Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly.

Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) machinery in differentiated glioma cells. PTEN was specifically succinated at cysteine (C) 211 in GSCs compared with matched differentiated glioma cells. Isotope tracing coupled with mass spectrometry analysis confirmed that fumarate, generated by adenylosuccinate lyase (ADSL) in the de novo purine synthesis pathway that is highly activated in GSCs, promoted PTEN C211 succination. This modification abrogated the interaction between PTEN and MMS19, reactivating the CIA machinery pathway in GSCs. Functionally, inhibiting PTEN C211 succination by reexpressing a PTEN C211S mutant, depleting ADSL by shRNAs, or consuming fumarate by the US Food and Drug Administration-approved prescription drug N-acetylcysteine (NAC) impaired GSC maintenance. Reexpressing PTEN C211S or treating with NAC sensitized GSC-derived brain tumors to temozolomide and irradiation, the standard-of-care treatments for patients with glioblastoma, by slowing CIA machinery-mediated DNA damage repair. These findings reveal an immediately practicable strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC.

Bifunctional cysteine gold nanoclusters for ß-amyloid fibril inhibition and fluorescence imaging: a distinctive approach to manage Alzheimer's disease.

Alzheimer's disease (AD) is a progressive complex neurodegenerative disorder affecting millions of individuals worldwide. Currently, there is no effective treatment for AD. AD is characterized by the deposition of amyloid plaques/fibrils. One major strategy for managing this disease is by slowing the progression of AD using different drugs which could potentially limit free-radical formation, oxidative stress and lipid peroxidation and promote the survival of neurons exposed to ß-amyloid. Inhibition of amyloid fibrillization and clearance of amyloid plaques/fibrils are essential for the prevention and treatment of AD. The thiophilic interaction between the side chain of an aromatic residue in a polypeptide and a sulphur atom of the compound can effectively inhibit amyloid fibril formation. In this work, we have synthesized cysteine-capped gold nanoclusters (Cy-AuNCs) which exhibit inherent red emission and can disintegrate amyloid fibrils through the aforementioned thiophilic interactions. Herein, we also used molecular docking to study the thiophilic interactions between the sulphur atom of Cy-AuNCs and the aromatic rings of the protein. Finally, the gold cluster was functionalized with a brain targeting molecule, Levodopa (AuCs-LD), to specifically target the brain and to facilitate passage through the blood brain barrier (BBB). Both Cy-AuNCs and AuCs-LD showed good biocompatibility and the inherent fluorescence properties of nanoclusters enabled real time imaging. The efficacy of the nanoclusters to disintegrate amyloid fibrils and their ability to cross the BBB were demonstrated both in vitro and in vivo in the BBB model and the AD animal model respectively. Our results imply that nanoparticle-based artificial molecular chaperones may offer a promising therapeutic approach for AD.

Broad-Spectrum Anti-Flavivirus Activity and Chemistry of Compounds Containing Sulfur and Oxygen Chalcogens.

Sulfur and oxygen containing-compounds are a relevant class of derivatives that is constantly growing due to their wide range of pharmacological activity, including the antiviral one. As proof of this, there are several FDA approved antiviral compounds having sulfur and oxygen in their structures. Among RNA viruses, the flavivirus genus (e.g. Dengue, West Nile, Yellow Fever and Zika viruses) holds a relevant place within zoonotic pathogens and thus flavivirus infections are considered a growing risk for the public health. As a consequence, the drug discovery process aimed at identify new anti- flavivirus agents is of great relevance and will help to find effective therapies not available yet. One of the most alarming features of flaviviruses is their ability to co-infect the host, thus aggravating the symptoms of the disease. Therefore, finding compounds endowed with a broad-spectrum anti-flavivirus activity is now becoming a pressing need. In this review, we describe the most promising compounds having both sulfur and oxygen in their structures characterized by a broad-spectrum activity against different flaviviruses. Furthermore, the synthetic procedures applied for the preparation of the described derivatives are also reported. Readers can be inspired by the contents of this review to design and synthesize more effective anti-flavivirus agents as well as to select viral or host targets to achieve an antiviral activity as broadly as possible.

Refractory Helicobacter pylori infection and the gastric microbiota.

Background: Curing refractory Helicobacter pylori infection is difficult. In addition, there is currently no research on the gastric microbiota of refractory H. pylori infection. Methods: We designed a clinical retrospective study involving 32 subjects divided into three groups: 1. nAGHp.a, treatment-naïve patients with H. pylori infection; 2. nAGHp.b, H. pylori-negative patients; and 3. EFHp.a, patients with refractory H. pylori infection. Gastric mucosal samples from the biobank of our research center were collected for 16S rRNA sequencing analysis and bacterial functions were predicted via PICRUSt. Results: There were significant differences between the H. pylori- positive group and the H. pylori-negative group in species diversity, gastric microbiota structure, and bacterial function. The beneficial Lactobacillus in the H. pylori-positive group were significantly enriched compared with those in the refractory H. pylori infection group. The bacterial interaction network diagram suggested that the microbiota interactions in the refractory H. pylori infection group decreased. The gastric microbiota of the refractory H. pylori infection group was enriched in the pathways of metabolism and infectious diseases (energy metabolism, bacterial secretion system, glutathione metabolism, protein folding and associated processing, sulphur metabolism, membrane and intracellular structural molecules, lipopolysaccharide biosynthesis, ubiquinone and other terpenoid-quinone biosynthesis, inorganic ion transport and metabolism, and metabolism of cofactors and vitamins) when compared with the H. pylori-positive group without treatment based on PICRUSt analysis. Conclusion: Significant alterations occurred in the gastric microbiota when eradication of H. pylori failed multiple times. A history of eradication of multiple H. pylori infections leads to an imbalance in the gastric mucosal microbiota to a certain extent, which was mainly reflected in the inhibition of the growth of beneficial Lactobacillus in the stomach. Patients with refractory H. pylori infection may be at a higher risk of developing gastric cancer than other H. pylori-positive patients.

Co-administration of sodium hydrosulfide and tadalafil modulates hypoxia and oxidative stress on bladder dysfunction in a rat model of bladder outlet obstruction.

PURPOSE: This study aimed to assess the possible healing effect of combination treatment with a hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS) plus tadalafil on partial bladder outlet obstruction (PBOO)-induced bladder dysfunction. MATERIALS AND METHODS: A total of 75 male Sprague-Dawley rats aged 10-wk and 300-350g were divided into five groups; control; PBOO; PBOO+NaHS (5.6mg/kg/day, i.p., 6-wk); PBOO+tadalafil (2mg/kg/day, oral, 6-wk) and PBOO+NaHS+tadalafil. PBOO was created by partial urethral ligation. 6 weeks after obstruction, the in vitro contractile responses of the detrusor muscle and Western blotting, H2S and malondialdehyde assay were performed in bladder tissues. RESULTS: There was an increase in bladder weight(p<0.001) and a decrease in contractile responses to KCL(p<0.001), carbachol(p<0.01), electrical field stimulation(p<0.05) and ATP (p<0.001) in the detrusor smooth muscle of obstructed rats which was normalized after the combination treatment. Cystathionine γ-lyase and cystathionine ß-synthase, and nuclear factor kappa B protein levels did not significantly differ among groups. The obstruction induced decrement in 3-mercaptopyruvate sulfur transferase protein expression(p<0.001) and H2S levels(p<0.01) as well as increment in protein expressions of neuronal nitric oxide synthase (NO, p<0.001), endothelial NOS (p<0.05), inducible NOS(p<0.001), hypoxia-inducible factor 1-alpha (p<0.01), and malondialdehyde levels (p<0.01), when combined treatment entirely normalized. CONCLUSIONS: Combination therapy has beneficial effects on bladder dysfunction via regulating both H2S and nitric oxide pathways as well as downregulation of oxidative stress and hypoxia. The synergistic effect of H2S and nitric oxide is likely to modulate bladder function, which supports the combined therapy for enhancing clinical outcomes in men with BPH/LUTS.

Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS-MAPK Pathway Inhibition in Pancreatic Cancer.

The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition of RAS-MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins. Under baseline conditions, c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fine-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-MYC downregulation and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopurified lysosomes uncovered reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron-sulfur cluster protein synthesis and enhanced mitochondrial respiration. Accordingly, suppressing iron utilization sensitizes PDA cells to MEKi, highlighting a critical and targetable reliance on lysosome-dependent iron supply during adaptation to KRAS-MAPK inhibition. SIGNIFICANCE: Reduced c-MYC levels following MAPK pathway suppression facilitate the upregulation of autophagy and lysosome biogenesis. Increased autophagy-lysosome activity is required for increased ferritinophagy-mediated iron supply, which supports mitochondrial respiration under therapy stress. Disruption of ferritinophagy synergizes with KRAS-MAPK inhibition and blocks PDA growth, thus highlighting a key targetable metabolic dependency. See related commentary by Jain and Amaravadi, p. 2023. See related article by Santana-Codina et al., p. 2180. This article is highlighted in the In This Issue feature, p. 2007.

Potential of sulfur-selenium isosteric replacement as a strategy for the development of new anti-chagasic drugs.

Current treatment for Chagas disease is based on only two drugs: benznidazole and nifurtimox. Compounds containing sulfur (S) in their structure have shown promising results in vitro and in vivo against Trypanosoma cruzi, the parasite causing Chagas disease. Notably, some reports show that the isosteric replacement of S by selenium (Se) could be an interesting strategy for the development of new compounds for the treatment of Chagas disease. To date, the activity against T. cruzi of three Se- containing groups has been compared with their S counterparts: selenosemicarbazones, selenoquinones, and selenocyanates. More studies are needed to confirm the positive results of Se compounds. Therefore, we have investigated S compounds described in the literature tested against T. cruzi. We focused on those tested in vivo that allowed isosteric replacement to propose their Se counterparts as promising compounds for the future development of new drugs against Chagas disease.

Study of the anticancer potential of Cd complexes of selenazoyl-hydrazones and their sulfur isosters.

The biological activity of Cd compounds has been investigated scarce since Cd has been recognized as a human carcinogen. However, the toxicity of cadmium is comparable to the toxicity of noble metals such as Pt and Pd. The paradigm of metal toxicity has been challenged suggesting that metal toxicity is not a constant property, yet it depends on many factors like the presence of appropriate ligands. Studies on anticancer activity of cadmium complexes showed that the complexation of various ligands resulted in complexes that showed better activities than approved drugs. In the present study, cadmium complexes with biologically potent thiazolyl/selenazoyl-hydrazone ligands have been prepared, and tested for their activity against different types of tumor cell models. The complexation of ligands with Cd(II) resulted in a synergistic effect. The antiproliferative activity study revealed that all complexes are more active compared to 5-fluorouracil and cisplatin. The mechanism of tumor cell growth inhibition reveal that selenium-based compounds induce cell death in T-47D (gland carcinoma) cells through apoptosis via caspase-3/7 activation. Additionally, their pro-apoptotic effect was stronger compared to etoposide and cisplatin. Nuclease activity, detected by gel electrophoresis, may be the possible mechanism of anticancer action of investigated complexes.

Health-Related Quality of Life (HRQoL) of Residents with Persistent Lower Respiratory Symptoms or Asthma Following a Sulphur Stockpile Fire Incident.

Background: This study evaluated health-related quality of life (HRQoL) in residents with persistent lower respiratory symptoms (PLRS) or asthma six years after exposure to sulphur dioxide vapours emanating from an ignited sulphur stockpile. Methods: A cross-sectional study was carried out, using interview data collected at three time points (prior to, one- and six-years post incident), medical history, respiratory symptoms and HRQOL using the Medical Outcomes Study Form 36 (SF-36). Results: A total of 246 records, 74 with and 172 without PLRS or asthma, were analysed. The mean age was 42 (SD:12) years in the symptomatic group and 41 (SD:13) years in the asymptomatic group. Mean SF-36 scores were significantly lower for the symptomatic group in the Physical Functioning (24 vs. 39), Role-Physical (33 vs. 48) and General Health (GH) domains (24 vs. 37). Symptomatic residents experienced a significant decline in their Role-Physical (OR = 1.97; CI 1.09, 3.55) and GH (OR = 3.50; CI 1.39, 8.79) at year 6 compared to asymptomatic participants. Residents with co-morbid reactive upper airways dysfunction syndrome demonstrated stronger associations for GH (OR = 7.04; CI 1.61, 30.7) at year 1 and at year 6 (OR = 8.58; CI 1.10, 65.02). Conclusions: This study highlights the long-term adverse impact on HRQoL among residents with PLRS or asthma following a sulphur stockpile fire disaster.

Paediatric pulmonary actinomycosis: A forgotten disease.

Actinomycosis is a rare, indolent and invasive infection caused by Actinomyces species. Actinomycosis develops when there is disruption of the mucosal barrier, and invasion and systemic spread of the organism, which can lead to endogenous infection affecting numerous organs. It is known to spread in tissue through fascial planes and most often involves the cervicofacial (55%), abdominopelvic (20%) and thoracic (15%) soft tissue. Pulmonary actinomycosis is rare in patients under the age of five years, with the median reported age in the fifth decade. Clinical findings include chest wall mass (49%), cough (40%), pain (back, chest, shoulders) (36%), weight loss (19%), fever (19%), Draining sinuses (15%) and hemoptysis (9%). Chest x-ray findings in pulmonary actinomycosis are mostly nonspecific and can overlap with pulmonary tuberculosis, foreign body aspiration and malignancy. Endobronchial tissue aggregates may show sulphur granules, with yellow to white conglomerate areas of gram positive Actinomyces. Removal or biopsy of these large endobronchial masses must be done with care, because of the risk of bleeding and large airway obstruction. The cytology on bronchoalveolar lavage fluid may show Periodic acid-Schiff (PAS) positive stain, ZN negative and Gram-positive filamentous bacilli which is morphologically suggestive of Actinomycosis. Actinomyces spp is highly susceptible to beta lactam antibiotics, penicillin G, and amoxicillin. A minimum of 3-6 months is needed but up to 20 months of treatment may be needed. Early diagnosis and correct treatment can lead to a good prognosis with a low mortality.

Negatively Charged Sulfur Quantum Dots for Treatment of Drug-Resistant Pathogenic Bacterial Infections.

Drug-resistant pathogenic bacteria as a worldwide health threat calls for valid antimicrobial agents and tactics in clinical practice. Positively charged materials usually achieve antibacteria through binding and disrupting bacterial membranes via electrostatic interaction, however, they also usually cause hemolysis and cytotoxicity. Herein, we engineered negatively charged sulfur quantum dots (SQDs) as an efficient broad-spectrum antibiotic to kill drug-resistant bacteria in vitro and in vivo. The SQDs can destroy the bacterial membrane system and affect their metabolism due to the intrinsic antibacterial activity of elemental sulfur and catalytic generation of reactive oxygen species, which exhibit effective therapeutic effect on subcutaneously implanted infection model induced by representative pathogenic Methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. Plus, the negatively charged surface makes the SQDs have excellent hemocompatibility and low toxicity, which all highlight the critical prospect of the SQDs as a potent biocompatible antibacterial agent in clinical infection therapy.

Sulfur Induces Resistance against Canker Caused by Pseudomonas syringae pv. actinidae via Phenolic Components Increase and Morphological Structure Modification in the Kiwifruit Stems.

Bacterial canker caused by Pseudomonas syringae pv. actinidiae (Psa) has led to considerable losses in all major kiwifruit-growing areas. There are no commercial products in the market to effectively control this disease. Therefore, the defense resistance of host plants is a prospective option. In our previous study, sulfur could improve the resistance of kiwifruit to Psa infection. However, the mechanisms of inducing resistance remain largely unclear. In this study, disease severity and protection efficiency were tested after applying sulfur, with different concentrations in the field. The results indicated that sulfur could reduce the disease index by 30.26 and 31.6 and recorded high protection efficiency of 76.67% and 77.00% after one and two years, respectively, when the concentration of induction treatments was 2.0 kg/m3. Ultrastructural changes in kiwifruit stems after induction were demonstrated by scanning electron microscopy (SEM) and transmission electron microscopy (TEM), and the activities of phenylalanine ammonia-lyase (PAL), peroxidase (POD) and polyphenol oxidase (PPO), and the accumulation of lignin were determined by biochemical analyses. Our results showed that the morphological characteristics of trichomes and lenticels of kiwifruit stem were in the best defensive state respectively when the sulfur concentration was 3.0 kg/m3 and 1.5 kg/m3. Meanwhile, in the range of 0.5 to 2.0 kg/m3, the sulfur could promote the chloroplast and mitochondria of kiwifruit stems infected with Psa to gradually return to health status, increasing the thickness of the cell wall. In addition, sulfur increased the activities of PAL, POD and PPO, and promoted the accumulation of lignin in kiwifruit stems. Moreover, the sulfur protection efficiency was positively correlated with PPO activity (p < 0.05) and lignin content (p < 0.01), which revealed that the synergistic effect of protective enzyme activity and the phenolic metabolism pathway was the physiological effect of sulfur-induced kiwifruit resistance to Psa. This evidence highlights the importance of lignin content in kiwifruit stems as a defense mechanism in sulfur-induced resistance. These results suggest that sulfur enhances kiwifruit canker resistance via an increase in phenolic components and morphology structure modification in the kiwifruit stems. Therefore, this study could provide insights into sulfur to control kiwifruit canker caused by Psa.

Bullous Scabies: Clinical, Dermoscopic, and Pathologic Characteristics of Ten Patients.

Bullous scabies (BS) is a rare atypical clinical variant of scabies and is easily confused with bullous disorders. The diagnosis of BS is always a challenge, and physicians often misdiagnose BS patients. Patients with BS admitted from 2012 to 2020 were enrolled in this study. The clinical, dermoscopic, and pathological characteristics of the patients were analyzed retrospectively. Ten patients with BS were enrolled in this study. Seven of the 10 patients were male. The bullae were most commonly found on the thighs and arms (80% of patients). Only 30% of patients (3/10) tested positive for mites and/or eggs by the initial skin scraping, but 100% (5/5) of the patients who received dermoscopy tested positive. Among these 10 patients, only five received a skin biopsy. Subepidermal (4/5) and intraepidermal (1/5) bullae with eosinophil and neutrophil infiltration were observed in five patients. Direct immunofluorescence (DIF) indicated linear deposition of IgG in the basement membrane zone in three patients. Physicians should consider the possibility of BS in patients with blisters, pruritus, and poor response to corticosteroids. Dermoscopy should be prioritized for the differential diagnosis of BS to exclude other bullous disorders. Finally, a biopsy should be performed on each patient with bullae.

Reactive sulfur species inhibit the migration of PDGF-treated vascular smooth muscle cells by blocking the reactive oxygen species-regulated Akt signaling pathway.

Vascular smooth muscle cell (VSMC) migration contributes to vascular remodeling after injury, whereas oxidative stress generated through dysfunctional redox homeostasis induces hypermigration, leading to arteriosclerosis. Platelet-derived growth factor (PDGF)-induced reactive oxygen species (ROS) serve as intracellular signaling molecules in VSMCs. Reactive sulfur species (RSS) may serve as a biological defense system because of the antioxidative properties of highly nucleophilic sulfane sulfur. However, insufficient information is available on its function in PDGF-induced VSMC migration. Here we show that PDGF significantly increased the levels of intracellular sulfane sulfur and that intracellular sulfane sulfur donors, donor 5a and Na2S4, inhibited the increase in ROS levels in PDGF-treated VSMCs and inhibited their migration. Consistent with the migration results, sulfane sulfur donors inhibited Akt phosphorylation, a downstream signaling molecule in the PDGF cascade, without affecting the autophosphorylation of PDGF receptor-ß. Further, sulfane sulfur donors inhibited vinculin and paxillin recruitment to the leading edge of VSMCs in response to PDGF to decrease focal adhesion formation. These findings suggest that RSS are required for PDGF-stimulated VSMC migration through the regulation of the ROS-regulated Akt pathway, which may contribute to focal adhesion formation. Our findings provide insight into RSS as novel regulators of vascular redox homeostasis.

Evidence-based topical treatments (azelaic acid, salicylic acid, nicotinamide, sulfur, zinc, and fruit acid) for acne: an abridged version of a Cochrane systematic review.

OBJECTIVE: The effects of topical azelaic acid, salicylic acid, nicotinamide, sulfur, zinc, and fruit acid (alpha-hydroxy acid) for acne are unclear. We aimed to assess the effects of these topical treatments by collecting randomized controlled trials. METHODS: We searched The Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS up to May 2019. We also searched five trials registers. Two review authors independently extracted data and assessed risk of bias. Meta analyses were performed by using Review Manager 5 software. RESULTS: We included a total of 49 trials involving 3880 participants. In terms of treatment response (measured using participants' global self-assessment of acne improvement, PGA), azelaic acid was probably less effective than benzoyl peroxide (RR = 0.82, 95% CI 0.72-0.95). However, there was probably little or no difference in PGA when comparing azelaic acid to tretinoin (RR = 0.94, 95% CI 0.78-1.14). There may be little or no difference when comparing salicylic acid to tretinoin (RR = 1.00, 95% CI 0.92-1.09). There were no studies measured PGA when evaluating nicotinamide. With respect to alpha-hydroxy acid, there may be no difference in PGA when comparing glycolic acid to salicylic-mandelic acid (RR = 1.06, 95% CI 0.88-1.26). We were uncertain about the effects of sulfur and zinc. Adverse events associated with these topical treatments were always mild and transient. CONCLUSIONS: Moderate-quality evidence was available for azelaic acid and low- to very-low-quality evidence for other topical treatments. Risk of bias and imprecision limit our confidence in the evidence.

Defect-engineered transition metal hydroxide nanosheets realizing tumor-microenvironment-responsive multimodal-imaging-guided NIR-II photothermal therapy.

Exploiting two-dimensional nanomaterials as photo-based theranostic agents is promising for the highly efficient ablation of deep-tissue-buried tumors. However, they are limited by their poor absorption in the second near-infrared-light (NIR-II) bio-window (1000-1300 nm) and intrinsic nonbiodegradability. Herein, defect-rich sulfur-doped Ni(OH)2 (S-Ni(OH)2) nanosheets decorated with bovine serum albumin (BSA) as a novel theranostic agent is developed, which can accomplish multimodal-imaging-guided photothermal ablation of mouse cancers in the NIR-II bio-window. Sulfur doping extends the absorption spectra of Ni(OH)2 nanosheets from the visible to NIR-II bio-window, affording highly efficient photothermal conversion (58.20% for 1064 nm), entailing it to become an excellent contrast agent for photoacoustic imaging. Further, because of their intrinsic paramagnetic property, they can be applied for magnetic resonance imaging. Owing to the abundant defective sites in S-Ni(OH)2 nanosheets, they exhibit response to the tumor microenvironment, resulting in effective biodegradation and excretion from the body. In vivo toxicity experiments indicated that S-Ni(OH)2-BSA NSs delivered no appreciable toxicity and good biocompatibility. This work provides an avenue for the rational design of effective theranostics agents.

Topical azelaic acid, salicylic acid, nicotinamide, sulphur, zinc and fruit acid (alpha-hydroxy acid) for acne.

BACKGROUND: Acne is an inflammatory disorder with a high global burden. It is common in adolescents and primarily affects sebaceous gland-rich areas. The clinical benefit of the topical acne treatments azelaic acid, salicylic acid, nicotinamide, sulphur, zinc, and alpha-hydroxy acid is unclear. OBJECTIVES: To assess the effects of topical treatments (azelaic acid, salicylic acid, nicotinamide, zinc, alpha-hydroxy acid, and sulphur) for acne. SEARCH METHODS: We searched the following databases up to May 2019: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers. SELECTION CRITERIA: Clinical randomised controlled trials of the six topical treatments compared with other topical treatments, placebo, or no treatment in people with acne. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Key outcomes included participants' global self-assessment of acne improvement (PGA), withdrawal for any reason, minor adverse events (assessed as total number of participants who experienced at least one minor adverse event), and quality of life. MAIN RESULTS: We included 49 trials (3880 reported participants) set in clinics, hospitals, research centres, and university settings in Europe, Asia, and the USA. The vast majority of participants had mild to moderate acne, were aged between 12 to 30 years (range: 10 to 45 years), and were female. Treatment lasted over eight weeks in 59% of the studies. Study duration ranged from three months to three years. We assessed 26 studies as being at high risk of bias in at least one domain, but most domains were at low or unclear risk of bias. We grouped outcome assessment into short-term (less than or equal to 4 weeks), medium-term (from 5 to 8 weeks), and long-term treatment (more than 8 weeks). The following results were measured at the end of treatment, which was mainly long-term for the PGA outcome and mixed length (medium-term mainly) for minor adverse events. Azelaic acid In terms of treatment response (PGA), azelaic acid is probably less effective than benzoyl peroxide (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.72 to 0.95; 1 study, 351 participants), but there is probably little or no difference when comparing azelaic acid to tretinoin (RR 0.94, 95% CI 0.78 to 1.14; 1 study, 289 participants) (both moderate-quality evidence). There may be little or no difference in PGA when comparing azelaic acid to clindamycin (RR 1.13, 95% CI 0.92 to 1.38; 1 study, 229 participants; low-quality evidence), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low-quality evidence). Low-quality evidence indicates there may be no differences in rates of withdrawal for any reason when comparing azelaic acid with benzoyl peroxide (RR 0.88, 95% CI 0.60 to 1.29; 1 study, 351 participants), clindamycin (RR 1.30, 95% CI 0.48 to 3.56; 2 studies, 329 participants), or tretinoin (RR 0.66, 95% CI 0.29 to 1.47; 2 studies, 309 participants), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low-quality evidence). In terms of total minor adverse events, we are uncertain if there is a difference between azelaic acid compared to adapalene (1 study; 55 participants) or benzoyl peroxide (1 study, 30 participants) (both very low-quality evidence). There may be no difference when comparing azelaic acid to clindamycin (RR 1.50, 95% CI 0.67 to 3.35; 1 study, 100 participants; low-quality evidence). Total minor adverse events were not reported in the comparison of azelaic acid versus tretinoin, but individual application site reactions were reported, such as scaling. Salicylic acid For PGA, there may be little or no difference between salicylic acid and tretinoin (RR 1.00, 95% CI 0.92 to 1.09; 1 study, 46 participants; low-quality evidence); we are not certain whether there is a difference between salicylic acid and pyruvic acid (1 study, 86 participants; very low-quality evidence); and PGA was not measured in the comparison of salicylic acid versus benzoyl peroxide. There may be no difference between groups in withdrawals when comparing salicylic acid and pyruvic acid (RR 0.89, 95% CI 0.53 to 1.50; 1 study, 86 participants); when salicylic acid was compared to tretinoin, neither group had withdrawals (both based on low-quality evidence (2 studies, 74 participants)). We are uncertain whether there is a difference in withdrawals between salicylic acid and benzoyl peroxide (1 study, 41 participants; very low-quality evidence). For total minor adverse events, we are uncertain if there is any difference between salicylic acid and benzoyl peroxide (1 study, 41 participants) or tretinoin (2 studies, 74 participants) (both very low-quality evidence). This outcome was not reported for salicylic acid versus pyruvic acid, but individual application site reactions were reported, such as scaling and redness. Nicotinamide Four studies evaluated nicotinamide against clindamycin or erythromycin, but none measured PGA. Low-quality evidence showed there may be no difference in withdrawals between nicotinamide and clindamycin (RR 1.12, 95% CI 0.49 to 2.60; 3 studies, 216 participants) or erythromycin (RR 1.40, 95% CI 0.46 to 4.22; 1 study, 158 participants), or in total minor adverse events between nicotinamide and clindamycin (RR 1.20, 95% CI 0.73 to 1.99; 3 studies, 216 participants; low-quality evidence). Total minor adverse events were not reported in the nicotinamide versus erythromycin comparison. Alpha-hydroxy (fruit) acid There may be no difference in PGA when comparing glycolic acid peel to salicylic-mandelic acid peel (RR 1.06, 95% CI 0.88 to 1.26; 1 study, 40 participants; low-quality evidence), and we are uncertain if there is a difference in total minor adverse events due to very low-quality evidence (1 study, 44 participants). Neither group had withdrawals (2 studies, 84 participants; low-quality evidence). AUTHORS' CONCLUSIONS: Compared to benzoyl peroxide, azelaic acid probably leads to a worse treatment response, measured using PGA. When compared to tretinoin, azelaic acid probably makes little or no difference to treatment response. For other comparisons and outcomes the quality of evidence was low or very low. Risk of bias and imprecision limit our confidence in the evidence. We encourage the comparison of more methodologically robust head-to-head trials against commonly used active drugs.

Sulfur controlled cadmium dissolution in pore water of cadmium-contaminated soil as affected by DOC under waterlogging.

Cadmium (Cd) precipitation and dissolution in pore water is associated with dissolved organic carbon (DOC)-induced reduction-oxidation of sulfur (S) under waterlogging and is vital for controlling the bioavailability in paddy soil. A 120-day soil incubation experiment, including application of sulfur (S, 30 mg kg-1) and wheat straw (W, 1.0%) alone or in combination (W + S) into Cd-contaminated paddy soil under waterlogging, was conducted to investigate the dynamic of dissolved Cd and its relationship with DOC, S2-, Fe2+, pH, Eh and pe + pH in soil pore water. The results showed that the lowest dissolved Cd concentration was observed in the W + S-treated soil pore water among all treatments when the soil Eh remained at lower values during the period of 15-60 days of incubation, which could be attributed to CdS precipitation and/or co-precipitation of Cd absorbed by FeS2 because of the reduction in sulfur. The application of S resulted in a Cd rebound in the pore water irrespective of W addition when the Eh began to increase from its lowest values during the period of 45-75 days of incubation, and SOB genera were observed in the S added soil. This could be attributed to re-dissolution of the precipitated Cd in soils under the SOB-driven oxidation of sulfide such as CdS and FeS2. In conclusion, DOC-driven reduction-oxidation of sulfur controls Cd dissolution in the pore water of Cd-contaminated paddy soil under waterlogging conditions. Further studies are required to investigate the interaction of sulfur and SOM-induced DOC on Cd bioavailability in rice-planted paddy soils.

Effect of Homeopathic Medicines and a Nosode on Larvae of Cochliomyia hominivorax (Diptera: Calliphoridae).

BACKGROUND: Cochliomyia hominivorax is the major fly causing primary myiasis in livestock animals in Brazil; its larvae develop in the host's living tissues, causing mutilations, which can even lead to death. In conventional treatments of myiasis, chemo-synthetic insecticides have been employed directly on larvae present in the wounds. Homeopathy may represent a healthy and sustainable alternative both to prevent and to treat myiasis in animals and humans. The current study evaluated how the emergence of adult insects is affected by the use of the homeopathic medicines Sulfur 12cH and Pyrogenium 12cH, and the nosode produced from C. hominivorax larvae at potencies 8cH and 12cH, on third-stage larvae of a C. hominivorax colony. MATERIALS AND METHODS: The homeopathic medicines and the nosodes were produced according to the Brazilian Homeopathic Pharmacopoeia. Control groups were distilled water, alcohol, no substance, and the organophosphate insecticide trichlorfon. For each group, 10 replicates were performed. Emergence rate of adult insects was evaluated by descriptive statistics followed by analysis of variance. Homogeneity of variances was verified by F-test and group means were compared with Tukey's test. RESULTS: Mortality rates in control groups were 2.7% for 30% (v/v) alcohol, 4.3% for distilled water, 3.2% for no substance (p > 0.05). In the trichlorfon group, the mortality rate of larvae was 90.8%. For Sulfur 12cH, the mortality of larvae was 94.6%, and for Pyrogenium 12cH it was 98.6%. The latter three means were not statistically different from each other or from the mean found for the trichlorfon group. The mortality rates of larvae were 61.3% and 66.6% for nosode C. hominivorax 8cH and 12cH, respectively (p > 0.05). CONCLUSIONS: Results suggest that homeopathy could be used therapeutically to prevent and treat animals and humans with myiasis caused by C. hominivorax.