A transcriptomics-based drug repositioning approach to identify drugs with similar activities for the treatment of muscle pathologies in spinal muscular atrophy (SMA) models.

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by the reduction of survival of motor neuron (SMN) protein levels. Although three SMN-augmentation therapies are clinically approved that significantly slow down disease progression, they are unfortunately not cures. Thus, complementary SMN-independent therapies that can target key SMA pathologies and that can support the clinically approved SMN-dependent drugs are the forefront of therapeutic development. We have previously demonstrated that prednisolone, a synthetic glucocorticoid (GC) improved muscle health and survival in severe Smn-/-;SMN2 and intermediate Smn2B/- SMA mice. However, long-term administration of prednisolone can promote myopathy. We thus wanted to identify genes and pathways targeted by prednisolone in skeletal muscle to discover clinically approved drugs that are predicted to emulate prednisolone's activities. Using an RNA-sequencing, bioinformatics, and drug repositioning pipeline on skeletal muscle from symptomatic prednisolone-treated and untreated Smn-/-; SMN2 SMA and Smn+/-; SMN2 healthy mice, we identified molecular targets linked to prednisolone's ameliorative effects and a list of 580 drug candidates with similar predicted activities. Two of these candidates, metformin and oxandrolone, were further investigated in SMA cellular and animal models, which highlighted that these compounds do not have the same ameliorative effects on SMA phenotypes as prednisolone; however, a number of other important drug targets remain. Overall, our work further supports the usefulness of prednisolone's potential as a second-generation therapy for SMA, identifies a list of potential SMA drug treatments and highlights improvements for future transcriptomic-based drug repositioning studies in SMA.

Larvicidal and repellent effects of essential oils on the brown dog tick (Rhipicephalus sanguineus Sensu lato) with description of new larval repellent activity test method.

The aim of this research was to investigate the larvicidal and repellent effects of essential oils (EOs) obtained from two Lamiaceae plant species, Origanum minutiflorum O. Schwarz & P.H. Davis and Dorystoechas hastata Boiss. & Heldr. ex Bentham, both endemic to Turkey, on Rhipicephalus sanguineus s.l. Latreille (Acari: Ixodidae). The study also introduces a new test method that can be used to assess the repellent effects against ticks. Both plant EOs exhibited the highest larvicidal activity against brown dog tick larvae after 24 h and LC50 and LC90 values were determined as 0.101% and 0.125% for O. minutiflorum essential oil and 0.937% and 2.1% for D. hastata essential oil, respectively. In this study, we have described a detailed protocol for a novel larval repellent activity test (LRAT) for essential oils and extracts, using simple equipment. The advantages and limitations of LRAT, when compared to other tests commonly used to determine repellent effect against ticks, are also included in this study. The LRAT was developed with modifications of the larval immersion test (LIT) and proves to be a highly efficient and easily observable method. It can be used to test any active substance that may be toxic to humans and animals. According to the LRAT, at the end of 3 h, O. minutiflorum essential oil showed a high repellent effect, varying between 84.14% and 100% at 1% concentration. This result was not statistically different from the DEET, the positive control. When comparing the larvicidal and repellent activities, O. minutiflorum essential oil was found to be more effective than D. hastata essential oil.

Exploring the Larvicidal and Repellent Potential of Taurus Cedar (Cedrus libani) Tar against the Brown Dog Tick (Rhipicephalus sanguineus sensu lato).

This study investigated the potential acaricidal and repellent effects of tar obtained from the Lebanon cedar (Cedrus libani A. Rich.) against the brown dog tick species Rhipicephalus sanguineus sensu lato Latreille (Acari: Ixodidae). The goal was to find an alternative, safe, and effective way to eliminate ticks. Tar is traditionally extracted from cedar trees in the Antalya region of Türkiye. The composition of the tar is primarily characterized by a diverse mixture of terpenes, with ß-himachalene (29.16%), α-atlantone (28.7%), ar-turmerone (8.82%), longifolene-(V4) (6.66%), α-himachalene (5.28%), and ß-turmerone (5.12%) emerging as the predominant constituents. The toxic effects of tar on tick larvae were studied through larval immersion tests (LIT), and its repellent activity was evaluated using a new larval repellent activity test (LRAT). The results revealed significant acaricidal effects, with mortality rates of 77.7% and 82.2% for the Konyaalti and Kepez strains of the brown dog tick, respectively, in response to a 1% concentration of tar. LC50 and LC90 values were determined as 0.47% and 1.52% for the Kepez strain and 0.58% and 1.63% for the Konyaalti strain, respectively. When comparing the repellent effect of tar to the widely used synthetic repellent DEET, repellency rates of up to 100% were observed. As a result, this study establishes, for the first time, the larvicidal and repellent effects of C. libani tar on ticks.

Rutin increases alpha-tubulin acetylation via histone deacetylase 6 inhibition.

Microtubules are dynamic cytoskeletal filaments composed of alpha- (α) and beta (ß)-tubulin proteins. α-tubulin proteins are posttranslationally acetylated, and loss of acetylation is associated with axonal transport defects, a common alteration contributing to the pathomechanisms of several neurodegenerative diseases. Restoring α-tubulin acetylation by pharmacological inhibition of HDAC6, a primary α-tubulin deacetylase, can rescue impaired transport. Therefore, HDAC6 is considered a promising therapeutic target for neurodegenerative diseases, but currently, there is no clinically approved inhibitor for this purpose. In this study, using drug repurposing strategy, we aimed to identify compounds possessing HDAC6 inhibition activity and inducing α-tubulin acetylation. We systematically analyzed the FDA-approved library by utilizing virtual screening and consensus scoring approaches. Inhibition activities of promising compounds were tested using in vitro assays. Motor neuron-like NSC34 cells were treated with the candidate compounds, and α-tubulin acetylation levels were determined by Western blot. Our results demonstrated that rutin, a natural flavonoid, inhibits cellular HDAC6 activity without inducing any toxicity, and it significantly increases α-tubulin acetylation level in motor neuron-like cells.

Genotoxicity assessment of perfluoroalkyl substances on human sperm.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are synthetic chemicals that have been used in industry and consumer products. Because the presence of PFAS has been identified in humans and the environment in the last decade, human exposure to PFAS is a current public health concern. It has been shown that some PFAS lead to adverse health effects in the male reproductive system. However, there is no information about probable genotoxic effects of these chemicals on sperm cells. This study aimed to investigate the possible genotoxic damage on human sperm cells exposed to certain major PFAS compounds that were selected considering their extensive usage, high persistence in the environment, and high bioaccumulation in humans. These PFAS are perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexanoic acid (PFHxA). The alkaline comet assay was used to detect the DNA damage to sperm. Sperm cells were treated with 0.1-1 mM of each PFAS at 32°C for 1 h to obtain optimal survival. As a result of the experiments, it was discovered that the exposure to PFOS, PFOA, PFNA, and PFHxA did not cause significant levels of cytotoxicity and did not cause damage to sperm DNA under these conditions. The results suggest that the exposure to these PFAS did not interfere with sperm DNA. Indirect toxicity mechanisms should be taken into account to assess the association between the PFAS exposure and male reproductive toxicity.

Use of micro and macroalgae extracts for the control of vector mosquitoes.

Mosquitoes are one of the most dangerous vectors of human diseases such as malaria, dengue, chikungunya, and Zika virus. Controlling these vectors is a challenging responsibility for public health authorities worldwide. In recent years, the use of products derived from living organisms has emerged as a promising approach for mosquito control. Among these living organisms, algae are of great interest due to their larvicidal properties. Some algal species provide nutritious food for larvae, while others produce allelochemicals that are toxic to mosquito larvae. In this article, we reviewed the existing literature on the larvicidal potential of extracts of micro- and macroalgae, transgenic microalgae, and nanoparticles of algae on mosquitoes and their underlying mechanisms. The results of many publications show that the toxic effects of micro- and macroalgae on mosquitoes vary according to the type of extraction, solvents, mosquito species, exposure time, larval stage, and algal components. A few studies suggest that the components of algae that have toxic effects on mosquitoes show through synergistic interaction between components, inhibition of feeding, damage to gut membrane cells, and inhibition of digestive and detoxification enzymes. In conclusion, algae extracts, transgenic microalgae, and nanoparticles of algae have shown significant larvicidal activity against mosquitoes, making them potential candidates for the development of new mosquito control products.

Pathogenicity of an Entomopathogenic Nematode, Steinernema carpocapsae on Alphitobius diaperinus (Coleoptera: Tenebrionidae) Strains From Turkey.

Alphitobius diaperinus Panzer (Coleoptera: Tenebrionidae) is an insect pest in poultry production systems. This insect has developed resistance to many chemical insecticides. As an alternative to chemicals, entomopathogenic nematodes (EPNs) are one of the most commonly used agents against several pest arthropods. The pathogenicity of the EPN Steinernema carpocapsae Weiser on four field strains of lesser mealworm, A. diaperinus, from Turkey was studied. In the experiments, larvae of A. diaperinus were found to be more sensitive than adults to S. carpocapsae infection. In terms of LC50 values in both larval and adult insects, Balikesir strain was found to be the most susceptible, Manisa strain the most resistant. The calculated LC50 values for adults were 85.9, 205.6, 135.4, and 418.8 IJs/ml, and for larvae 31.2, 39.8, 34.8, and 70.9 IJs/ml for the Balikesir, Canakkale, Izmir, and Manisa strains, respectively. This is the first report about the pathogenicity of EPNs against larvae and adults of lesser mealworm A. diaperinus strains from Turkey. We conclude that S. carpocapsae can be used as a control agent for lesser mealworms.

Bisphosphonate-related osteonecrosis: laser-assisted surgical treatment or conventional surgery?

Bisphosphonates (BSPs) are used for the treatment of multiple myeloma, metastatic breast and lung cancer, Paget's disease, osteoporosis, hypercalcemia due to malignancy, and many other skeletal diseases. BSPs reduce osteoclastic functions, which result in bone resorption. Bisphosphonates-related osteonecrosis of jaws (BRONJ) is a newly developed term that is used to describe the significant complication in patients receiving bisphosphonates. BSPs are known to exhibit an anti-angiogenetic effect that initiates tissue necrosis of the hard tissue. There is currently no consensus on the correct approach to this issue. The aim of this retrospective study is to compare the effects of laser surgery with biostimulation to conventional surgery in the treatment of BSP-induced avascular bone necrosis on 20 patients who have been treated in our clinic. BRONJ was evaluated in patients with lung, prostate, and breast cancer under intravenous BSP treatment. Twenty patients in this study developed mandibular or maxillary avascular necrosis after a minor tooth extraction surgery or spontaneously. Bone turnover rates were evaluated by serum terminal C-telopeptide levels (CTX) using the electrochemiluminescence immunoassay technique and patients were treated with laser or conventional surgical treatments and medical therapy. Ten patients were treated with laser surgery and biostimulation. An Er:YAG laser (Fotona Fidelis Plus II® Combine laser equipment, Slovenia) very long pulse (VLP) mode (200 mJ, 20 Hz) using a fiber tip 1.3 mm in diameter and 12 mm in length was used to remove the necrotic and granulation tissues from the area of avascular necrosis. Biostimulation was applied postoperatively using an Nd:YAG laser. Low-level laser therapy (LLLT) was applied to the tissues for 1 min from 4 cm distance using an Nd:YAG laser (Fotona-Slovenia) with a R24 950-µm fiber handpiece long-pulse (LP) mode, 0.25-W, 10 Hz power/cm(2) from the mentioned distance the spot size was 0.4 cm(2), and power output was 2.5 J. Energy density from the mentioned distance was calculated to be 6.25 J/cm(2). The other ten patients were treated with conventional surgery. Treatment outcomes were noted as either complete healing or incomplete healing. There were no statistically significant differences between laser surgery and conventional surgery (p > 0.05). CTX values also did not affect the prognosis of the patients. Treatment outcomes were significantly better in patients with stage II osteonecrosis than in patients with stage I osteonecrosis. Our findings suggest that dental evaluation of the patients prior to medication is an important factor in the prevention of BRONJ. Laser surgery is a beneficial alternative in the treatment of patients with this situation. Further randomized studies with larger patient numbers may also improve our understanding of treatment protocols for this situation.

Desmoplastic ameloblastoma.

Ameloblastoma is a rare benign odontogenic epithelial tumor characterized by abnormal cell growth, which easily infiltrates and destroys surrounding bony tissues. Clinically, it is mostly seen in the ascending ramus area, in men in their fourth and fifth decades more frequently than in women. One of the 3 clinical variants of ameloblastoma is desmoplastic type, with involvement of the maxillary arch more often than the mandible. Its histopathologic variant characterized by extensive squamous metaplasia, islands of tumor cells, and sometimes keratin formation is known as desmoplastic acanthomatous ameloblastoma.The aim of this report was to present an unusual case of symphysis located desmoplastic acanthomatous ameloblastoma in a 56-year-old female patient, who was experiencing laryngeal carcinoma 2 years ago.

Insecticidal activity of major lichen compounds, (-)- and (+)-usnic acid, against the larvae of house mosquito, Culex pipiens L.

In this research, (-)-usnic acid and (+)-usnic acid, commonly encountered lichen secondary metabolites, were evaluated for their insecticidal effects against the larvae of Culex pipiens L. (Diptera: Culicidae) under laboratory conditions. Both compounds showed strong larvicidal activity and caused 100% mortality on third-fourth larval stages of the species at 24 h at the doses of 5 and 10 ppm. Bioassays with (-)- and (+)-usnic acids against larvae of C. pipiens revealed that the LC50 values were 0.8 and 0.9 ppm, respectively. The results suggest that lichen compounds could be useful in the search of new insecticides.