Natural Rubrolides and Their Synthetic Congeners as Inhibitors of the Photosynthetic Electron Transport Chain.

Rubrolides are a family of naturally occurring 5-benzylidenebutenolides, which generally contain brominated phenol groups, and nearly half of them also present a chlorine attached to the butenolide core. Seven natural rubrolides were previously synthesized. When these compounds were tested against the model plant Raphanus sativus, six were found to exert a slight inhibition on plant growth. Aiming to exploit their scaffold as a model for the synthesis of new compounds targeting photosynthesis, nine new rubrolide analogues were prepared. The synthesis was accomplished in 2-4 steps with a 10-39% overall yield from 3,4-dichlorofuran-2(5H)-one. All compounds were evaluated for their ability to inhibit the whole Hill reaction or excluding photosystem I (PSI). Several natural rubrolides and their analogues displayed good inhibitory potential (IC50 = 2-8 µM). Molecular docking studies on the photosystem II-light harvesting complex II (PSII-LHCII supercomplex) binding site were also performed. Overall, data support the use of rubrolides as a model for the development of new active principles targeting the photosynthetic electron transport chain to be used as herbicides.

Oxidation State and Surface Reconstruction of Cu under CO2 Reduction Conditions from In Situ X-ray Characterization.

The electrochemical CO2 reduction reaction (CO2RR) using Cu-based catalysts holds great potential for producing valuable multi-carbon products from renewable energy. However, the chemical and structural state of Cu catalyst surfaces during the CO2RR remains a matter of debate. Here, we show the structural evolution of the near-surface region of polycrystalline Cu electrodes under in situ conditions through a combination of grazing incidence X-ray absorption spectroscopy (GIXAS) and X-ray diffraction (GIXRD). The in situ GIXAS reveals that the surface oxide layer is fully reduced to metallic Cu before the onset potential for CO2RR, and the catalyst maintains the metallic state across the potentials relevant to the CO2RR. We also find a preferential surface reconstruction of the polycrystalline Cu surface toward (100) facets in the presence of CO2. Quantitative analysis of the reconstruction profiles reveals that the degree of reconstruction increases with increasingly negative applied potentials, and it persists when the applied potential returns to more positive values. These findings show that the surface of Cu electrocatalysts is dynamic during the CO2RR, and emphasize the importance of in situ characterization to understand the surface structure and its role in electrocatalysis.

Synthesis of the Marine Myxobacterial Antibiotic Enhygrolide A.

The first synthesis of enhygrolide A, a scarce γ-alkylidenebutenolide antibiotic of the obligate marine myxobacterium Enhygromyxa salina, was achieved in five steps and 54% overall yield from tetronic acid. Key steps include (i) organocatalytic reductive alkylation, (ii) iron-catalyzed sp2-sp3 cross-coupling, and (iii) vinylogous aldol condensation. Aside from its brevity and reliance on environmentally sustainable processes, the synthesis demonstrates the serviceability of butenolide pivalates in cross-coupling reactions.

Total Synthesis of the Antitumor Antibiotic Basidalin.

The first synthesis of the tetronamide antibiotic basidalin was accomplished in five steps and 39% overall yield from readily available 4-bromo-2-triisopropylsilyloxyfuran and 2-formyl-1,3-dithiane. Highlights include: (i) regio- and stereocontrolled assemblage of a pivotal (Z)-γ-ylidene-ß-bromobutenolide intermediate by stereodirected vinylogous aldol condensation (SVAC), (ii) installation of the amino group via aza-Michael addition/elimination, and crucially (iii) facile access to basidalin by late-stage dithiane removal.

Thermodynamically driven, syn-selective vinylogous aldol reaction of tetronamides.

A stereoselective vinylogous aldol reaction of N-monosubstituted tetronamides with aldehydes is described. The procedure is simple and scalable, works well with both aromatic and aliphatic aldehydes, and affords mainly the corresponding syn-aldol adducts. In many cases, the latter are obtained essentially free of their anti-isomers (dr > 99 : 1) in high yields (70-90%). Experimental and computational studies suggest that the observed diastereoselectivity arises through anti-syn isomer interconversion, enabled by an iterative retro-aldol/aldol reaction.

Pathway Analysis using Gene-expression Profiles of HPV-positive and HPV-negative Oropharyngeal Cancer Patients in a Hispanic Population: Methodological Procedures.

OBJECTIVE: The incidence of oral cavity and pharyngeal cancer in Puerto Rican men is higher than it is in the men of any other ethnic/racial group in the United States of America (US). The information regarding the effect of the human papilloma virus (HPV) in the gene-expression profile among patients with this cancer is limited in Hispanic community. We aim to describe the methodology for future studies to identify the molecular networks for determining overrepresented signaling and metabolic canonical pathways, based on the differential gene-expression profiles of HPV+ and HPV- samples from patients with oropharyngeal squamous cell carcinoma in Puerto Rico. METHODS: We analyzed the RNA expression of 5 tissue samples from subjects diagnosed with oropharyngeal squamous cell carcinoma, 2 HPV+ and 3 HPV-, using Affymetrix GeneChips. The relative difference between the average gene expressions of the HPV+ and HPV- samples was assessed, based on the fold change (log2-scale). RESULTS: Our analysis revealed 10 up regulated molecules (Mup1, LRP1, P14KA, ALYREF, and BHMT) and 5 down regulated ones (PSME4, KEAP1, ELK3, FAM186B, and PRELID1), at a cutoff of 1.5-fold change. Ingenuity Pathway Analysis showed the following biological functions to be affected in the HPV+ samples: cancer, hematological disease, and RNA post-transcriptional modification. QRT-PCR analysis confirmed only the differential regulation of ALYREF, KEAP1, and FAM186B genes. CONCLUSION: The relevant methodological procedures described are sufficient to detect the most significant biological functions and pathways according to the HPV status in patients with oropharyngeal cancer in Puerto Rico.

Robotic-assisted salvage supraglottic laryngectomy.

Traditional open surgery has historically been the standard approach to treating many head and neck conditions. The introduction of the first robot into the surgical world in 1985 has been a keystone in the development of minimally invasive surgical (MIS) techniques. Transoral robotic surgery (TORS) is a minimally invasive technique used for the treatment of head and neck pathologies, including benign and malignant lesions. When performed in select patients, TORS offers low post-operative morbidity, along with very few functional and cosmetic compromises. Herein, we present the first TORS supraglottic partial laryngectomy performed in Puerto Rico or in any region in Latin America. A 68-year-old male who had previously undergone radiation therapy presented with hoarseness and weight loss. A suspension microlaryngoscopy showed a lesion of the left false vocal cord; a biopsy was performed. The patient was diagnosed with a supraglottic squamous cell carcinoma (T2N0M0); the tumor was completely excised using TORS. No post-operative complications occurred.

Effects of Synthetic Tetronamides and Methylated Denigrins on Bacterial Quorum Sensing and Biofilm Formation.

Detrimental biofilms of bacterial pathogens cause chronic infections with a high-level tolerance to antibiotics. To identify new control agents, we synthesized and tested a total of 14 tetronamides (including 5 new compounds) and 6 denigrin intermediates on the model species Escherichia coli. At a concentration of 50 µg/mL, two tetronamides and two methylated denigrins exhibited significant inhibitory effects against biofilm formation of E. coli RP437, e.g., by 60 and 94%, respectively. Structural analysis of the tested compounds revealed that p-methoxybenzylidene and p-methoxyphenethyl moieties of denigrins are important for biofilm inhibition, while the former group is also essential to the activity against quorum sensing (QS) via AI-2. Specifically, tetramethyldenigrin B has strong inhibitory effects against both E. coli biofilm formation and AI-2-mediated QS and thus provides a promising lead structure for designing better control agents. Consistently, tetramethyldenigrin B also showed inhibitory activity against biofilm formation of uropathogenic E. coli. Together, these findings provide new insights for the rational design of novel biofilm and QS inhibitors.

Designing a Zn-Ag Catalyst Matrix and Electrolyzer System for CO2 Conversion to CO and Beyond.

CO2 emissions can be transformed into high-added-value commodities through CO2 electrocatalysis; however, efficient low-cost electrocatalysts are needed for global scale-up. Inspired by other emerging technologies, the authors report the development of a gas diffusion electrode containing highly dispersed Ag sites in a low-cost Zn matrix. This catalyst shows unprecedented Ag mass activity for CO production: -614 mA cm-2 at 0.17 mg of Ag. Subsequent electrolyte engineering demonstrates that halide anions can further improve stability and activity of the Zn-Ag catalyst, outperforming pure Ag and Au. Membrane electrode assemblies are constructed and coupled to a microbial process that converts the CO to acetate and ethanol. Combined, these concepts present pathways to design catalysts and systems for CO2 conversion toward sought-after products.

Synthesis of new tetronamides displaying inhibitory activity against bloom-forming cyanobacteria.

BACKGROUND: The increasing frequency and intensity of cyanobacterial blooms pose a serious threat to aquatic ecosystems. These blooms produce potent toxins that can contaminate drinking water and endanger the life of wild and domestic animals as well as humans. Consequently, the development of effective methods for their control is a matter of high priority. We have previously shown that some γ-benzylidenebutenolides, related to the rubrolide family of natural products, are capable of inhibiting the photosynthetic electron transport chain (Hill reaction), a target of commercial herbicides. Here we report the synthesis and biological properties of a new class of rubrolide-inspired molecules featuring a tetronamide motif. RESULTS: A total of 47 N-aryl tetronamides, including 38 aldol adducts, were prepared bearing phenyl, biphenyl, naphthyl, aliphatic and heteroaromatic groups. Some of the aldol adducts were dehydrated to the corresponding γ-benzylidenetetronamides, although satisfactory yields were obtained in only three cases (52-97%). None of the synthesized compounds were capable of blocking the Hill reaction. This notwithstanding, several aldol adducts equipped with a biphenyl substituent displayed excellent inhibitory activity against Synechococcus elongatus and other cyanobacterial strains (IC50  = 1-5 µM). Further, these tetronamides were found to be essentially inactive against eukaryotic microorganisms. CONCLUSION: Several newly synthesized biphenyl-containing tetronamides were shown to display potent and selective inhibitory activity against cyanobacteria. These compounds appear to exert their biological effects without interfering with the Hill reaction. As such, they represent novel leads in the search of environmentally benign agents for controlling cyanobacterial blooms. © 2019 Society of Chemical Industry.

Laparoscopic nephrectomy with laparoscopically assisted transvaginal extraction of intact kidney.

PURPOSE: Describe the first laparoscopic transperitoneal nephroureterectomy followed by laparoscopically assisted transvaginal extraction of the intact kidney performed in Puerto Rico. CASE HISTORY/RESULTS: A 39 year-old female patient consulted her urologist regarding chronic urinary tract infection. A diagnosis of a non-functioning left kidney was made, secondary to long standing obstruction due to a distal ureteral stone. Laparoscopic nephroureterectomy procedure was performed and the intact specimen was removed through a transverse posterior colpotomy. Patient was discharged home the next day without intraoperative or post-operative complications. CONCLUSIONS: Laparoscopic nephrec-tomy with transvaginal extraction of the intact specimen provides a surgical option as a minimally invasive technique with very few functional and cosmetic compromises and with low post-operative morbidity when performed in appropriate female patients.

[Adult urachal cyst]. / Quiste del Uraco en un adulto.

Urachal Cyst pathologies comprise lesions that arise at the medial infraumblical line which is rarely seen in an adult. It has interesting and varied forms of clinical presentations which represent a diagnostic challenge for the clinician. Persistency of the Urachus is due to failure of the normal obliteration process which occurs embriologically during the 4th gestational month. This gives way to a lesion that should be taken into account while considering the differential diagnoses of the cystic pathologies of the region. We present the case of an adult woman with a Urachal Cyst, which was surgically excised at the Hospital Interamericano de Medicina Avanzada in Caguas, Puerto Rico, followed by a brief literature review.

Complete Genome Sequence of Hepatitis B Virus Genotype E, the First Molecular Characterization from an Imported Case in Mexico.

Hepatitis B virus infection is currently a global public health problem. Here, we present the first characterization and complete genome sequence of a strain belonging to genotype E in Mexico, obtained from a foreign carrier with chronic infection.

Hemodynamics of hyperuricemia.

Prolonged hyperuricemia is associated with the development of hypertension, renal arteriolosclerosis, glomerulosclerosis, and tubulointerstitial injury. It confers a greater risk than proteinuria for developing chronic renal disease and is associated with the development of hypertension. Mild chronic hyperuricemia without intrarenal crystal deposition was induced in rats by inhibiting uricase with oxonic acid. Hyperuricemic rats developed hypertension, afferent arteriolar thickening, and mild renal interstitial fibrosis. Additionally, hyperuricemia accelerated renal damage and vascular disease in rats undergoing renal ablation. To better understand the role of hyperuricemia in the kidney, micropuncture studies were performed. Hyperuricemia resulted in renal cortical vasoconstriction (single nephron glomerular filtration rate (SNGFR) 35%, P < .05) and glomerular hypertension (P < .05). The possibility that hyperuricemia could modify renal hemodynamic disturbances during progression of renal disease was tested in rats with 5/6 nephrectomy. Hyperuricemia accentuated the renal vascular damage and caused cortical vasoconstriction (SNGFR 40%, P < .05) and persistent glomerular hypertension. In conclusion, hyperuricemia impairs the autoregulatory response of preglomerular vessels, resulting in glomerular hypertension. Lumen obliteration induced by vascular wall thickening results in severe vasoconstriction. The resulting ischemia is a potent stimulus that induces tubulointerstitial inflammation and fibrosis as well as arterial hypertension.

A unifying pathway for essential hypertension.

We present the hypothesis that most cases of essential hypertension occur via two phases. The first phase is initiated by episodes of renal vasoconstriction induced by a hyperactive sympathetic nervous system, activation of the renin-angiotensin system, or hyperuricemia resulting from diet or genetics. During this phase the hypertension is salt resistant and renin dependent, and the kidney normal. Over time, preglomerular vascular disease develops (arteriolosclerosis), associated with tubulointerstitial inflammation; this shifts the hypertension to a salt-sensitive, volume-dependent, and renal-dependent pathway. This pathway unites many of the previous hypotheses on the etiology of hypertension, and offers insights into ways to prevent, ameliorate, or cure the underlying process.

Tubulointerstitial damage and progression of renal failure.

The present work reviews the mechanisms and close association between glomerular and tubular damage and its relationship to renal functional impairment. In addition, we present an overview of the pathways involved in the progression of tubulointerstitial fibrosis and a brief summary of the treatments used to retard the progression to end-stage renal failure.

Prevalance of proteinuria in Mexico: a conjunctive consolidation approach with other cardiovascular risk factors: the Mexican Health Survey 2000.

BACKGROUND: A number of cross-sectional or serial studies have demonstrated the clinical impact of microproteinuria and macroproteinuria by identifying individuals at risk of both end-stage renal disease and major cardiovascular events. This study focused on the prevalence of proteinuria in Mexico and its relationship with other cardiovascular risk factors such as hypertension, type 2 diabetes mellitus, body mass index, smoking, age, and gender. METHODS: The prevalence of proteinuria in Mexico was obtained from the probabilistic cross-sectional national health survey performed in the year 2000. The proportion of urine dipstick samples that tested positive for protein (defined as > or =1+) in adults from 20 to 69 years of age was determined. The analysis was performed using both algebraic and multicategorical models. Potential interactions between proteinuria and other major cardiovascular risk factors were investigated. RESULTS: A total of 46,523 adult survey participants were included in the analysis. In the general population, 9.2% had proteinuria. By univariate, multivariate, and multicategorical analysis, hypertension, diabetes, obesity, and age were strongly associated with the prevalence of proteinuria (P < 0.001). However, in Mexico, the specific distribution of age groups demonstrated that the absolute number of patients without hypertension that had proteinuria is not irrelevant. To identify 1 case of proteinuria, one would need to screen 3 persons with diabetes mellitus, 5 patients with hypertension without diabetes, or 6 persons over the age of 55 years. When proteinuria is present, the probability of having a noncommunicable chronic disease or other major cardiovascular risk factor is more than 85%. CONCLUSION: Proteinuria is prevalent. When considered together, dipstick-positive proteinuria, blood pressure level, body mass index > or =30 m(2)/kg, and abnormal fasting blood glucose measured on a single occasion identifies different segments of the population. Studies such as this may be a suitable initial clinical approach to general population screening for renal and cardiovascular risk stratification.

[National Re-survey of Arterial Hypertension (RENAHTA). Mexican consolidation of the cardiovascular risk factors. national follow-up cohort]. / Re-encuesta Nacional de Hipertensión Arterial (RENAHTA): consolidación Mexicana de los factores de riesgo cardiovascular. Cohorte nacional de seguimiento.

OBJECTIVE: Based on a National Re-survey on Hypertension (HTA) and other cardiovascular risk factors performed in Mexico during 2003 and 2004 in the adult population with HTA, as identified in the 2000 National Survey of Health, this study was planed to determine: 1) morbidity and mortality rates; 2) the incidence and interrelation with other risk factors, such as overweight, obesity, dyslipidemia, nephropathy and diabetes; 3) the main risk factors associated to HTA involved in its complications, need for hospitalization and number of days; and, 4) the degree of therapeutical adhesion and the type of antihypertensive drugs used. METHODS: The survey was of type III using the step by step method described by WHO. Sampling was weighed a priori taking into account a national prevalence average of HTA of 30.05% and its corresponding rate for each federal state. Permissible maximum error in the estimation = 0.28. Effect of design = 4.5; and, Rate of awaited answer (0.70). RESULTS: From the initial 14,567 interviewed patients, 1,165 (8%) subjects were considered non-hypertensive or false positives at the 2000 survey. From the 13,402 remaining patients, 335 died during the first 2 years of pursuit, which implies an annual mortality of approximately 1.15% in the hypertensive population. Thus, 13,067 survivors were subjected to the final analysis. The mean age at the re-survey was 45.6 +/- 12.6; 40.5% were men (n = 5,295). There was a statistically significant difference in height, but not in weight between both genders. The control HTA was raised 14.6% in the year 2000 and 19.2% in 2004. The prevalence of diabetes was duplicated from 16% to 30% (< .001). Fifty four percent of the whole population required hospitalization at least once during the period of study. The rates of overweight, obesity, and dyslipidemia rose significantly (p < 0.05) independently from age, federal state, and gender. CONCLUSION: RENAHTA shows the impact of hypertension on the morbidity and mortality during the 3.1 +/- 1.5 years of follow-up in Mexico. It alerts us on the need to reinforce the strategies of attention and prevention of this crucial risk factor and of screening the dynamic nonlinear interaction between the main cardiovascular risk factors in Mexico. New hypotheses are proposed for the metabolic syndrome.

Glomerular hemodynamic changes associated with arteriolar lesions and tubulointerstitial inflammation.

Glomerular hemodynamic adaptations to loss of renal mass are thought to be the initiating factor of progression to renal failure; however, tubulointerstitial (TI) injury correlates better with progression than with glomerular damage. Thus, it is conceivable that tubulointerstitial alterations participate in the pathophysiology of renal disease progression by modifying the adaptive responses of glomerular hemodynamics. In experimental models of progressive renal disease, suppressing tubulointerstitial inflammatory cell infiltration with anti-inflammatory drugs reduces renal damage despite persistence of systemic hypertension. In recent studies in rats with subtotal renal ablation, we found that treatment with polysulphate pentosan (PPS) and with mycophenolate mofetil (MMF) prevented proteinuria, glomerular hypertension, and hyperfiltration, despite persisting arterial hypertension due to higher afferent resistance. In addition, arteriolopathy was significantly attenuated by MMF, suggesting preservation of vascular structure and function. Association of vascular injury of afferent arterioles, glomerular hemodynamic changes, and renal lesions has been described in other conditions such as hyperuricemia, protein overload, fawn-hooded rats, and aging spontaneously hypertensive rats (SHR). Arteriolopathy results in a maladaptive function that permits the transmission of systemic hypertension to glomerular capillaries. Glomerular hypertension results in mechanical damage to the capillary wall and increased filtration of proteins to tubular lumen. Enhanced tubular reabsorption induces synthesis of proinflammatory and profibrotic factors, resulting in tubulointerstitial inflammation and fibrosis. In conditions in which there is overactivity of the renin-angiotensin system (RAS), such as mild hyperuricemia and protein overload, arteriolopathy is associated with increased glomerular pressure and reduced glomerular plasma flow that results in post-glomerular ischemia and tubulointerstitial injury.

Apoptosis and NFkappaB activation are simultaneously induced in renal tubulointerstitium in experimental hypertension.

BACKGROUND: Oxidative stress is known to induce apoptosis and activation of pro-inflammatory transcription factor nuclear factor kappa B (NFkappaB), which are biologic effects that may play a role in the renal damage associated with arterial hypertension. We investigated if increased apoptosis and NFkappaB activation were present in experimental models of hypertension. METHODS: Sprague-Dawley rats fed with regular rodent chow and free access to water were studied. The Ang II group (N = 6) received 435 ng/kg/min of angiotensin II during 2 weeks by subcutaneous minipumps. The l-NAME group (N = 5) received Nomega-nitro-l-arginine-methyl-ester (l-NAME) in the drinking water (70 mg/100 mL) for 3 weeks. The control group consisted of 6 rats. Systolic blood pressure (tail cuff plethysmography), serum creatinine, and proteinuria were determined weekly. Kidneys were examined for superoxide-positive cells (histochemistry) and for apoptosis [terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labeling (TUNEL)-positive cells], proliferation [proliferating cell nuclear antigen (PCNA)-positive cells), and activation of NFkappaB (p65 subunit) with the appropriate antibodies. RESULTS: As expected, hypertension developed in experimental groups. Tubulointerstitial superoxide-positive cells were increased 7 times (P < 0.001), TUNEL-positive cells were increased 3 to 4 times (P < 0.001), PCNA-positive cells were increased 20 to 30 times (P < 0.001), and NFkappaB activation was increased 4 to 5 times (P < 0.001) in the experimental groups. NFkappaB expression correlated with the number of interstitial lymphocytes (r = 0.667, P < 0.01) and macrophages (r = 0.835, P < 0.001). CONCLUSION: Angiotensin II infusion and l-NAME administration induce oxidative stress and increased apoptosis and activation of the transcription factor NFkappaB. These effects may participate in the development of progressive renal injury resulting from uncontrolled hypertension