The impact of cultural stress on family functioning among Puerto Rican displaced families and the effect on mental health.

Hurricane María caused significant devastation on the island of Puerto Rico, impacting thousands of lives. Puerto Rican crisis migrant families faced stress related to displacement and relocation (cultural stress), often exhibited mental health symptoms, and experienced distress at the family level. Although cultural stress has been examined as an individual experience, little work has focused on the experience as a family. To address this gap, we conducted a mixed-methods study designed to examine the predictive effects of cultural stress on family conflict and its mental health implications among Puerto Rican Hurricane María parent and child dyads living on the U.S. mainland. In the quantitative phase of the study, 110 parent-child dyads completed an online survey assessing cultural stress, family dynamics, and mental health. As part of our primary analysis, we estimated a structural equation path model. Findings from the quantitative phase showed a significant positive relationship between family cultural stress and family conflict, as well as individual parent and child mental health symptoms. In the qualitative phase of the study, 35 parent-child dyads participated in individual interviews. Findings from the interviews revealed variations in difficulties related to language, discrimination, and financial burdens, with some participants adapting more quickly and experiencing fewer stressors. Findings also highlight the impact on mental health for both parents and youth, emphasizing the family-level nature of cultural stress, while noting a potential discrepancy between qualitative and quantitative findings in the discussion of family conflict.

Technology-based communication among Hurricane Maria survivors in the United States: a trans-territorial lens.

PURPOSE: Rooted in a trans-territorial framework, the present study was designed to provide new evidence regarding the patterns of communication among Hurricane Maria survivors who migrated to the U.S. in the aftermath of the storm. METHODS: A total of 319 Hurricane Maria survivor adults ages 18 and older were recruited into the Adelante Boricua study between August 2020 and October 2021. Most participants had relocated to the U.S. between 2017 and 2018. We used latent profile analysis and multinomial regression to examine the relationship of technology-based communication with depressive symptoms, well-being, cultural connection, and migration stress. RESULTS: We identified a five-class solution, consisting of (1) moderate communication (32%), (2) disengaged (24%), (3) no social media (18%), (4) daily with family in Puerto Rico (6%), and (5) daily trans-territorial (13%) typologies. Participants in the disengaged class were more likely to report elevated depressive symptoms and limited English proficiency, lower prosocial behaviors, lower levels of religiosity, lower attendance at religious services in the U.S., and less engagement in social activities, compared to participants in the Moderate Communication class. CONCLUSION: Roughly one in four individuals in our sample reported very limited technology-based communication with friends/family in their sending and new-receiving communities. As technology and smartphones continue to become integrated into 21st-century life, it is vital that researchers explore how the tremendous potential for connectedness relates to trans-territorial crisis migrants' well-being and adaptation.

Rapid optimization of an ICE inhibitor synthesis using multiple reaction conditions in a parallel array.

Optimization of a 2-step reaction sequence was accomplished in 3-4 days, with over 200 different reaction conditions evaluated. Combinatorial arrays were performed using the optimized conditions to synthesize 590 new compounds which were tested for inhibition against N-His (D381E) ICE. Thirty-five compounds showed at least a tenfold improvement in activity compared to an initial standard.

Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase.

Mutational activation of ras has been found in many types of human cancers, including a greater than 50% incidence in colon and about 90% in pancreatic carcinomas. The activity of both native and oncogenic ras proteins requires a series of post-translational processing steps. The first event in this process is the farnesylation of a cysteine residue located in the fourth position from the carboxyl terminus of the ras protein, catalyzed by the enzyme farnesyltransferase (FTase). Inhibitors of FTase are potential candidates for development as antitumor agents. Through a high-volume screening program, the pentapeptide derivative PD083176 (1), Cbz-His-Tyr(OBn)-Ser(OBn)-Trp-DAla-NH2, was identified as an inhibitor of rat brain FTase, with an IC50 of 20 nM. Structure-activity relationships were carried out to determine the importance of the side chain and chirality of each residue. This investigation led to a series of potent FTase inhibitors which lack a cysteine residue as found in the ras peptide substrate. The parent compound (1) inhibited the insulin-induced maturation of Xenopus oocytes (concentration: 5 pmol/oocyte), a process which is dependent on the activation of the ras pathway.

Solid-supported syntheses of 3-thio-1,2,4-triazoles.

Two solid-supported synthesis strategies for the preparation of 3-thio-1,2,4-triazoles are described. In the first, Rink amide resin is combined with Fmoc-protected omega-amino acids, acid hydrazides, and alkyl halides to provide diverse sets of starting materials from which numerous triazoles may be prepared. The second employs t-alkylcarbamate resin (Boc resin) which permits the use of additional pools of starting materials, including isothiocyanates and alpha- and omega-amino esters, resulting in triazoles with patterns of functional groups that are not possible from the initial route. The combination of multiple resins and resin attachment sites allows the preparation of a diverse library based upon the 3-thio-1,2,4-triazole scaffold and avoids the pitfall of having a single linker functionality present at the same position in all library members. General synthetic procedures and representative products from each route are presented. A similarity analysis of representative sublibraries from each synthesis strategy concludes that variation of the solid-phase linker chemistry and attachment site can enhance molecular diversity of the combined triazole library.

Derivatives of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins as orally active angiotensin II receptor antagonists.

A series of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins have been prepared and evaluated as in vitro and in vivo angiotensin II (Ang II) antagonists. Variation of substituents on the hydantoin ring leads to potent and selective Ang II antagonists with nanomolar IC50 values at the AT1 receptor and negligible affinity for the AT2 receptor. Preferred substituents include an n-butyl at R1 and an alkyl or heteroarylmethyl substituent at R2. The selection of the R2 substituent was guided in part by the calculation of its log P since a significant correlation was observed between CLOGP and AT1 binding affinity. The biphenyl tetrazole pharmacophore, common to a number of AT1 antagonists, could be replaced by, for example, a 4-carbomethoxyphenyl substituent resulting in potent Ang II antagonists both in vitro and in vivo. A representative compound of this series is 57, which reduced the mean arterial blood pressure of renal hypertensive rats by 40% at 30 mg/kg po and by 25% at 10 mg/kg po. In addition this compound was efficacious in the salt-deplete normotensive monkey model maximally decreasing blood pressure 27% at 10 mg/kg po. In summary, these compounds belong to a novel class of Ang II antagonists that lack the biphenyl tetrazole moiety yet display appreciable and long lasting oral activity.

Functional studies but not receptor binding can distinguish surmountable from insurmountable AT1 antagonism.

Our study demonstrated that inhibition of angiotensin II- (Ang II) mediated contractions of rabbit aorta by structurally diverse nonpeptide AT1 antagonists could distinguish surmountable from insurmountable AT1 antagonism. CI-996, L158809, EXP 3174 and SKF 108834 produced concentration-related rightward shifts in Ang II response curves and reduced the maximal contraction to Ang II, characteristic of insurmountable antagonism. In contrast, DuP 753 and SKF 108566, produced parallel rightward shifts in Ang II contractile curves without affecting the maximal response which is consistent with the definition of surmountable or competitive antagonism. In addition, CI-996 demonstrated potent inhibition of Ang II-stimulated inositol phosphate accumulation in rat aortic smooth muscle cells, behaving as an insurmountable antagonist. However, DuP 753 was a surmountable antagonist of Ang II-stimulated inositol phosphate accumulation. Repeated washing of rabbit aorta preincubated with either CI-996 or EXP 3174 did not restore the blunted Ang II contractions. In contrast, both DuP 753 and the structurally dissimilar SKF 108566 at a concentration of 100 nM showed complete recovery of Ang II responses within 2 hr of repeated washing. Surprisingly, repeated rinsing of rabbit aorta for up to 5 hr after incubation with 1 microM DuP 753 failed to restore responses to Ang II. In addition, Scatchard analysis of [125I] Ang II saturation binding experiments revealed a competitive and rapidly reversible nature of AT1 receptor antagonism for all the AT1 antagonists examined. Taken together, the results of this study provide evidence for a competitive and rapidly reversible binding interaction of structurally diverse non-peptide antagonists at the AT1 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacologic characterization of CI-996, a new angiotensin receptor antagonist.

CI-996, a novel potent angiotensin II (Ang II) type 1 (AT1) receptor antagonist was characterized in a number of in vitro and in vivo assays. In addition, CI-996 was compared with several reported AT1 receptor antagonists including losartan, SK&F 108566 and L-158,809. In rat liver membranes CI-996 displaced specifically bound [125I]Ang II with an IC50 of 0.8 +/- 0.1 nM. In isolated rabbit aorta CI-996 produced a concentration-dependent inhibition of Ang II-induced contraction and decreased the maximal contractile response to Ang II. CI-996 had no effect on the contractile responses to KCl, norepinephrine or endothelin. In anesthetized, ganglionic-blocked rats CI-996 produced dose-dependent inhibition of the Ang II pressor dose-response curve with an IC50 of 6.2 micrograms/kg/min i.v. Orally administered CI-996 dose dependently lowered mean arterial blood pressure in conscious renal hypertensive rats, conscious sodium-depleted dogs, conscious sodium-depleted monkeys and conscious renal hypertensive monkeys. The duration of antihypertensive activity of CI-996 in rats was > 24 hr after a single oral dose. The blood pressure lowering potency of CI-996 in dogs was less than that observed in either rats or monkeys. There was no tachyphylaxis to the antihypertensive effects of CI-996 after repeated administration in renal hypertensive monkeys. These data demonstrate that CI-996 is a potent, selective Ang II antagonist. Furthermore, CI-996 has demonstrated blood pressure-lowering activity after oral administration in rats, dogs and monkeys.

Analyses of ligand binding in five endothiapepsin crystal complexes and their use in the design and evaluation of novel renin inhibitors.

Five renin inhibitors were cocrystallized with endothiapepsin, a fungal enzyme homologous to renin. Crystal structures of inhibitor-bound complexes have provided invaluable insight regarding the three-dimensional structure of the aspartic proteinase family of enzymes, as well as the steric and polar interactions that occur between the proteins and the bound ligands. Beyond this, subtleties of binding have been revealed, including multiple subsite binding modes and subsite interdependencies. This information has been applied in the design of novel potent renin inhibitors and in the understanding of structure-activity relationships and enzyme selectivities.

Nonpeptide angiotensin II receptor antagonists. 2. Design, synthesis, and structure-activity relationships of 2-alkyl-4-(1H-pyrrol-1-yl)-1H-imidazole derivatives: profile of 2-propyl-1-[[2'-(1H-tetrazol-5-yl)-[1,1' -biphenyl]-4-yl]-methyl]-4-[2-(trifluoroacetyl)-1H-pyrrol-1-yl]-1H- imidazole-5-carboxylic acid (CI-996).

A novel series of nonpeptide angiotensin II (AII) receptor antagonists containing a 1H-pyrrol-1-yl moiety at the 4-position of the imidazole have been developed. The pyrrole group occupies the same lipophilic pocket at the receptor as the chloro group in DuP 753 (68) and EXP 3174 (69) and the pentafluoro group in DuP 532 (70), respectively. The impetus for its selection came from bioisosteric considerations based on hydrophobic and electronic substituent constants. An extensive study of the structure-activity relationships revealed several highly potent AII receptor antagonists. An acyl substitution at the 2-position of the pyrrole ring improved activity, most notably in the in vivo rat model. In addition, the 2-substituted pyrrole compounds improved chemical stability toward extremely facile decarboxylation reaction associated with unsubstituted pyrrole analogues, thus facilitating development of these agents. The IC50's of 18, 20, and 42 (< 1 nM) were better than the reference compounds 69 and 70, respectively. These compounds were selective AII antagonists that compete at the AT1 receptor and showed no affinity at the AT2 receptor at concentrations up to 10 microM. Upon intravenous administration in a normotensive rat model, compound 18 inhibited the AII-induced responses with ED50 of 6 micrograms/kg per min. In a renal hypertensive rat model, the antihypertensive potency of compound 18, at a dose of 10 mg/kg, was very similar to those 68 and 69, respectively. Compound 18 demonstrated a dose-related (3-30 mg/kg) decrease in blood pressure that was sustained for greater than 24 h. On the basis of its profile, compound 18, designated as CI-996, has been selected for in-depth studies. The design, synthesis, in vitro, and in vivo structure-activity relationships are described.

Renal hemodynamic and excretory responses to PD 123319 and losartan, nonpeptide AT1 and AT2 subtype-specific angiotensin II ligands.

Angiotensin receptor subtypes have been described and pharmacologically characterized. DuP 753 (losartan) selectively antagonizes the angiotensin type 1 receptor, whereas PD 123319 selectively binds to an angiotensin type 2 receptor. These studies compared the renal response to treatment with the nonpeptides, DuP 753 and PD 123319, and the peptide antagonist, saralasin, in anesthetized mongrel dogs. Saralasin and DuP 753 increased renal blood flow and were mildly natriuretic. DuP 753 was roughly 10-fold less potent than saralasin. PD 123319 had no effect on renal hemodynamics, but produced dose-related increases in urine volume and free water clearance. PD 123319 had no effect on circulating vasopressin levels, suggesting the change in water handling by the kidney was not due to inhibition of vasopressin release. A direct effect of PD 123319 at the level of the renal tubule has not been ruled out. This is the first report of a renal functional response to an angiotensin type 2 receptor ligand and suggests that the angiotensin type 2 receptor may be related to water handling by the kidney.

Synthesis and structure-activity relationships of a novel series of non-peptide angiotensin II receptor binding inhibitors specific for the AT2 subtype.

Structure-activity relationships are reported for a novel class of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid derivatives that displace 125I-labeled angiotensin II from a specific subset of angiotensin II (Ang II) binding sites in rat adrenal preparations. This binding site is not the Ang II receptor mediating vascular contraction or aldosterone release, but, rather, is one whose function has not yet been fully elucidated. It has been identified in a number of tissues and has a similar affinity for Ang II and its peptide analogues as does the vascular receptor. The non-peptide compounds reported here are uniquely specific in displacing Ang II at this binding site and are inactive in antagonizing Ang II at the vascular receptor or in pharmacological assays measuring vascular effects. PD 123,319 (79), one of the most potent compounds, has an IC50 of 34 nM. Certain of these compounds may have utility in the definition and study of Ang II receptor subtypes.

Renin inhibitors containing esters at the P2-position. Oral activity in a derivative of methyl aminomalonate.

A series of renin inhibitors containing ester side chains at the P2 subsite are potent inhibitors of primate renin. Derivatives containing the diol isostere (ACDMH) at P1-P1' were the most potent inhibitors. Moderate selectivity for renin was observed relative to the closely related aspartic proteinase cathepsin D. The prototype compound, 4 (PD 132002), inhibited pepsin only weakly. In both high-renin normotensive and high-renin renal hypertensive monkeys, 4 produced substantial reductions in blood pressure after oral administration of 30 mg/kg. The maximum drop in blood pressure observed (24 +/- 4 mmHg) in the renal hypertensive monkey model was comparable to the drop produced by an intravenous infusion of saralasin at a maximally effective dose. Both the magnitude and duration of the oral antihypertensive effect of 4 is greater than that produced by enalkiren, CGP-38560, or CP-80794 by direct comparison in the same hypertensive monkey model. The malonate ester derivatives were prepared as ca. 65:35 mixtures of epimers. The kinetics of epimerization of 4 were investigated in detail, and it was shown to equilibrate rapidly at physiological pH (t1/2 less than 2 min). Fractional crystallization was employed to obtain the individual diastereomers in greater than 98% purity, which were indistinguishable in terms of their activity in vitro or in vivo, presumably due to rapid epimerization under the testing conditions.

Biochemical properties of the ovarian granulosa cell type 2-angiotensin II receptor.

Angiotensin II (Ang II) receptors, estimated by the specific binding of the peptide Ang II receptor antagonist [125I] [Sar1,Ile8]Ang II, are localized on multiple ovarian structures, including follicular granulosa cells. Using the Ang II receptor subtype-selective nonpeptide antagonists, DuP 753 [selective for the type 1 Ang II (AT1) receptor] and PD 123319 [selective for the type 2 Ang II (AT2) receptor], we show that follicular granulosa cells, in vivo and in vitro, exclusively express the AT2 receptor. To understand the function of Ang II in ovarian follicles, we compared the biochemical properties and transmembrane signaling pathways of the granulosa cell AT2 receptor with those properties generally associated with Ang II receptors found in the adrenal zona glomerulosa, where the AT1 receptor predominates. The mol wt of the granulosa cell AT2 receptor (approximately 79,000), estimated by affinity cross-linking studies, is similar to that of the adrenal zona glomerulosa Ang II receptor. Like the adrenal zona glomerulosa Ang II receptor, binding inhibition studies show that the granulosa cell AT2 receptor binds Ang II and Ang III with high affinity (IC50, approximately 0.5 nM for both peptides), but not Ang-(1-7) (IC50, approximately 0.5 microM) or Ang-(1-5) (IC50, greater than 10 microM). However, unlike the adrenal zona glomerulosa Ang II receptor, the granulosa cell AT2 receptor does not undergo agonist-induced endocytosis. Further, Ang II does not affect basal or stimulated inositol phosphate production, intracellular Ca2+ mobilization, or adenylyl cyclase or guanylyl cyclase activity in granulosa cells. The granulosa cell AT2 receptor does not appear to directly interact with guanine nucleotide binding regulatory proteins, since agonist dissociation from the AT2 receptor is unaffected by the GTP analog guanosine 5'-O-(3-thiotriphosphate); in contrast, the AT1 receptor appears to directly interact with guanine nucleotide binding regulatory protein, because agonist dissociation from the AT1 receptor is stimulated by guanosine 5'-O-(3-thiotriphosphate). These studies clearly demonstrate that the granulosa cell AT2 receptor is functionally distinct from the well characterized adrenal zona glomerulosa Ang II receptor. The exclusive presence of the AT2 receptor on the granulosa cell makes it an ideal cell type for studying the potential, but as yet unknown, function of this receptor.

New inhibitors of human renin that contain novel replacements at the P2 site.

A series of renin inhibitors with novel modifications at the P2 site has been prepared. Structure-activity relationships reveal that for a particular P2 fragment the in vitro potency is highly dependent on the nature of the P2' portion in addition to the P1-P1' group. The length of the P2 side chain and choice of epsilon-N P2 substitution have been found to be important for in vitro potency although the degree of unsaturation in the P2 side chain is not particularly significant. Molecular modeling studies have shown that it is possible for the P2 side chain to interact unfavorably with the P2' binding site. It has been possible to control the specificity for renin over cathepsin D by correct modification at the P2' and P1-P1' sites. Variations at the P4 site have been utilized to lower the log P values of these renin inhibitors while maintaining high potency. Compound 42, which exhibited an IC50 of 3.70 nM, log P of 2.3, and showed high specificity for renin, was selected for further studies. It was found to be very stable under neutral, acidic, and basic conditions. In simulated intestinal juice, compound 42 had a half-life of 37 min while it was virtually unaffected by simulated gastric juice after 4 h. Compound 42 produced a significant hypotensive response upon intravenous administration to the salt-depleted normotensive cynomolgus monkey.

Subclasses of angiotensin II binding sites and their functional significance.

Specific binding sites for angiotensin II were identified in the rabbit adrenal gland and uterus and in the rat liver and were divided into two subclasses based on inhibition by nonpeptide ligands. Peptide ligands affected binding equally in all three tissues. However, the nonpeptide antagonists Dup 753 and Exp 6803 blocked angiotensin II binding to adrenal and liver homogenates at nanomolar concentrations but exerted only a minimal effect on binding to uterine homogenates. The nonpeptide PD 123319 potently blocked angiotensin II binding to uterine homogenates but had no effect on adrenal or liver homogenates at concentrations up to 10 microM. Further analysis of angiotensin II binding in uterus showed that both sites are present, with the PD 123319-sensitive site predominating. Additionally, the nonhydrolyzable GTP analogue 5'-guanylyl-imidodiphosphate was able to modulate binding to liver and to the Dup 753-sensitive site in uterus but not that to the PD 123319-sensitive site. Saralasin and the nonpeptide antagonists Dup 753 and Exp 6803 blocked angiotensin II-stimulated accumulation of inositol phosphates in cultured Clone 9 cells and also relaxed aortic rings previously contracted with angiotensin II. In contrast, PD 123319 had no effect on either angiotensin II-stimulated inositol phosphate accumulation or vasoconstriction. Saralasin and Exp 6803, but not PD 123319, lowered blood pressure in renal hypertensive rats following intravenous administration. These results suggest the existence of two subclasses of angiotensin II binding sites, which differ in their tissue distribution and affinity for the nonpeptide ligands Dup 763, Exp 6803, and PD 123319. Although no functional role for the PD 123319-sensitive subclass has yet been identified, the Dup 753/Exp 6803-sensitive subclass plays an important role in mediating inositol phosphate metabolism, vascular contractile activity, and blood pressure regulation.

Synthesis and antineoplastic activity of mitosene analogues of the mitomycins.

A series of 1-substituted mitosene analogues of the mitomycin antitumor antibiotics was prepared by total synthesis and screened for activity against P388 leukemia in mice. In general, analogues with moderately good leaving groups (mostly esters) at the 1 position were active, whereas analogues without such substituents were inactive or barely active. These results lend support to the idea that mitosenes with leaving groups at position 1 are capable of bifunctional alkylation of DNA in a manner similar to that of mitomycin C. The most active mitosenes were equal in potency (minimum effective dose) to a corresponding aziridinomitosene, but they were less effective in prolonging life span.