and practices

BackgroundCutaneous leishmaniasis (CL) affects 25% of the population living in the highlands of Ethiopia. CL intervention has not decreased the number of leishmaniasis patients. A cross-sectional study was conducted to determine CL prevalence, community’s knowledge, attitude and practices (KAP), and the sand fly fauna in Kutaber district, northeast Ethiopia. MethodsA retrospective, community-based cross-sectional study was conducted in Boru Meda Hospital from December 2014–March 2021 to study CL prevalence of Kutaber district. A Pre-tested, well-structured questionnaire was used to collect data on the participants' socio-demographic characteristics, KAP towards CL and knowledge about sand fly vectors. Chi-square test and logistic regression analysis were used in the study, and data were analyzed using SPSS version 23 (p < 0.05). ResultsA total of 10,002 (14.02%), of which 71,325 samples were confirmed as positive for CL. The infection rate of CL in females (7.1%) was a little bit higher than males (7.0%). More cases were recorded among 15–29 age category. The study also revealed that 77.1% of the respondents had poor knowledge about CL treatment, prevention, clinical presentation and disease transmission. Farmers tended to have poorer knowledge about sand flies than non-workers and students (32.7 vs. 35 and 44.1%; P = 0.049). Housewives had poorer knowledge about sand flies than farmers and workers (22.2 vs. 32.7 and 33.3%; P = 0.023). Phlebotomus longipes comprised the highest composition (80%) of the sand fly species identified in Kutaber district. ConclusionsThe data showed that the community had poor knowledge about CL, vector, and transmission mode. CL preventive measures were prevalent, implying the need to raise CL awareness. Phlebotomus longipes was identified as the most dominant sand fly species which accounted for CL. The findings can be used in developing an effective control strategy to reduce CL transmission in the study area and elsewhere in Ethiopia.

Microbiological and physicochemical quality of tilapia fillets treated with ozone and chlorine solution and stored under refrigeration

Fish are foods of high nutritional value for the human diet. However, they deteriorate easily due to microbial activity. The combined action of sanitizing solutions on fillets, the antimicrobial and physicochemical effects of aqueous ozone and chlorine used to wash fillets were investigated immediately after application and during storage. The fillets were treated with demineralized water (control), 5 ppm chlorine solution (Cl), 5 ppm ozone solution (Oz) or 5 ppm chlorine solution with 5 ppm ozone (Cl+Oz). The proximate composition and pH of the fillets were not altered immediately after treatment. The mesophilic count decreased by 0.49 log CFU/g at Cl and 0.56 log CFU/g at Cl+Oz. The Cl treatment showed lower values of lipid oxidation, and the control and Cl treatments showed lower values for total volatile base nitrogen (TVB-N). The treatments did not differ from each other during storage; increases in lipids, TVB-N, lipid oxidation and mesophilic and psychrotrophic counts, as well as a reduction in proteins, were observed. These results were expected due to microbial degradation during storage. The results indicated that the combined action of the sanitizers regulated microbial activity better than the control but was not able to promote the shelf life of the product.

78-OR: Adipose Lysosomal Acid Lipase Is Indispensable for Starvation- and Cold-Induced Lipolysis

Lipolysis is a metabolic process by which triglycerides (TGs) are hydrolyzed into free fatty acids (FFAs) and glycerol to serve as fuels during fasting or cold-induced nonshivering thermogenesis. Cytoplasmic lipases are thought to be the predominant mechanism of liberating FFA from lipid stores. However, lysosomes also contain lipolytic activity via lysosomal acid lipase (Lipa). In adipocytes, the primary lipid-storing cell in the body with significant involvement in metabolism, the roles of Lipa and lysosomal lipolysis are unclear. We found that Lipa expression increases in the adipose tissue of mice in response to fasting, cold exposure, and CL316,243 (CL) treatment, a mimic of cold-induced lipolysis. Similar results were obtained in cultured adipocytes with nutrient-depletion or isoproterenol treatment, mimicking fasting or cold, respectively. Treatment of C57BL/6J mice with Lalistat (Lali), a specific inhibitor of Lipa, impaired thermogenesis, as evidenced by suppression of cold- and fasting-enhanced increases in plasma FFAs levels during cold exposure or CL treatment. Lipolysis was inhibited by Lali treatment in cultured adipocytes and fresh adipose tissue of C57BL/6J mice under fasting- or cold-mimic conditions. To conduct more detailed in vivo studies, we developed adipose-specific Lipa knockout (A-Lipa) mice, which exhibited lower plasma FFAs when challenged with fasting, cold exposure, or CL treatment. Furthermore, A-Lipa mice were significantly thermogenesis-impaired with exposure to cold or treatment with CL. To determine whether autophagy is involved in these phenomena, adipose-specific Atg5 knockout (A-Atg5) mice were challenged with fasting, cold exposure, or CL treatment. As was found in A-Lipa mice, A-Atg5 mice had lower levels of plasma FFAs and obliteration of stress-induced thermogenesis. Overall, our data suggest a previously unrecognized contribution of lysosomal lipolysis in adipocytes, possibly involving autophagy-related lipophagy. Disclosure Y.Yeh: None. B.Razani: None. Funding American Heart Association (897628); National Institutes of Health (DK131188)

Sleep Quality and Quantity in Caregivers of Children with Type 1 Diabetes Using Closed-Loop Insulin Delivery or a Sensor-Augmented Pump

Introduction. Parents of children living with type 1 diabetes (T1D) often report short and/or poor quality sleep. The development of closed-loop systems promises to transform the management of T1D. This study compared sleep quality and quantity in caregivers of children using a closed-loop system (CL) or sensor-augmented pump (SAP) therapy. Method. Data from sleep diaries, accelerometers, and questionnaires were provided by forty parents (classified as caregiver 1 (main analyses) or 2 (supplementary analyses) based on their contribution towards treatment management) of 21 very young children aged 1 to 7 years living with T1D (mean age: 4.7 (SD = 1.7)). Assessments were made at a single post-randomisation time point when the child was completing either the 16-week CL arm (n = 10) or the 16-week SAP arm (n = 11) of the main study. Results. Overall, there was a mixed pattern of results and group differences were not statistically significant at the p &lt; 0.05 level. However, when we consider the direction of results and results from caregiver 1, sleep diary data showed that parents of the CL (as compared to the SAP) group reported a shorter sleep duration but better sleep quality, fewer awakenings, and less wake after sleep onset (WASO). Actiwatch data showed that caregiver 1 of the CL (as compared to the SAP) group had a shorter sleep latency; greater sleep efficiency; and less wake after sleep onset. Results from the Pittsburgh Sleep Quality Index also showed better sleep quality for caregiver 1 of the CL group as compared to the SAP group. Conclusions. Results from this study suggest that sleep quality and quantity in parents of children using CL were not significantly different to those using SAP. Considering effect sizes and the direction of the non-significant results, CL treatment could be associated with better sleep quality in the primary caregiver. However, further research is needed to confirm these findings. This trial is registered with NCT05158816.

Effects of Long-Term Application of Cl-Containing Fertilizers on Chloride Content and Acidification in Brown Soil

Chloride is a necessary micronutrient for plant growth, and with long-term application of chlorine-containing fertilizer, significant amounts of Cl− are introduced into farmland ecosystems. Many recent studies have focused on chlorinated fertilizers’ effects on crop yield and quality, while few studies have examined their effects on soil properties. To determine the effects of the long-term application of chlorinated fertilizer on soil Cl− ions and soil acidification, we conducted a 35 year long-term study of chlorine-containing fertilizer in a peanut–corn rotation (since 1984). We chose three of eight experimental treatments: (1) no fertilization (CK), (2) urea + monoammonium phosphate + potassium chloride (lower Cl), and (3) urea + ammonium chlorophosphite + potassium chloride (higher Cl). We measured the Cl− concentrations, pH, cation exchange capacity (CEC), exchangeable H+ and Al3+, and exchangeable alkali ions (K+, Na+, Ca2+, and Mg2+) at different soil depths (0–20, 20–40, and 40–60 cm). Compared to CK, chlorine-containing fertilizer application significantly increased the content of Cl− in the soil profile. Compared to the control, the Cl− content of lower Cl treatment of 0–20, 20–40, and 40–60 cm soil layers increased 11.08, 9.01, 15.21 mg kg−1 respectively, and the higher Cl treatment increased 38.71, 34.71, 32.05 mg kg−1 respectively. Compared to CK, chlorine-containing fertilizer application significantly reduced the soil pH by 0.41, 0.17, and 0.25 and 1.25, 0.91, and 0.88, respectively, in the 0–20, 20–40, and 40–60 cm soil layers. The higher chlorine treatment significantly increased the exchangeable Al3+ content in the 0–20, 20–40, and 40–60 cm soil layers by 2.79, 1.64, and 0.94 mg kg−1, respectively, significantly increasing the risk of aluminum toxicity. Furthermore, the soil exchangeable Ca2+ and Mg2+ contents and soil base saturation were significantly reduced. Although the Cl− content in the high-chlorine-treated soil was far from endangering crop growth, it accelerates soil acidification and the loss of base ions and increases the risk of Al3+ toxicity, which will not only affect the topsoil, but also the subsoil. Therefore, the long-term application of high content chloride fertilizers should be avoided in agricultural production.

Combination Curcuma longa and Phyllanthus niruri Extract Potentiate Antiproliferative in Triple Negative Breast Cancer MDAMB-231 Cells.

Triple negative breast cancer cells (TNBC) are a small part of cancer-inducing cells in breast cancer, which are characterized by high metastatic and self-renewal. Self-renewal has the ability to renew itself and loses control of proliferation. Curcuma longa extract (CL) and Phyllanthus niruri extract (PN) known to have anti-proliferative effects on cancer cells. However, the effects of combination CL and PN on TNBC proliferation still unclear. This study aimed to evaluate the antiproliferative effects of the combination CL and PN on TNBC MDAMB-231 and attempted to elucidate the underlying molecular mechanisms. The dried rhizomes of Curcuma longa and the herbs of Phyllanthus niruri were macerated with ethanol for 72 h.The antiproliferative and synergistic effects of combination CL and PN were investigated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Combination index values were calculated using CompuSyn (ComboSyn, Inc, Paramus, NJ). The cell cycle and apoptosis assay were determined by propidium iodide (PI) and PI-AnnexinV assay under flow cytometer, respectively. The intracellular ROS levels were evaluated using 2',7'-Dichlorodihydrofluorescein diacetate (DCFDA) assay. The mRNA expressions of proliferation-related genes in the cells were determined using bioinformatic assay. The CL and PN single treatment caused a potent and dose-dependent decrease in the percentage of viable cells with IC50 value of 13 μg/mL and 45 μg/mL for 24 h, respectively. The combination index values of the different combinations ranged from 0.08 - 0.90, indicating slightly strong to very strong synergistic effects. The combination of CL and PN also remarkably induced the S- and G2/M-phases cell cycle arrest that leading to apoptosis induction. Furthermore, the combination of CL and PN treatment induced the intracellular reactive oxygen species (ROS) levels. Mechanistically, the AKT1, EP300, STAT3 and EGFR signaling as potential targets of combination CL and PN in antiproliferation and antimetastatic of TNBC. The combination of CL and PN exerted promising antiproliferative effects in TNBC. Therefore, CL and PN may be considered a potential source for the development of potent anticancer drugs for breast cancer treatment.

Towards effective natural anthraquinones to mediate antimicrobial photodynamic therapy of cutaneous leishmaniasis

BackgroundCutaneous leishmaniasis (CL) is an important tropical neglected disease with broad geographical dispersion. The lack of effective drugs has raised an urgent need to improve CL treatment, and antimicrobial photodynamic therapy (APDT) has been investigated as a new strategy to face it with positive outcomes. Natural compounds have emerged as promising photosensitizers (PSs), but their use in vivo remains unexplored. PurposeIn this work, we investigated the potential of three natural anthraquinones (AQs) on CL induced by Leishmania amazonensis in BALB/c mice. Study Design/Methods: Animals were infected and randomly divided into four groupsCG (control, non-treated group), G5ClSor-gL (treated with 5-chlorosoranjidiol and green LED, 520±10 nm), GSor-bL and GBisor-bL (treated with soranjidiol and bisoranjidiol, respectively, exposed to violet-blue LED, 410±10 nm). All AQs were assayed at 10 μM and LEDs delivered a radiant exposure of 45 J/cm2 with an irradiance of 50 mW/cm2. We assessed the parasite burden in real time for three consecutive days. Lesion evolution and pain score were assessed over 3 weeks after a single APDT session. ResultsG5ClSor-gL was able to sustain low levels of parasite burden over time. Besides, GSor-bL showed a smaller lesion area than the control group, inhibiting the disease progression. ConclusionTaken together, our data demonstrate that monoAQs are promising compounds for pursuing the best protocol for treating CL and helping to face this serious health problem. Studies involving host-pathogen interaction as well as monoAQ-mediated PDT immune response are also encouraged.

Beta-adrenergic agonist induces unique transcriptomic signature in inguinal white adipose tissue.

Activation of thermogenic adipose tissue depots has been linked to improved metabolism and weight loss. To study the molecular regulation of adipocyte thermogenesis, we performed RNA-Seq on brown adipose tissue (BAT), gonadal white adipose tissue (gWAT), and inguinal white adipose tissue (iWAT) from mice treated with β3-adrenoreceptor agonist CL316,243 (CL). Our analysis revealed diverse transcriptional profile and identified pathways in response to CL treatment. Differentially expressed genes (DEGs) in iWATCL were associated with the upregulation of pathways involved in cellular immune responses and with the upregulation of the browning program. We identified 39 DEGs in beige adipose which included certain heat shock proteins (Hspa1a and Hspa1b), and others suggesting potential associations with browning. Our results highlight transcriptional heterogeneity across adipose tissues and reveal genes specifically regulated in beige adipose, potentially aiding in identifying novel browning pathways.

The Therapeutic Effects of Curcumin-coated Gold Nanoparticle Against Leishmania Major Causative Agent of Zoonotic Cutaneous Leishmaniasis (ZCL): An In Vitro and In Vivo Study

We synthesized and characterized curcumin-coated gold nanoparticles (Cur@AuNPs) and investigated their stability, cytotoxicity, leishmanicidal activity in in vitro and in in vivo experiments. Cur@AuNPs synthesized through a simple one-pot green chemistry technique. The in vitro leishmanicidal activity of curcumin-coated gold nanoparticles against extracellular promastigotes and intracellular amastigotes of protozoan parasite Leishmania major (L. major) was determined by applying the tetrazolium reduction colorimetric quantitative MTT technique. For in vivo assessment, the footpad lesion size and parasite burden in two infection site organs including lymph nodes and footpads of susceptible BALB/c mice infected with L. major were measured. Mice immune responses in all study groups were quantified by measuring the levels of gamma interferon (IFN-γ) and interleukin-4 (IL-4). Viability of Leishmania promastigotes significantly diminished with the inhibition in promastigotes growth (IC50) of 64.79μg/mL and 29.89μg/mL for 24h and 48h, respectively. In vitro nanoparticles treatment efficiently cleared the L. major amastigotes explanted in macrophages but had no harmful toxicity on the mice cells. In the in vivo condition, in the treated infected BALB/c mice the CL lesion size, Leishmania parasite burden, and IL-4 were decreased, while IFN-γ was significantly increased. The results suggest that Cur@AuNP was an effective compound against Leishmania parasite in vitro and in vivo, efficiently induced T-helper 1 (Th1) responses and augmented host cellular immune responses, and ending in a reduced Leishmania parasite burden. Therefore, it may be identified as a novel potential therapeutic approach for the local therapy of zoonotic CL treatment with high cure rates.

Effect of ionic liquids on the microstructure and combustion performance of Shengli lignite.

To ensure the safe transportation and efficient utilisation of lignite, it is important to inhibit its spontaneous combustion. In this study, Shengli lignite (SL+) was used as the research object and ionic liquids (ILs) were used to pretreat the lignite to investigate their effect on the combustion performance of lignite. On this basis, the relationship between the structure and combustion performance of lignite with different structures (heat treatment, oxidation) after ILs treatment was investigated. Results indicated that the combustion of lignite treated with ILs shifted towards higher temperatures. The most pronounced effect was observed in coal samples treated with [BMIM]Cl (1-butyl-3-methylimidazolium chloride), with the maximum combustion rate corresponding to a temperature increase of approximately 57 °C compared to that of the untreated lignite. For the heat-treated lignite, the temperature corresponding to the maximum combustion rate was approximately 38 °C higher than that of the untreated lignite. After [BMIM]Cl treatment, the combustion performance of the heat-treated lignite changed very slightly. In contrast, for oxidised lignite, the temperature corresponding to the maximum combustion rate decreased by approximately 54 °C compared with that of the untreated lignite and increased by approximately 135 °C after treatment with [BMIM]Cl. The characterisation results show that the content of aliphatic hydrogen and oxygen-containing functional groups decreased in the heat-treated lignite, while the content of hydroxyl and carboxyl groups increased in the oxidised lignite. The microstructure of the heat-treated lignite after [BMIM]Cl treatment changed slightly. In contrast, in the oxidised lignite after [BMIM]Cl treatment, the content of hydroxyl and carboxyl groups decreased, whereas the content of ether (C-O-) structures increased. The increased content of ether (C-O-) structures improved the stability of the coal samples. It is believed that the inhibition of lignite combustion is mainly attributed to the high stability of the ether (C-O-) structures. The kinetic analysis demonstrated that the ILs treatment increased the activation energy of lignite combustion.

Effect of Curcuma longa extract on serum inflammatory markers and MRI-based synovitis in knee osteoarthritis: secondary analyses from the CurKOA randomised trial

BackgroundCurcuma longa (CL) extract is modestly effective for relieving knee symptoms in knee osteoarthritis (OA) patients; however, its mechanism of action is unclear. PurposeWe aimed to determine the effects of CL treatment on serum inflammatory markers over 12 weeks and to explore its potential effects on synovitis assessed by contrast-enhanced magnetic resonance imaging (CE-MRI) of the knee. MethodsSecondary analyses were conducted on the CL for knee OA (CurKOA) trial, which compared CL (n = 36) and placebo (n = 34) over 12 weeks for the treatment of knee OA. Systemic inflammatory markers (TNFα, IL6, and hsCRP) and a cartilage extracellular matrix degradative enzyme (MMP-3) were measured. A subgroup of participants (CL, n = 7; placebo, n = 5) underwent CE-MRI at baseline and a 12-week follow-up. ResultsOver 12 weeks, there were no between-group differences in change in hsCRP, IL-6, and TNFα levels. MMP-3 levels decreased in both CL (-1.31 ng/ml [95%CI: -1.89 to -0.73]) and placebo (-2.34 ng/ml [95%CI: -2.95 to -1.73]) groups, with the placebo group having a slightly greater decrease (1.03 ng/ml [95%CI: 0.19 to 1.88]). Most (10 of 12) sub-study participants had normal synovial thickness scores at baseline. One participant had mild synovitis in each of the placebo and CL groups. Synovitis status was stable for all except two participants, one each in the CL and placebo group, whose synovitis score increased. ConclusionThis is the first study that explored the effect of CL treatment on local and systemic inflammation using biochemical markers and CE-MRI outcomes on knee OA patients. Secondary analyses from this pilot study suggest that CL is unlikely to have clinically significant effects on systemic (inflammatory and cartilage) or local synovitis (CE-MRI) biomarkers compared to placebo. The mechanism of action for CL effect on pain remains unclear.

Comparative effects of different potassium sources on soluble sugars and organic acids in tomato

Soluble sugars and organic acids are mainly decisive factor of flavor quality in tomato. Potassium (K), an essential macroelement, plays key roles in regulation of plant growth, stress responses and fruit quality. However, the comparative effects of different K fertilizer on soluble sugars and organic acids accumulation and the differential mechanisms are still unknown. The aim of this study was to investigate how K fertizliers (K_Cl, K_S) affect the accumulations of soluble sugars and organic acids in tomato fruits. The results indicated that K applications improved fruit flavor quality of tomato, as supported by the increased concentrations of soluble solid, titratable acid, fructose, glucose, sucrose (Suc), citric acid (CA) and malic acid (MA). Further study showed that K application increased the accumulations of soluble sugars by improving Suc metabolism, sink strength and Suc transport due to the increased expressions of Suc-metabolizing enzyme genes and SlSWEETs and SlSUTs in tomato. K applications increased the accumulations of MA and CA by improving CA synthesis and TCA cycle due to the increased expressions CA-metabolizing enzyme genes. Moreover, more Suc of leaves were transferred into fruits in K4_Cl treatment, which was supported by the lower concentrations of soluble sugars and higher expressions of SlSUT1 and SlSWEET11b in leaves. More carbohydrates were allocated to form yield and metabolic substrate in K4_S treatment, which was supported by the higher expressions of SlSUT4 and more differential metabolic pathway in fruits. Finally, the carbohydrates transports and allocations were involved in the differential mechanisms of soluble sugar accumulations in response to K_S and K_Cl in tomato.