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There is a well-established link between abnormal sperm chromatin states and poor motility, however, how these two processes are interdependent is unknown. Here, we identified a possible mechanistic insight by showing that Protamine 2, a nuclear DNA packaging protein in sperm, directly interacts with cytoskeletal protein Septin 12, which is associated with sperm motility. Septin 12 has several isoforms, and we show, that in the Prm2 −/− sperm, the short one (Mw 36 kDa) is mis-localized, while two long isoforms (Mw 40 and 41 kDa) are unexpectedly lost in Prm2 −/− sperm chromatin-bound protein fractions. Septin 12 co-immunoprecipitated with Protamine 2 in the testicular cell lysate of WT mice and with Lamin B1/2/3 in co-transfected HEK cells despite we did not observe changes in Lamin B2/B3 proteins or SUN4 expression in Prm2 −/− testes. Furthermore, the Prm2 −/− sperm have on average a smaller sperm nucleus and aberrant acrosome biogenesis. In humans, patients with low sperm motility (asthenozoospermia) have imbalanced histone–protamine 1/2 ratio, modified levels of cytoskeletal proteins and we detected retained Septin 12 isoforms (Mw 40 and 41 kDa) in the sperm membrane, chromatin-bound and tubulin/mitochondria protein fractions. In conclusion, our findings present potential interaction between Septin 12 and Protamine 2 or Lamin B2/3 and describe a new connection between their expression and localization, contributing likely to low sperm motility and morphological abnormalities. [ABSTRACT FROM AUTHOR]

Dynamic changes in maternal‒zygotic transition (MZT) require complex regulation of zygote formation, maternal transcript decay, embryonic genome activation (EGA), and cell cycle progression. Although these changes are well described, some key regulatory factors are still elusive. Sirtuin-1 (SIRT1), an NAD+-dependent histone deacetylase, is a versatile driver of MZT via its epigenetic and nonepigenetic substrates. This study focused on the dynamics of SIRT1 in early embryos and its contribution to MZT. A conditional SIRT1-deficient knockout mouse model was used, accompanied by porcine and human embryos. Embryos across mammalian species showed the prominent localization of SIRT1 in the nucleus throughout early embryonic development. Accordingly, SIRT1 interacts with histone H4 on lysine K16 (H4K16) in both mouse and human blastocysts. While maternal SIRT1 is dispensable for MZT, at least one allele of embryonic Sirt1 is required for early embryonic development around the time of EGA. This role of SIRT1 is surprisingly mediated via a transcription-independent mode of action. [ABSTRACT FROM AUTHOR]

Simple Summary: In our study, we investigated the association between pepsin levels in bronchoalveolar lavage and factors such as hemorrhagic/non-hemorrhagic character of BAL, type of lung disease, tumor location, patient demographics, and smoking history. Our objective was to investigate the possible influence of extraesophageal reflux on the development of lung adenocarcinoma. Contrary to our hypothesis, we did not find significant differences in pepsin levels among patients with lung adenocarcinoma, pulmonary metastases, and lung sarcoidosis. Pepsin levels were even lower in lung adenocarcinoma patients after excluding hemorrhagic samples. By rigorously excluding smokers and carefully classifying patients, we minimized biases common in similar studies. However, our study was limited by small sample sizes, especially in the sarcoidosis group, and the absence of standardized thresholds for BAL pepsin as a reflux biomarker. The significance of extraesophageal reflux as a risk factor in lung adenocarcinoma has been understudied. In this study, we investigated whether extraesophageal reflux leads to higher pepsin concentrations in bronchoalveolar lavage (BAL) in patients with lung adenocarcinoma compared to controls. Subjects were recruited from non-smoker patients (lifelong non-smokers and ex-smokers with more than 5 years of non-smoking history) who had undergone bronchoscopy due to pulmonary abnormalities on a CT scan and met the inclusion criteria. Based on histological verification of the lung process, the patients were divided into three groups: (1) lung adenocarcinoma, (2) pulmonary metastases, and (3) lung sarcoidosis. Lung adenocarcinoma cases were further categorized as central or peripheral. BAL samples collected during bronchoscopy were quantitatively analyzed by enzyme-linked immunosorbent assay (ELISA) to measure pepsin levels. No statistically significant difference in pepsin concentration was observed between the lung adenocarcinoma group and control groups (p = 0.135). After excluding hemorrhagic BAL samples, the pepsin concentration was significantly the lowest in patients with lung adenocarcinoma (p = 0.023) compared to the control groups. The results of the study do not support the hypothesis of a higher occurrence of extraesophageal reflux (evaluated as the amount of pepsin in BAL) in non-smoker patients with lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

This study extends the use of two lathyrogens, β- aminopropionitrile (BAPN) and D-penicillamine (DPA) from daily systemic or local-topical administration to long-time acting agents. This was achieved by converting the hydrophilic drugs into lipophilic derivatives. The synthesis of functional derivatives of DPA consisted in esterification with methyl-, hexyl-, or benzyl alcohols in the presence of thionylchloride. The esters formed were hydrochlorides, acidic and soluble in water. During neutralization in vitro or in vivo by tissue fluid, an oily substance is formed that elutes from a hydrogel polymer at a much slower rate than hydroplilic DPA itself. The degree of lipophilicity, measured as a partition coefficient between octanol/water, was highest for hexyl ester and lowest for methyl ester DPA. A single injection of either DPA hexyl ester HCI or 3-hexyl(amino) propionitrile into the full thickness skin incision wound in rats significantly lowered the breaking strength of the wound 12 days after injection, indicating the interference with collagen cross-linking. Both agents injected into the breast adenocarcinoma in Fisher rats significantly inhibited tumor growth without any signs of local or systemic toxicity. We conclude that these lipophilic lathyrogens with prolonged effectiveness are suitable in the treatment of pathologies, consisting of excessively cross-linked or deposited collagen (fibrotic adhesions, strictures, stenosis, and scar contractures) and in the treatment of single, solitary tumors, malignant and benign. [ABSTRACT FROM AUTHOR]

Reactivators of acetylcholinesterase (AChE; EC 3.1.1.7) are able to treat intoxication by organophosphorus compounds, especially with pesticides or nerve agents. Owing to the fact that there exists no universal “broad-spectrum” reactivator of organophosphates-inhibited AChE, many laboratories have synthesized new AChE reactivators. Here, we synthesized five new and three previously known quaternary monopyridinium oximes as potential reactivators of AChE inhibited by nerve agents. Potencies to cleave p -nitrophenyl acetate (PNPA), which is commonly used as a model substrate of nerve agents, were measured. Their cleaving potencies were compared with 4-PAM (4-hydroxyiminomethyl-1-methylpyridinium iodide), which is derived from the structure of the currently used AChE-reactivator 2-PAM (2-hydroxyiminomethyl-1-methylpyridinium iodide). Three newly synthesized oximes achieved similar nucleophilicity at the similar p K a according to 4-PAM, which is very promising for using these derivatives as AChE reactivators. [ABSTRACT FROM AUTHOR]