Few data are available concerning the roles of polymorphisms of inosine triphosphatase (ITPA) gene and ribavirin (RBV) transporter genes in the prediction of RBV‐induced anaemia among Egyptians with chronic hepatitis C (CHC). Genotyping of three ITPA gene variants and two variants of RBV transporter genes has been performed in 123 patients under pegylated interferon‐α/ribavirin treatment. The baseline haemoglobin and ITPA rs1127354 CA/AA have been found as predictors of anaemia at 4, 8 and 12 weeks of RBV therapy. In addition, ITPA rs7270101 AC/CC and age predicted anaemia after 12 weeks of therapy. In conclusion, the ITPA variant rs1127354C>A significantly predict RBV‐induced anaemia during the first 3 months of treatment and it is recommended to be assessed before RBV administration

Glucocorticoid use is the main cause of secondary osteoporosis. This study aimed to assess the potential protective effects of tocotrienols (T) and CoQ10(C), singly and in combination, against dexamethasone (DEX)-induced osteoporosis in rats and their possible mechanisms. Thirty adult male albino rats were divided into five groups: control group (CON), DEX-treated group received DEX (2.5 mg/kg) intramuscularly twice weekly. The DEX+C, DEX+T, and DEX+TC groups received DEX with T (60 mg/kg), C (20 mg/kg) daily, and their combination respectively, daily orally for 8 weeks. Results revealed that T, C and TC ameliorated DEX-induced osteoporosis through improved osteocalcin (OC), alkaline phosphatase (ALP), Ca and TAC serum levels. Restoration of the expression levels of Nrf2, LC3, and Bcl-2 and improved histological structure of the bones were observed. The combination of the drugs was more effective than each single agent. Both drugs might be promising agents as prophylaxis against osteoporosis via suppressing oxidative stress and apoptosis and enhancing autophagy.

Purpose: Neuropathic pain is characterized by poor treatment response. While previous studies on granulocyte colony-stimulating factor (GCSF) have primarily explored its effects on peripheral nerves, recent evidence suggests the central nervous system, particularly the brainstem pons, plays a crucial role in neuropathic pain modulation. This study investigated the effects of GCSF on the pons and sciatic nerve to alleviate neuropathic pain. Methods: Four groups of rats were created: the normal control, sham group, neuropathic group induced by chronic constriction injury of the sciatic nerve (CCI), and the GCSF-treated group received 50 μg/kg of GCSF subcutaneously starting on the 7th day of CCI for 5 consecutive days. Experimental testing for heat hyperalgesia, mechanical allodynia and mechanical hyperalgesia was performed. Immunohistochemical analyses were conducted to evaluate the central (pons) expression of glial fibrillary acidic protein (GFAP), proliferating cell nuclear antigen (PCNA), and S100 protein in the peripheral (sciatic nerve) tissues. Results: GCSF significantly alleviated heat hyperalgesia, mechanical allodynia, and mechanical hyperalgesia in CCI rats. In the pons, GCSF reduced GFAP expression, indicating inhibition of astrogliosis, and enhanced PCNA expression, suggesting promotion of neurogenesis. In the sciatic nerve, S100 expression was markedly elevated, implying enhanced remyelination. Conclusion: GCSF alleviates neuropathic pain not only by modulating peripheral nerve repair but also by inhibiting pontine astrogliosis and promoting central neuronal regeneration. These findings suggest GCSF may be a promising therapeutic agent for central and peripheral components of neuropathic pain.

Metformin exerts antidiabetic and pleiotropic effects. This study investigated the function and mechanisms of gasotransmitters and autophagy in the metformin-induced protection against ischemia/reperfusion injury (I/RI). According to measurements of serum hepatic function indicators and histopathological evaluation, metformin protected against hepatic I/RI-induced impairment of liver function and structure. In addition, metformin inhibited hepatic I/RI-induced hepatic oxidative stress, nitrosative stress, inflammation, and apoptosis. Also, it suppressed hepatic I/RI-induced decrease in hepatic heme oxygenase-1 (HO-1) and hydrogen sulfide (H2S) levels and increase in nitric oxide (NO) production. Furthermore, metformin inhibited hepatic I/RI-induced decrease in protein expressions of endothelial NO synthase (eNOS), HO-1, cystathionine γ-lyase (CSE), and Beclin-1 and increase in the protein expression of inducible NO synthase (iNOS) in the liver tissue. Co-administration of the NO biosynthesis inhibitor, L-NAME, carbon monoxide(CO)-releasing molecule-A1 (CORM-A1), the H2S donor, NaHS, or the autophagy stimulator, rapamycin (RAPA), enhanced all effects of metformin. The NO donor, L-arginine, the CO biosynthesis inhibitor, zinc protoporphyrin, the H2S biosynthesis inhibitor, DL-propargylglycine, or the autophagy inhibi tor, chloroquine (CQ), antagonized the effects of metformin. These findings reveal, for the first time, that increasing CO, H2S, and autophagy levels with subsequent decreasing NO level play a critical role in metformin's protective action against hepatic I/RI. The ability of L-NAME, CORM-A1, NaHS, and RAPA to boost metformin’s protective effect in hepatic I/RI may positively be attributed to their ability to lower hepatic oxidative stress, nitrosative stress, inflammation, and apoptosis.

Aims: Cigarette smoking (CS) is the main cause of chronic obstructive pulmonary disease (COPD). Endothelial dysfunction is related to the severity of pulmonary disease in COPD. This study aimed to evaluate the effectiveness of single and combined administration of pioglitazone (Pio) and irbesartan (Irb) against COPD-induced endothelial dysfunction in mice and the involvement of NO and H2S in their effects.

Materials and methods: Adult male Swiss mice (n = 40, weighing 25–30 g) were assigned into 5 groups. The normal control group received 1% carboxy methyl cellulose (CMC). The CS group was exposed to CS and administered 1% CMC for 3 months. The CS + Pio, CS + Irb, and CS + Pio/Irb groups were subjected to CS and received Pio (60 mg/kg), Irb (50 mg/kg), and their combination respectively, daily orally for 3 months. Body weight gain, mean blood pressure, urinary albumin, serum NO and ET-1 levels with TNF-α and IL-2 levels in lung tissue and bronchoalveolar lavage were measured. Lung H2S and ET-1 levels, protein expression of PPARγ in lung and VEGF in lung and aortic tissues with histological changes were assessed.

Key findings: Our results illustrated that CS induced a model of COPD with endothelial dysfunction in mice. Pio/Irb singly and in combination elicited protective effects against the pathophysiology of the disease with more improvement in the combined group. There is a strong correlation between NO and H2S as well as the other measured parameters.

Signifcance: Collectively, both drugs performed these effects via their anti-inflammatory potential and increasing H2S and NO levels.