The potential role of short chain fatty acids improving T and CAR-T cell fitness and expansion for cancer immunotherapies.

Adoptive cell therapies, like tumor-infiltrating lymphocytes or chimeric antigen receptor T cells, have become an important immunotherapeutic approach against cancer. One of the main struggles of T cell immunotherapies is how to obtain the most effective T cell phenotype, persistence, and differentiation potential to infuse into patients. Adjusting the T cell cell culture conditions is a key factor to increase and improve the efficacy of cellular immunotherapies.

Prolonged exposure to melatonin leads to time-dependent sensitization of adenylate cyclase and down-regulates melatonin receptors in pars tuberalis cells from ovine pituitary.

In photoperiodic mammals, seasonal cycles of growth and reproduction are cued by changes in the duration of the nocturnal profile of secretion of the pineal hormone melatonin. To investigate the likely mode of action of this hormone on target tissues, the effect of prolonged treatment with melatonin on the sensitivity of the adenylate cyclase (AC) system was examined in primary cultures of ovine pars tuberalis (PT) cells. When cells were exposed to melatonin (100 pM or 1 microM) for 16 h, and the hormone was then removed by a series of washes, basal production of cAMP was elevated over that observed in cells not treated with melatonin.

mRNA transcription determines the lag period for the induction of pineal melatonin synthesis in the Syrian hamster pineal gland.

The nocturnal pattern of Syrian hamster pineal melatonin synthesis is characterized by a 6-8 h lag period, followed by a late-night, short-duration peak in both N-acetyltransferase (NAT) activity and melatonin content. Administration of cycloheximide (20 mg/kg body weight) given either at the time of lights out or 4 h into the dark phase to Syrian hamsters blocked the nocturnal increase in both pineal NAT activity and melatonin content. Actinomycin D (5 mg/kg body weight) prevented the nocturnal increase in both constituents only when it was administered at darkness onset, being significantly less effective when injected after 4 h of dark exposure.

Androgenic control of N-acetyltransferase activity in the harderian glands of the Syrian hamster is mediated by 5 alpha-dihydrotestosterone.

N-acetyltransferase (NAT) activity in the Harderian glands of intact and gonadectomized male and female Syrian hamsters was evaluated. The exogenous administration of 5 alpha-dihydrotestosterone (DHT) to castrated males and intact females produced an increase in NAT values, which reached the values present in the glands of intact males. The administration of a 5 alpha-reductase inhibitor to intact males led to a decrease in NAT activity, suggesting that testosterone is converted in DHT within the glands.

5 alpha-dihydrotestosterone administration converts indolamine metabolism and porphyrin content of the female Syrian hamster Harderian gland to the male type.

The effects of ovariectomy and exogenous androgen administration on the indole and porphyrin metabolism of Syrian hamster Harderian glands were studied. Ovariectomy alone had no effect on any of the parameters analyzed. The administration of either testosterone or 5 alpha-dihydrotestosterone increased the activity of N-acetyltransferase in the Harderian glands.

Pineal sensitivity to nighttime swimming stress changes during the active season in Richardson's ground squirrels (Spermophilus richardsonii).

Melatonin synthesis in the pineal gland, which is primarily regulated by the environmental lighting regime, can also be influenced by other factors that elicit modifications in sympathetic tone. The objectives of this study were to determine if forced swimming alters the normal pattern of melatonin production in the pineal gland of the Richardson's ground squirrel (Spermophilus richardsonii). In early June, the squirrels were forced to swim for 10 min during the photophase or during the scotophase.

Nocturnal increase of type II thyroxine 5'-deiodinase activity in the Syrian hamster harderian gland is abolished by light exposure and induced by isoproterenol.

The presence of type II 5'-deiodinase activity in the Syrian hamster Harderian gland was investigated. This enzyme exhibited an increase of its activity after animals entered the normal dark phase, with maximal activity occurring at 04.00 hr (8 hr after lights off).

N-acetyltransferase activity and indole contents of the male Syrian hamster Harderian gland: changes during the light:dark cycle.

The activities of N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) and the indole contents of the Harderian glands of male Syrian hamsters were studied throughout a 24-h period. NAT activity exhibited a sharp rise 1 h after lights on, decreasing to basal levels 1 h later. Neither a HIOMT activity nor a melatonin concentration rhythm was detected throughout the 24 h.

Beta-adrenergic stimulation prior to darkness advances the nocturnal increase of Syrian hamster pineal melatonin synthesis.

Pineal glands of male Syrian hamsters stimulated in vivo with isoproterenol (ISO) for 4 h before the onset of darkness showed a 4-h advance in the timing of the nighttime increases in both N-acetyltransferase activity and melatonin levels. When ISO (1 mg/kg) was administered every 2 h to animals kept in light during the night, a significant increase in melatonin synthesis was observed after 4-6 h. The results suggest that the Syrian hamster pineal gland can respond in vivo to continuous beta-adrenergic stimulation, but a lag period of 4-6 h is required before there is an increase in melatonin synthesis.

Adrenalectomy but not gonadectomy affects rat pineal beta-adrenergic receptor density.

Bilateral adrenalectomy, like chronic pineal denervation by means of superior cervical ganglionectomy, induced an increase in the morning levels of [125I]iodopindolol (IPIN) binding to rat pineal membranes; this change may be related to the reduced input of catecholamines to the pinealocytes as suggested by the decrease in nocturnal pineal melatonin synthesis previously reported in adrenalectomized rats. Castrated rats did not show changes in IPIN binding to pineal membranes when measured either at middark or in chronically superior cervical ganglionectomized rats, suggesting that the regulation of pineal beta-adrenergic receptors is independent from gonadal control.

Forskolin, an activator of adenylate cyclase activity, promotes large increases in N-acetyl transferase activity and melatonin production in the Syrian hamster pineal gland only during the late dark period.

The exposure of organ cultured pineal glands of Syrian hamsters to forskolin, an adenylate cyclase activator, caused marked increases in serotonin N-acetyltransferase activity and melatonin content in a dose-related manner (1-100 microM) when glands were collected in the second half of the dark period. However, addition of forskolin to glands collected anytime during the light period or at the beginning of the dark period failed or only modestly stimulated either pineal N-acetyltransferase activity or melatonin levels. Similar results were obtained with isoproterenol.

Effects of short-term cold exposure on pineal biosynthetic function in rats.

In light of recent studies demonstrating stress-induced changes in pineal indoleamine metabolism, we tested the effect of acute cold stress on pineal biosynthetic function. Adult male rats were subjected to 30, 60, or 120 min of cold exposure (Ta = 2 degrees C) during either the light or dark phase of the daily photoperiodic cycle. Controls were kept at room temperature (22 +/- 2 degrees C).

The depression in rat pineal melatonin production after saline injection at night may be elicited by corticosterone.

A hind-leg subcutaneous saline injection into rats at night elicits a decrease in N-acetyltransferase (NAT) activity and melatonin content of the pineal gland. The decrement in pineal melatonin production after saline injection is prevented by adrenalectomy. The present studies were undertaken to determine what factor(s) from the adrenal gland cause(s) the drop in pineal melatonin production after saline injection at night.

Characterization and measurement of [125I]iodopindolol binding in individual rat pineal glands: existence of a 24-h rhythm in beta-adrenergic receptor density.

A simple procedure has been developed that permits measurement of beta-receptors in membrane preparations from individual rat pineal glands using [125I]iodopindolol ([125I]PIN). [125I]PIN binding to pineal membranes was stereospecific and saturable. Scatchard analysis of saturation isotherms yielded a Kd of 147.

Elevated environmental temperature alters the responses of the reproductive and thyroid axes of female Syrian hamsters to afternoon melatonin injections.

Female Syrian hamsters were kept in a light (14:10 h light:dark cycle, lights on 0600 h)- and temperature (22 or 30 degrees C)-controlled room; some groups were treated with an afternoon s.c. injection of melatonin (6.

Darkness-induced changes in noradrenergic input determine the 24 hour variation in beta-adrenergic receptor density in the rat pineal gland: in vivo physiological and pharmacological evidence.

In male rats housed under a 14:10 LD cycle (lights on at 0600 h), pineal beta-adrenergic receptors, assessed as 125Iodopindolol (IPIN) binding to membrane preparations, showed a 24 hour variation characterized by a nocturnal increase that peaked around middark (2300 h-0200 h) and a decrease during the latter half of the dark period. Animals exposed to light for 3 hours into the normal dark period showed a similar increase in IPIN binding that was prevented by a single sc injection (0.5 mg/kg) of isoproterenol (ISO).

N-acetyltransferase activity, hydroxyindole-O-methyltransferase activity, and melatonin levels in the Harderian glands of the female Syrian hamster: changes during the light:dark cycle and the effect of 6-parachlorophenylalanine administration.

The activities of NAT and HIOMT and the melatonin content of the Harderian glands of female Syrian hamsters were studied. When hamsters were kept under a light:dark cycle of 14:10 (lights on at 06.00 h), NAT activity exhibited a sharp, short term rise at one hour after lights on.

Nocturnal increase in the sensitivity of the Syrian hamster pineal gland to isoproterenol is darkness dependent.

The sensitivity of the Syrian hamster pineal gland to stimulation by isoproterenol is greatly increased in the latter half of the daily dark phase. This increased sensitivity requires a period of dark exposure for up to 6.5 hr.

Adrenalectomy prevents changes in rat pineal melatonin content and N-acetyltransferase activity induced by acute insulin stress.

The activity of N-acetyltransferase (NAT) and the content of melatonin (MEL) in the rat pineal have been shown to be sensitive to several types of stressors. This study was designed to assess the role of the adrenals in mediating the effect of one such stressor, insulin-induced hypoglycemia, on pineal synthetic activity. Intact and bilaterally adrenalectomized (ADX) adult male rats were kept under light:dark cycles of 14:10 (lights on 0600 h) and injected intraperitoneally with 10 IU insulin at 1300 h, and groups (n = 8) were killed 2, 3, or 4 h postinjection.