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Background The retinoic acid receptor alpha (Rarα) has been validated as a male contraceptive target by genetic knockouts resulting in male sterility. The effects on spermatogenesis in the absence of RARα resemble the loss of RAR signaling in vitamin A deficiency, and the mice are otherwise normal. The effects on spermatogenesis in animals treated orally with the dual RARα/RARγ antagonist BMS-189453 closely phenocopies the absence of RARα function. Notably, the resulting male sterility is reversible. We, therefore, wished to identify RARα−selective inhibitors for potential male non-hormonal contraception. Methods YCT-529 was investigated for RARα selective inhibition, physicochemical characteristics, oral bioavailability, and pharmacokinetic properties in mice and non-human primates. It was assessed in mouse mating trials to determine the most effective dosing regimen to induce infertility in male mice and in male non-human primates to reduce sperm levels. Results Characterization of YCT-529 shows suitable biochemical, physicochemical, and pharmacokinetic properties for in vivo testing. YCT-529 inhibits mouse fertility of male mice within 4 weeks of oral administration, correlating with disrupted spermatogenesis demonstrating specific inhibition of the RARα pathway. Within 6 weeks after cessation of dosing, mouse fertility reverses. Furthermore, YCT-529 inhibits sperm production in a non-human primate model within 2 weeks of oral dosing without adverse side effects. Within 10–15 weeks after cessation of dosing, non-human primates’ sperm counts fully reverses. Conclusions These results lay the groundwork for evaluating YCT-529 in human clinical trials. Plain language summary There is currently no oral birth control option available to men to prevent pregnancy in their sexual partners. YCT-529 is a non-hormonal male contraceptive that could be a potential drug for men to take to prevent pregnancy. YCT-529 works by interfering with vitamin A signaling necessary for sperm production and fertility. Our study examined its effectiveness and side effects in mice and non-human primates. We show that this oral drug causes infertility in mice, which can be reversed after stopping its consumption. In male non-human primates, sperm production is inhibited (this is how the drug prevents pregnancy) within 2 weeks of starting YCT-529 without adverse side effects and the animals regain fertility after stopping treatment. Mannowetz and Chung et al. investigated the properties and efficacy of the RARα selective antagonist YCT-529 as a male contraceptive. Mouse and non-human primates experienced fertility inhibition through disruption of spermatogenesis which was reversed upon cessation of oral administration.

Male contraception remains an unmet need. Na,K-ATPase α4 (NKA α4), a specific Na⁺/K⁺ transporter of the sperm flagellum, is an attractive target for male contraception. NKA α4 is critical for sperm motility and fertility, and its deletion in male mice causes complete infertility. Our previous structure–activity relationship (SAR) studies on a cardenolide scaffold identified a highly selective, safe NKAα4 inhibitor, but its complex, heavily hydroxylated structure posed challenges for modification and optimization. To address this, we employed a structural simplification strategy to synthesize novel steroidal and non-steroidal analogs and examined their effects on NKAα4 inhibition and sperm motility. Both series reduced sperm motility (up to ~50%), with IC50 values in the picomolar range. Compounds 13 and 45 displayed specificities for NKAα4 over NKAα1, did not affect sperm viability, and showed no reversibility in vitro. Notably, 45, featuring a hexahydronaphthalene core and a benzyltriazole moiety at C5, exhibited potent, highly selective NKAα4 inhibition, reduced sperm motility in vitro and in vivo, and blocked fertilization in vitro. This highlights 45 as a promising lead for non-hormonal male contraception and indicates that the newly generated series of compounds possess the key characteristics needed for further development as potential non-hormonal male contraceptive agents.

This study shows for the first time that an iminosugar exerts anti-spermiogenic effect, inducing reversible infertility in a species that is not related to C57BL/6 male mice. In CD rats, N-butyldeoxygalactonojirimycin (NB-DGJ) caused reversible infertility at 150 mg/kg/day when administered daily as single oral dose. NB-DGJ inhibited CD rat-derived testicular β-glucosidase 2 (GBA2) activity at 10 µM but did not inhibit CD rat-derived testicular ceramide-specific glucosyltransferase (CGT) at doses up to 1000 µM. Pharmacokinetic studies revealed that sufficient plasma levels of NB-DGJ (50 µM) were achieved to inhibit the enzyme. Fertility was blocked after 35 days of treatment and reversed one week after termination of treatment. The rapid return of fertility indicates that the major effect of NB-DGJ may be epididymal rather than testicular. Collectively, our in vitro and in vivo studies in rats suggest that iminosugars should continue to be pursued as potential lead compounds for development of oral, non-hormonal male contraceptives. The study also adds evidence that GBA2, and not CGT, is the major target for the contraceptive effect of iminosugars.

Transforming growth factor β (TGF-β), secreted within an inflammatory site or injected locally, induces leukocyte margination, chemotaxis, and accumulation. In addition to its potent direct chemotactic activity, TGF-β may promote this leukocyte response by influencing cell surface integrin expression. At picomolar concentrations, TGF-β increases steady-state mRNA levels for both the α5and the β1chain of the fibronectin receptor in human blood monocytes. This increase in gene expression is reflected by selectively enhanced expression of α5(CDw49e), β1(CDw29), and also α3(CDw49c) adhesion molecules on the cell surface. Functionally, TGF-β promotes, in a dose- and time-dependent fashion, monocyte adhesion to type IV collagen, laminin, and fibronectin. Potentially facilitating the movement of monocytes through the extracellular matrix, TGF-β triggers transcriptional and posttranscriptional regulation of both the 92-kDa and the 72-kDa gelatinase/type IV collagenase. Thus, TGF-β may play a pivotal role in the early phases of inflammation and repair through its ability to mediate monocyte adhesion, chemotaxis, and enzymatic digestion of extracellular matrix, whereas in chronic lesions, excess TGF-β may contribute to persistent leukocyte accumulation.

Protein Kinase CK2 is a holoenzyme composed of two regulatory subunits (CK2β) and two catalytic subunits (CK2α and CK2α′). CK2 controls several cellular processes including proliferation, inflammation, and cell death. However, CK2α and CK2α′ possess different expression patterns and substrates and therefore impact each of these processes differently. Elevated CK2α participates in the development of cancer, while increased CK2α′ has been associated with neurodegeneration, especially Huntington′s disease (HD). HD is a fatal disease for which no effective therapies are available. Genetic deletion of CK2α′ in HD mouse models has ameliorated neurodegeneration. Therefore, pharmacological inhibition of CK2α′ presents a promising therapeutic strategy for treating HD. However, current CK2 inhibitors are unable to discriminate between CK2α and CK2α′ due to their high structural homology, especially in the targeted ATP binding site. Using computational analyses, we found a potential Type IV (″D″ pocket) allosteric site on CK2α′ that contained different residues than CK2α and was distal from the ATP binding pocket featured in both kinases. With this potential allosteric site in mind, we screened a commercial library containing ≈29,000 allosteric-kinase-inhibitor-like compounds using a CK2α′ activity-dependent ADP-GloTM Kinase assay. Obtained hits were counter-screened against CK2α revealing two CK2α′ selective compounds. These two compounds might serve as the basis for further medicinal chemistry optimization for the potential treatment of HD.Competing Interest StatementThe authors have declared no competing interest.

Seepage-induced fines migration under rainfall infiltration is a main cause leading to shallow failures in loose colluvial slopes. To describe the full process of fines migration within unsaturated soils during rainfall infiltration and the associated hydromechanical behaviors, a seepage-erosion-deformation coupled formulation is proposed in this paper. The governing equations proposed are implemented into a finite element code and used to investigate the influences of skeleton deformation on the rainfall infiltration process through unsaturated soil columns.The numerical results were presented in detail for a better understanding of the rainfall-induced fines migration process within unsaturated soils. Further,the obtained results are integrated into an infinite slope model for slope stability analysis. The results show that, the skeleton deformation will affect the rainfall infiltration rate and hence the timing of slope failures; meanwhile their influences are more evident if the fines deposition process is taken into account.Moreover, the slope stability could be reduced gradually due to the soil strength loss along with loss of fine particles. Therefore, particular attentions should be paid to analyzing the stability of soil slopes susceptible to internal erosion.

Transforming growth factor Beta (TGF-Beta), which is released by platelets in an inflammatory response, and subsequently by inflammatory cells themselves, is studied to see whether it can influence integrin expression on mononuclear phagocytic cells. Results are given.

CB Bancshares, Inc. (NASDAQ: CBBI) announced today that it executed a definitive agreement for the previously announced acquisition of International Holding Capital Corp. (NASDAQ: ISLH) for approximately $51.74 million or $34.50 per share in cash and CBBI stock. Under the terms of the agreement, CBBI will exchange $15.53 in cash and .602 shares of CBBI common stock for each share of ISLH outstanding, subject to adjustment as provided in the agreement. The number of shares of CBBI common stock to be delivered in the exchange will be based upon the average of the closing bid and asked price of CBBI common stock on the NASDAQ-NMS for 20 trading days ending five calendar days prior to the closing date of the transaction. Stockholders of ISLH will receive not less than .547 shares or more than .669 shares of CBBI common stock in the exchange. The transaction will be accounted for as a purchase and is expected to be completed in last first quarter/early second quarter 1994, pending approval by appropriate regulatory authorities and stockholders of both companies. The transaction is expected to have no dilutive effect on future earnings per share of CBBI. (excerpt)